Method for identifying patients

Abstract

The present invention provides methods for identifying or selecting cancer patients for treatment with a Nectin-4 targeted therapeutic on the basis of the patients having a Nectin-4 copy number of 4 or more.

Description

[0001] METHOD FOR IDENTIFYING PATIENTS TECHNICAL FIELD OF THE INVENTION The present invention relates to methods for identifying or selecting cancer patients 5 for treatment with a Nectin-4 targeted therapeutic. More specifically, the present invention provides methods for identifying or selecting cancer patients for treatment with a Nectin-4 targeted therapeutic on the basis of the patients having a Nectin-4 copy number of 4 or more. 10 BACKGROUND OF THE INVENTION The phenomenon of the presence of tumor gene amplifications being associated with the up regulation of the associated encoded protein and the use of tests that determine the presence or absence of gene amplifications as a predictor of response to therapy is well established in the treatment of solid tumors. Amplifications of ERBB2 (HER2), MET and 15 EGER have all been demonstrated to be predictive of response to therapeutics targeting these specific proteins {Arnoud et al. Clinical Cancer Research 2007; Cui JJ, J of Med Chem, 2014; Pearson et al. Cancer Discovery 2016}. Over-expression of Nectin-4 has been reported in multiple tumor types {Challita-Eid et al. Cancer Research, 2016} and has been associated with underlying Nectin-4 gene amplification in breast cancer {N Pavlova et al, 20 Elife, 2013}. Analyses of TCGA data indicated that amplification of Nectin-4 occurs in additional indications and therefore may represent a way of identifying patients for Nectin- 4 targeted therapeutics such as BT8009 or enfortumab vedotin (EV). Membranous Nectin-4 expression frequently decreases during metastatic spread of urothelial carcinoma (Klümper et al. 2023. Clin Cancer Res 29(8) 1496-1505), which may 25 contribute to primary resistance to treatment with the antibody drug conjugate enfortumab vedotin (EV). Recently, Nectin-4 amplification has been identified as being predictive of enfortumab vedotin response in metastatic urothelial cancer (mUC) (Klümper et al. 2024. J Clin Oncol Apr 2024:JCO2301983). In the course of making the present invention, the inventors have identified that an 30 increase in Nectin-4 copy number may serve as a better predictor of response to treatment with a Nectin-4 targeted therapeutic, rather than measuring Nectin-4 protein expression, in patients with cancer, particularly breast cancer / TNBC and lung cancer / NSCLC. The inventors have identified that whilst approximately one third of breast / TNBC and lung / NSCLC patients have Nectin-4 amplifications, Nectin-4 gene amplifications may 1 predict a higher response rate to treatment with the Bicycle® drug conjugate BT8009, and that all breast / TNBC and lung / NSCLC patients who showed a partial response to treatment had a Nectin-4 copy number of four or more. Without wishing to be bound by theory, an increased Nectin-4 copy number may result in more stable long-term expression of Nectin- 5 4 (e.g. in tumor metastases), and thus may be a better predictor for whether a patient might respond to treatment with a Nectin-4 targeted therapeutic than membrane Nectin-4 expression, particularly in breast cancer, particularly triple negative breast cancer (TNBC) and lung cancer, particularly, non-small cell lung cancer (NSCLC). 10 BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 shows an illustration of tumors with and without Nectin-4 amplification. A tumor without Nectin-4 amplification is predicted to lose Nectin-4 expression as the tumor progresses e.g. in metastasis, whereas a tumor with Nectin-4 amplification is predicted to maintain higher long-term levels of Nectin-4 expression. This may provide a mechanism 15 by which tumors with stable Nectin-4 expression are more susceptible to treatment with Nectin-4 targeted therapeutics, resulting in a higher ORR than for tumors which do not have Nectin-4 amplification. FIGURE 2 shows that Nectin-4 amplifications occur relatively frequently in breast cancer / TNBC and lung cancer / NSCLC. Approximately one third of breast / TNBC and 20 lung cancer / NSCLC patients in the BT8009-100 trial were identified as having Nectin-4 amplifications (Figure 2A). This corresponds closely with the frequency of Nectin-4 amplification observed in additional TNBC tumor samples (not part of the BT8009-100 cohort) (Figure 2B). FIGURE 3 shows that in a preliminary dataset, Nectin-4 gene amplifications may predict 25 higher response rate to treatment with BT8009 in breast / TNBC and lung cancer / NSCLC. 67% of breast / TNBC patients and 40% of lung cancer / NSCLC patients with a Nectin-4 amplification showed a partial response to treatment with BT8009 vs 23% and 13% respectively of total patients (Figure 3A). In the clinical dataset, all breast / TNBC and lung cancer / NSCLC patients with a Nectin-4 amplification (Ratio Nectin-4 copy number / CEN1 30 >=2.0) had stable disease (SD) or a partial response (PR) (Figure 3B).

[0002] 2

[0003] FIGURE 4 shows that patients with Nectin-4 gene amplifications are more likely to respond to treatment with BT8009. Most patients who responded to treatment with BT8009 have a Nectin-4 amplification (post-baseline measurement data are available for n=37 patients tested for Nectin-4 gene amplification) (Figure 4A). Of the 5 evaluable 5 Nectin-4 amplified NSCLC patients, all had stable disease or better: 2 had confirmed PRs and 3 had SD. 2 PRs were non-squamous. 3 SDs included 2 non-squamous and 1 squamous cell carcinoma. 3 of 5 amplified patients had received prior taxane include 1 responder to BT8009. The ORR for Nectin-4 amplification positive NSCLC patients was 40% (5.3%, 85.3%) and a disease control rate (DCR) was 100% (Figure 4B). 10 FIGURE 5 shows a waterfall plot that indicates patients with Nectin-4 gene amplifications are more likely to respond to treatment with BT8009. Post baseline measurement data are available for n=37 patients tested for Nectin-4 gene amplification. Breast / TNBC (n=22): patients with Nectin-4 amplifications had an ORR of 67%, CBR (CR+PR+SD≥16 weeks) of 67% and DCR (CR+PR+SD) of 100% (Figure 5A). Lung cancer / NSCLC (n=15): 15 patients with Nectin-4 amplifications had an ORR of 40%, CBR of 80% and DCR of 100% (Figure 5B). FIGURE 6 shows a spider plot that indicates that patients with Nectin-4 gene amplifications are more likely to respond to treatment with BT8009 and that responses can be observed for an extended period of time. Breast / TNBC (Figure 6A). Lung 20 cancer / NSCLC (Figure 6B) FIGURE 7 shows that although there is a higher frequency of elevated Nectin-4 protein expression (H-score ≥ 100) than Nectin-4 amplification (64% vs 30% for breast / TNBC; 71% vs 32% for lung cancer / NSCLC), a higher proportion of patients selected on the basis of having a Nectin-4 amplification respond to treatment with BT8009 than patients 25 selected on the basis of having elevated Nectin-4 expression. The ORR for patients with a Nectin-4 amplification vs high (H-score ≥ 100) Nectin-4 expression is 67% vs 31% for breast / TNBC and 40% vs 11% for lung cancer / NSCLC. FIGURE 8 shows that all patients who had a partial response have a Nectin-4 copy number ≥4 and no patients who had progressive disease have a Nectin-4 amplification.

[0004] 3

[0005] FIGURE 9 shows Nectin-4 membrane expression levels for breast / TNBC patients and lung cancer / / NSCLC patients with and without a Nectin-4 amplification as well as best response. FIGURE 10 indicates the Nectin-4 protein expression levels for the patients of Figure 5. 5 High Nectin-4 expression (H-score) is ≥100. Top panel – breast / TNBC. Bottom panel – lung / NSCLC. FIGURE 11 shows that Nectin-4 amplification has an impact on the response to BT8009 in urothelial cancer. 24 / 58 (41%) of urothelial patients with confirmed MIBC histology were found to have Nectin-4 amplifications (Nectin-4 / CEN1 CN ratio ≥2 in 50+ cancer cells). 10 Patients with a Nectin-4 amplification administered a 5 mg / m2QW dose of BT8009 showed a 45% (5 / 11) ORR, compared to a 27% (4 / 15) ORR for patients who do not have a Nectin-4 amplification, and across all doses patients with a Nectin-4 amplification showed a 38% (5 / 13) ORR, compared to a 26% (5 / 19) ORR in patients who do not have a Nectin-4 amplification (Figure 11A). Figure 11B shows a waterfall plot for EV naïve patients 15 administered a 5 mg / m2QW dose of BT8009. 27 urothelial samples from BT8009-100 were evaluable for FISH and had histology for muscle invasive urothelial cancer in naïve monotherapy cohorts at 5 mg / m2QW. Responses are best overall responses. FIGURE 12 shows a spider plot that indicates that breast cancer patients with Nectin-4 gene polysomy and amplifications are more likely to respond to treatment with BT8009 20 and that responses can be observed for an extended period of time. FIGURE 13 shows the effect of using Nectin-4 membrane H-score or TPS as a predictor of OR in TNBC compared to using Nectin-4 copy number or copy number ratio. Using Nectin-4 membrane H score ≥158 as a cutoff identifies an ORR to treatment with BT8009 of 44%, compared to 18% unselected. Membrane TPS was found to be a poor predictor of 25 response to treatment with BT8009. Using a Nectin-4 copy number ratio of ≥1.93 increased the ORR to 57%, and using a Nectin-4 copy number of ≥ 5.13 increased the ORR to 50%. FIGURE 14 shows the effect of using different thresholds as predictors of OR in TNBC / breast cancer patients enrolled in the A1 and B5 cohorts in the BT8009-100 trial at 30 all doses of BT8009. All biomarker assays reveal at least one cut-off to increase ORR

[0006] 4

[0007] compared to unselected with similar sensitivity and specificity, and Nectin-4 / CEN1 CN Ratio ≥ 2 or Nectin-4 CN ≥ 6 (FISH) identified the highest selected ORR of 63% FIGURE 15 shows the effect of using different thresholds as predictors of OR in a MIBC cohort enrolled in the A1 and B3 cohorts in the BT8009-100 trial in patients administered 5 BT8009 at 5 mg / m2weekly. FISH and NGS-based cut-offs increase ORR compared to unselected, IHC does not. FIGURE 16 shows the effect of applying different cut-offs for selecting lung / NSCLC patients. The ROC identified cut-off for FISH of Nectin-4 / CEN1 CN ratio ≥ 2.2 identifies highest ORR of 67%. Various cut-offs for Nectin-4 copy number or copy number ratio 10 revealed an improved ORR among selected patients versus un-selected patients (Figure 16A). A copy number ratio of ≥ 2.2 allowed all responders to be identified (Figure 16B). FIGURE 17 shows the frequency (%) of Nectin-4 amplification (copy number ratio ≥ 2) or polysomy (copy number ≥ 6) in various cancer types within the TCGA database. 15

[0008] 5

[0009] SUMMARY OF THE INVENTION In a first aspect, the present invention thus provides a method of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining Nectin-4 copy number in a tumor of the patient; and 5 ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the Nectin-4 copy number in the tumor of the patient is 4 or more. The present invention also provides a method of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining Nectin-4 copy number in a tumor of the patient; and 10 ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the Nectin-4 copy number in the tumor of the patient is 4 or more and / or the Nectin-4 copy number ratio in the tumor of the patient is 2 or more. In a second aspect, the present invention provides a method comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been 15 selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. In a third aspect, the present invention provides a method comprising: i) identifying or selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and 20 ii) administering to the patient a Nectin-4 targeted therapeutic. In a fourth aspect, the present invention provides a method comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and 25 iii) administering to the patient a Nectin-4 targeted therapeutic. In a fifth aspect, the present invention provides a method comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 30 In a sixth aspect, the present invention provides a method comprising:

[0010] 6

[0011] i) determining Nectin-4 copy number in a tumor of the patient and / or Nectin-4 copy number ratio in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number 5 ratio of 2 or more. In a seventh aspect, the present invention provides a method of suppressing or treating cancer in a patient comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. 10 In an eighth aspect, the present invention provides a method of suppressing or treating cancer in a patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 15 In a ninth aspect, the present invention provides a method of suppressing or treating cancer in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 20 In a tenth aspect, the present invention provides a method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and 25 iii) administering to the patient a Nectin-4 targeted therapeutic. In an eleventh aspect, the present invention provides a method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 30 identified as having a Nectin-4 copy number of 4 or more in the tumor.

[0012] 7

[0013] The present invention also provides a method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 5 identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. In a twelfth aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 10 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. In a thirteenth aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a 15 Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. In a fourteenth aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a 20 Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. In a fifteenth aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; 25 ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. In a sixteenth aspect, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: 30 i) determining Nectin-4 copy number in a tumor of the patient; and

[0014] 8

[0015] ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: 5 i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. In a seventeenth aspect, the present invention provides a method for increasing 10 survival time and / or the progression free survival time of a cancer patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. In an eighteenth aspect, the present invention provides a method for increasing 15 survival time and / or the progression free survival time of a cancer patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. In a nineteenth aspect, the present invention provides a method for increasing 20 survival time and / or the progression free survival time of a cancer patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. In a twentieth aspect, the present invention provides a method for increasing 25 survival time and / or the progression free survival time of a cancer patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio or 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 30 In a twenty-first aspect, the present invention provides a method for improving survival time and / or the progression-free survival time of a cancer patient, comprising:

[0016] 9

[0017] i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor. The present invention also provides a method for increasing survival time and / or 5 the progression-free survival time of a cancer patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. 10 In certain embodiments, the cancer is selected from breast cancer, optionally TNBC, and lung cancer, optionally NSCLC. In certain embodiments, the cancer is selected from breast cancer, optionally TNBC, HR+ / HER2- breast cancer or HR+ / HER2-low breast cancer, and lung cancer, optionally NSCLC. 15 DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Identifying and treating a patient with a Nectin-4 copy number of at least 4 and / or a Nectin-4 copy number ratio of at least 2 As described herein, the inventors have identified that there is a particularly strong20 correlation between Nectin-4 copy number, and the effectiveness of therapy with a Nectin- 4 targeted therapeutic in breast cancer, particularly TNBC, and lung cancer, particularly NSCLC patients. Whilst Nectin-4 has previously been shown to be over-expressed in a number of different types of tumors, the inventors have identified that even within breast / TNBC and lung / NSCLC patients with tumors that have elevated levels of membrane 25 Nectin-4 expression, there are significant advantages associated with identifying or selecting patients for treatment with a Nectin-4 targeted therapeutic on the basis of the tumor having an increased Nectin-4 copy number and / or copy number ratio. Determining Nectin-4 copy number thus provides an effective marker for identifying cancer patients who might benefit from treatment with a Nectin-4 targeted therapeutic. 30 The present invention provides methods of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising:

[0018] 10

[0019] i) determining Nectin-4 copy number in a tumor of the patient and ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the Nectin-4 copy number in the tumor of the patient is 4 or more and / or if the Nectin-4 copy number ratio in the tumor of the patient is 2 or more. 5 As demonstrated in the present Examples, breast and lung cancer patients who have a Nectin-4 amplification in a tumor, show substantially improved clinical outcomes relative to patients who do not have a Nectin-4 amplification in a tumor. A patient who has a Nectin-4 copy number in a tumor of 4 or more and / or who has a Nectin-4 copy number ratio of 2 or more, optionally who has been identified or selected 10 according to methods of the invention, may be administered a Nectin-4 targeted therapeutic. The present invention thus provides methods comprising administering a Nectin-4 targeted therapeutic to a cancer patient who has a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. In one embodiment, the present invention provides a method comprising 15 administering to a patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. Put another way, the present invention provides a method comprising i) identifying or selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) 20 administering to the patient a Nectin-4 targeted therapeutic. In a further embodiment, the identification / selection methods of the invention may further comprise administering a Nectin-4 targeted therapeutic to the patient. The present application thus provides a method comprising: i) determining Nectin-4 copy number in a tumor of the patient; 25 ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient 30 and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and

[0020] 11

[0021] ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 5 identified as having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more. As demonstrated in the present Examples, breast / TNBC and lung / NSCLC patients who have a Nectin-4 copy number of 4 or more in a tumor, or who have a Nectin-4 copy number ratio of 2 or more in a tumor, show substantially improved clinical outcomes 10 relative to patients who do not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. Advantageously, a patient having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more (e.g. a patient who has been identified or selected as having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 15 or more) in the tumor may be more likely to respond to treatment with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. In certain embodiments, a patient having a Nectin-4 copy number of 4 or more in a tumor and / or a Nectin-4 copy number ratio of 2 or more in a tumor (e.g. a patient who has been identified or selected 20 according to the methods of the present invention) may have a cancer that is more likely to be suppressed or treated with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. In one embodiment, the present invention thus provides a method of suppressing or 25 treating cancer in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. Put another way, the present invention provides a method of suppressing or treating cancer in a patient, comprising i) selecting a patient having a Nectin-4 copy number in a tumor of 4 of 30 more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic.

[0022] 12

[0023] The present invention also provides a method of suppressing or treating cancer in a patient comprising i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 5 identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. The present invention also provides a method of suppressing or treating cancer in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient 10 and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; 15 ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. Advantageously, a patient identified as having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more in the tumor may be more likely to 20 respond to treatment with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more or a Nectin-4 copy number ratio of 2 or more in a tumor. In certain embodiments, a patient identified or selected according to the methods of the present invention may have a cancer that is more likely to be suppressed or treated with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number 25 of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. "Suppression" refers to maintaining the volume or preventing the growth, spread or progression of the cancer. "Treatment" refers to partially or completely reducing the volume of the cancer or eliminating one or more tumors in the patient. Thus, in some embodiments, the volume of a solid tumor in the patient is maintained or reduced 30 following administration of the Nectin-4 targeted therapeutic.

[0024] 13

[0025] A patient having a Nectin-4 copy number of 4 or more in a tumor and / or a Nectin-4 copy number ratio of 2 or more in a tumor (e.g. a patient who has been identified or selected according to the methods of the present invention) may have a cancer that is more likely to maintain its volume or reduce in volume following administration of a Nectin-4 5 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor who receives corresponding treatment with a Nectin-4 targeted therapeutic. The present invention thus provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: 10 i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. Administering a Nectin-4 targeted therapeutic to a patient (i.e. treating a patient) 15 who has a Nectin-4 copy number of 4 or more in a tumor, and / or who has a Nectin-4 copy number ratio of 2 or more in a tumor, is more likely to maintain or reduce the volume of a tumor (e.g. partially or completely) in the patient than treating a patient who does not have a Nectin-4 copy number of 4 or more in a tumor, or who does not have a Nectin-4 copy number ratio of 2 or more. Put another way, administering a Nectin-4 targeted therapeutic 20 to a patient who has a Nectin-4 copy number of 4 or more and / or who has a Nectin-4 copy number ratio of 2 or more is more likely to prevent tumor growth and / or progression than treating a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or does not have a Nectin-4 copy number ratio of 2 or more. In particular, in certain embodiments, a patient having a Nectin-4 copy number of 4 25 or more in a tumor and / or a Nectin-4 copy number ratio of 2 or more in a tumor (e.g. a patient who has been identified or selected according to the methods of the present invention) has a cancer that may be more likely to maintain its volume or reduce in volume following administration of the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in the tumor or a Nectin-4 copy number ratio of 30 2 or more in a tumor. In further embodiments, a patient having a Nectin-4 copy number of 4 or more in a tumor and / or a Nectin-4 copy number ratio of 2 or more in a tumor (e.g. a

[0026] 14

[0027] patient who has been identified or selected according to the methods of the invention) has a cancer that may be less likely to increase in volume following administration of the Nectin- 4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more. Similarly, in certain embodiments, a patient having a Nectin-4 copy number of 4 or 5 more in a tumor and / or a Nectin-4 copy number ratio or 2 or more in a tumor (e.g. a patient who has been identified or selected according to the methods of the present invention) has a cancer that may be more likely to maintain its volume or reduce in volume following administration of the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number ratio of 2 or more in the tumor. In further embodiments, a patient 10 having a Nectin-4 copy number of 4 or more in a tumor and / or a Nectin-4 copy number ratio or 2 or more (e.g. a patient who has been identified or selected according to the methods of the invention) has a cancer that may be less likely to increase in volume following administration of the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number ratio of 2 or more. 15 Thus, in certain embodiments, the volume of a solid tumor is maintained or reduced following administration of a Nectin-4 targeted therapeutic to the patient. In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 20 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. Put another way, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 25 The present invention thus also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a 30 Nectin-4 copy number ratio of 2 or more in the tumor.

[0028] 15

[0029] The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and 5 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the 10 tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. In some embodiments, the tumor or tumors disappear(s) following administration of the Nectin-4 targeted therapeutic. In other words, in certain embodiments, administration of the Nectin-4 targeted therapeutic results in disappearance of the tumor. 15 The term “disappears” and “disappearance” can be used interchangeably with the terms “eradicated” and “eradication” and refer to the tumor shrinking in size to such an extent that it can no longer be detected within the patient e.g. by the methods described herein. In some embodiments, maintaining the volume of a solid tumor refers to an 20 increase in the volume of the tumor by no more than 75%, no more than 50%, no more than 25%, no more than 10% or no more than 5%. In some embodiments, maintaining the volume of a solid tumor refers to the volume of the tumor being unchanged. In some embodiments, reducing the volume of a solid tumor refers to a reduction in the volume of the tumor by 100%, by at least 95%, at least 90%, at least 85%, at least 80%, 25 at least 75% or at least 70%, at least 65%, at least 60%, at least 55%, at least 50%, at least 45%, at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10% or at least 5%. In some embodiments, maintaining or reducing the volume of a solid tumor in a patient as described herein may refer to maintaining or reducing the sum or average 30 volume of two or more solid tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) in a patient.

[0030] 16

[0031] In some embodiments, reference to a volume of a tumor may refer to an average volume of two or more tumors in a patient (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors). In some embodiments, this can be determined by measuring the sum of an axis (e.g. a short axis or the longest diameter) of two or more solid tumors (e.g. 5 two, three, four, five, six, seven, eight, nine or ten or more tumors) in the patient and dividing the sum by the number of tumors measured. Thus, in some embodiments, maintaining or reducing the volume of a solid tumor in a patient as described herein may refer to maintaining or reducing the sum or average volume of two or more solid tumors (e.g. two, three, four, five, six, seven, eight, nine or 10 ten or more tumors) in a patient. Thus, in some embodiments, maintaining the volume of a solid tumor refers to an increase in the sum or average volume of two or more tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) of no more than 75%, no more than 50%, no more than 25%, no more than 10% or no more than 5%. In some embodiments, 15 maintaining the volume of a solid tumor refers to the sum or average volume of the tumors being unchanged. In some embodiments, reducing the volume of a solid tumor refers to a reduction in the sum or average volume of two or more tumors (e.g. two, three, four, five, six, seven, eight, nine or ten or more tumors) by 100%, by at least 95%, at least 90%, at least 85%, at 20 least 80%, at least 75% or at least 70%, at least 65%, at least 60%, at least 55%, at least 50%, at least 45%, at least 40%, at least 35%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10% or at least 5%. Optionally, the change in the sum or average volume of the tumor is a change relative to the sum or average volume of the tumor prior to the commencement of 25 treatment. A patient having a Nectin-4 copy number of 4 or more in a tumor who is treated with a Nectin-4 targeted therapeutic may experience a longer period of progression-free disease than a patient who does not have a Nectin-4 copy number of 4 or more in the tumor. Similarly, a patient having a Nectin-4 copy number of 2 or more in a tumor who is30 treated with a Nectin-4 targeted therapeutic may experience a longer period of progression- free disease than a patient who does not have a Nectin-4 copy number ratio or 2 or more in

[0032] 17

[0033] the tumor. The volume of the tumor can be maintained or reduced for a period of time until disease progression is documented. In some embodiments, disease progression refers to a measurement of the volume of the tumor of greater than a 75% increase in the volume of the tumor relative to the volume of the tumor prior to the commencement of treatment. 5 In some embodiments, disease progression refers to a measurement of the length of an axis of a tumor (or the sum or average of two or more tumors) of greater than 20%. Optionally, the volume of the tumor is maintained or reduced for at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at 10 least 20 weeks, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months. In some embodiments, the volume of a tumor over time may be measured by determining the length of an axis of the tumor. In some embodiments, the volume of a solid tumor over time may be measured by determining the length of the longest diameter 15 of the solid tumor. In some embodiments, the volume of a solid tumor over time may be measured by determining the length of the short axis of a tumor. By way of representative embodiment, a 20% increase in the length of an axis or diameter of a solid tumor corresponds to an increase in the volume of the solid tumor of approximately 75% (i.e. 1.23). 20 The length of an axis of a tumor may be determined, for example, by a CT scan slice, MRI scan slice, caliper measurement or X-ray. In other embodiments, the volume of a solid tumor over time may be measured by volumetric assessment e.g. using a three-dimensional scan such as a CT scan or MRI scan. In some embodiments, the treatment of the patient may cause a complete response 25 (CR) to the treatment, i.e. the disappearance of all target lesions and all non-target lesions and normalisation of tumor marker level. In some embodiments, the treatment of the patient may cause partial response (PR) to the treatment, i.e. at least a 30% decrease in the sum of the lengths of an axis (e.g. the longest diameter (LD)) of the target lesions, taking as reference the baseline sum of the lengths of the axis (e.g. LD) of the lesions. In some 30 embodiments, the treatment of the patient results in stable disease (SD), i.e. not more than a 30% decrease in the sum of the axis (e.g. LD), but less than a 20% increase in the sum of

[0034] 18

[0035] the axis (e.g. LD) with no new lesions. In some embodiments, a patient treated according to the methods of the invention does not have progressive disease (PD). In some embodiments, cancer progression is determined by measuring the sum of the longest diameters (SLD) of up to five tumors in the patient. 5 In some embodiments, the SLD increases by less than 20% when compared to a baseline measurement following administration of the Nectin-4 targeted therapeutic, optionally wherein the SLD increases by less than 10% when compared to a baseline measurement, optionally wherein there is SLD is unchanged when compared to a baseline measurement, optionally wherein the SLD decreases by up to 10% when compared to a 10 baseline measurement, optionally wherein the SLD decreases by up to 20% when compared to a baseline measurement, optionally wherein the SLD decreases by up to 30% when compared to a baseline measurement. In some embodiments, the SLD increases by less than 5 mm. In some embodiments, the SLD decreases by 30% or more when compared to a 15 baseline measurement following administration of the Nectin-4 targeted therapeutic, optionally wherein the SLD decreases by 40% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 50% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 60% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 70% or 20 more when compared to a baseline measurement, optionally wherein the SLD decreases by 80% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 90% or more when compared to a baseline measurement A patient having a Nectin-4 copy number of 4 or more in a tumor and / or a Nectin-4 copy number ratio of 2 or more in a tumor who is treated with a Nectin-4 targeted 25 therapeutic agent may have increased survival time compared to a patient who does not have a Nectin-4 copy number of 4 or more or a Nectin-4 copy number ratio of 2 or more. A patient having a Nectin-4 copy number of 4 or more in a tumor and / or a Nectin-4 copy number ratio of 2 or more in a tumor who is treated with a Nectin-4 targeted therapeutic may have an increased progression-free survival time (PFS) compared to a patient who 30 does not have a Nectin-4 copy number of 4 or more or a Nectin-4 copy number ratio of 2 or more.

[0036] 19

[0037] In certain embodiments, a patient having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more (e.g. a patient who has been identified or selected according to the methods of present invention) is more likely to have an increased survival time following initiation of treatment with a Nectin-4 targeted therapeutic than a 5 patient who does not have a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more in a tissue. In certain embodiments, a patient having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more (e.g. a patient who has been identified or selected according to the methods of present invention) is more likely to have an increased progression-free survival time following initiation of treatment 10 with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more or a Nectin-4 copy number ratio of 2 or more in a tumor. In one embodiment, the present invention provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been 15 selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. Put another way, the present invention provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to 20 the patient a Nectin-4 targeted therapeutic. In a further embodiment, the present invention provides a method for increasing survival time of a cancer patient, comprising i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 25 identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. The present invention thus provides a method for increasing progression-free survival time of a cancer patient, comprising i) determining Nectin-4 copy number in a tumor of the patient; and

[0038] 20

[0039] ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor. The present invention also provides a method for increasing survival time and / or 5 the progression-free survival time of a cancer patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or 10 the progression-free survival time of a cancer patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 15 Progression-free survival time refers to how long a person lives without the disease worsening. Optionally, progression-free survival time is increased compared to a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor, i.e. who receives corresponding treatment with a Nectin-4 20 targeted therapeutic. Optionally, progression-free survival time of the patient is increased by at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 25 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months compared to a patient who does not have a Nectin-4 copy number of 4 or more in a tumor. Optionally, survival time is increased compared to a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or 30 more in a tumor, i.e. who receives corresponding treatment with a Nectin-4 targeted therapeutic.

[0040] 21

[0041] Optionally, survival time of the patient is increased by at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 9 5 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months compared to a patient who does not have a Nectin-4 copy number of 4 or more in a tumor. The present invention provides methods for identifying or selecting cancer patients who would particularly benefit from treatment with a Nectin-4 targeted therapeutic, as well 10 as methods for treating the same. In some embodiments, the patient is a human patient. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced malignancy. In some embodiments, the cancer, solid tumor or advanced malignancy is uterine cancer, endometrial cancer, ovarian cancer, gastrointestinal cancer, oesophageal cancer, 15 cervical cancer, head and neck cancer (optionally squamous head and neck cancer (HNSCC)), pancreatic cancer, thyroid cancer, colorectal cancer, thymoma, sarcoma, renal clear cell carcinoma (RCC), prostate cancer or stomach cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is breast cancer. In some embodiments, the breast cancer is locally advanced (unresectable) or 20 metastatic breast cancer. In some embodiments, the breast cancer is recurrent. In some embodiments, the breast cancer is recurrent unresectable or metastatic breast cancer. In some embodiments, the breast cancer is invasive breast cancer of no special type (NST). In some embodiments, the breast cancer is invasive lobular breast cancer. In some embodiments, the breast cancer is medullary breast cancer. In some embodiments, the 25 breast cancer is invasive ductal breast cancer with medullary histology. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is tubular breast cancer. In some embodiments, the breast cancer has mixed histology. Breast cancers can be categorised according to the expression of particular markers 30 at the cell surface, including hormone receptors (HR) (including the estrogen receptor (ER) and the progesterone receptor (PR)) and human epidermal growth factor receptor 2

[0042] 22

[0043] (HER2). Breast cancers can be positive (e.g. HR+) or negative (e.g. HER2-) for different receptors. Triple negative breast cancer (TNBC) does not express receptors for estrogen or progesterone, or HER2. HER2 status in particular has been used as a predictive biomarker for categorising 5 cancers for treatment with different therapeutic agents. HER2 status can be defined based on the level of staining observed in an IHC assay – HER2+ corresponds to a score of 3 when measured by IHC, whereas HER2- tumors are those with IHC scores of 0, 1+ and 2+, and which do not have an amplification of the HER2 gene. Within HER2- tumors are HER2-ultralow (0 IHC) and HER2-low (1+ IHC or 2+ IHC). 10 In some embodiments, the cancer, solid tumor or advanced malignancy is HER2+ breast cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is HER2- breast cancer. In some embodiments, a patient having HER2- breast cancer has received 1 or more prior lines of therapy. In some embodiments, a patient having HER2- breast 15 cancer has received 1 or more prior lines of systemic therapy for locally advanced or metastatic breast cancer. In some embodiments, a patient having HER2- breast cancer has received up to 3 prior lines of therapy. In some embodiments, a patient having HER2- breast cancer has received 1 to 3 prior lines of therapy. In some embodiments, a patient having HER2- breast cancer has received 1 to 3 prior lines of systemic therapy. In some 20 embodiments, a patient having HER2- breast cancer has received 1 to 3 prior lines of systemic therapy, wherein one of the prior lines of therapy is an antibody drug conjugate comprising a topoisomerase I inhibitor. In some embodiments, the antibody drug conjugate comprising a topoisomerase I inhibitor is Trastuzumab deruxtecan. In some embodiments, the antibody drug conjugate comprising a topoisomerase I inhibitor is 25 Sacituzumab govitecan. In some embodiments the HER2- breast cancer is HER2-low breast cancer. In some embodiments, the HER2- breast cancer is HER2-ultralow breast cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is HR+ breast cancer. In some embodiments HR+ breast cancer is resistant or refractory to 30 treatment with an endocrine-based therapy. In some embodiments, the HR+ breast cancer has been treated with at least one prior line of non-endocrine based therapy.

[0044] 23

[0045] In some embodiments, the HR+ breast cancer is HR+ / HER2- breast cancer. In some embodiments, a patient having HR+ / HER2- breast cancer has received one or more prior lines of therapy. In some embodiments, a patient having HR+ / HER2- breast cancer has received one or more prior lines of systemic therapy for locally advanced or metastatic 5 breast cancer. In some embodiments the HR+ / HER2- breast cancer is resistant or refractory to treatment with an endocrine-based therapy (defined as a relapse within 2 years of adjuvant endocrine treatment, disease progression during the first 6 months of first-line endocrine therapy for advanced or metastatic breast cancer or disease progression after more than 6 months of endocrine therapy in advanced or metastatic setting). In some 10 embodiments, the HR+ / HER2- breast cancer has been treated with at least one prior line of non-endocrine based therapy. In some embodiments, a patient having HR+ / HER2- breast cancer has received up to 3 prior lines of therapy. In some embodiments, a patient having HR+ / HER2- breast cancer has received up to 3 prior lines of non-endocrine therapy for locally advanced or metastatic breast cancer. In some embodiments, a patient having 15 HR+ / HER2- breast cancer has received 1 to 3 prior lines of therapy. In some embodiments, a patient having HR+ / HER2- breast cancer has received 1 to 3 prior lines of systemic therapy. In some embodiments, a patient having HR+ / HER2- breast cancer has received 1 to 3 prior lines of systemic therapy in the metastatic setting. In some embodiments, the cancer, solid tumor or advanced malignancy is HR+ / HER2- breast 20 cancer and the patient has received 1 to 3 prior lines of systemic therapy, wherein one of the prior lines of therapy is an antibody drug conjugate comprising a topoisomerase I inhibitor. In some embodiments, the antibody drug conjugate comprising a topoisomerase I inhibitor is Trastuzumab deruxtecan. In some embodiments, the antibody drug conjugate comprising a topoisomerase I inhibitor is Sacituzumab govitecan. In some embodiments, 25 the cancer, solid tumor or advanced malignancy is HR+ / HER2- breast cancer and the patient has not previously received Trastuzumab deruxtecan. In some embodiments, the cancer, solid tumor or advanced malignancy is HR+ / HER2- breast cancer and the patient has previously received Trastuzumab deruxtecan. In some embodiments, the HR+ breast cancer is HR+ / HER2-low breast cancer. In some embodiments, the HR+ breast cancer is 30 HR+ / HER2-ultralow breast cancer.

[0046] 24

[0047] In some embodiments, the cancer, solid tumor or advanced malignancy is TNBC. In some embodiments, a patient having TNBC has received 1 or more prior lines of therapy. In some embodiments, the cancer, solid tumor or advanced malignancy is TNBC and the patient has received one or more prior lines of systemic therapy for locally 5 advanced or metastatic breast cancer. In some embodiments, a patient having TNBC has received one or more prior lines of therapy. In some embodiments, a patient having TNBC has received up to 3 prior lines of therapy. In some embodiments, a patient having TNBC has received up to 3 prior lines of systemic therapy for locally advanced or metastatic breast cancer. In some embodiments, a patient having TNBC has received 1 to 3 prior 10 lines of therapy. In some embodiments, a patient having TNBC has received 1 to 3 prior lines of systemic therapy. In some embodiments, a patient having TNBC has received 1 to 3 prior lines of systemic therapy in the metastatic setting. In some embodiments, a patient having TNBC has previously received sacituzumab govitecan. In some embodiments, the cancer, solid tumor or advanced malignancy is lung 15 cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is lung adenocarcinoma. In some embodiments, the cancer, solid tumor or advanced malignancy is squamous cell carcinoma (SCC). In some embodiments, the cancer, solid tumor or advanced malignancy is NSCLC. In some embodiment, the cancer is advanced non-small cell lung cancer (NSCLC). In some embodiments, the cancer is metastatic non-small cell 20 lung cancer (NSCLC). In some embodiment, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC does not have common driver genomic alterations (e.g. EGFR, KRAS, ALK, BRAF, MET, ROS1, NTRK1 / 2 / 3, RET). In some embodiments, the NSCLC has progressed on at least one line or therapy in the advanced or metastatic setting. In some embodiments, the 25 NSCLC (non-squamous or squamous) does not have common driver genomic alterations and has progressed on at least one line of therapy in the advanced / metastatic setting. In some embodiments, the NSCLC has a common driver genomic alteration and the patient is not eligible for available targeted therapy. In some embodiments, the NSCLC has a common driver genomic alteration and the patient has received a prior platinum-based 30 therapy. In some embodiments, the NSCLC has a common driver genomic alteration and the patient has received a prior immuno-oncology based therapy. In some embodiments,

[0048] 25

[0049] the NSCLC has a common driver genomic alteration and the patient has received prior platinum-based and immuno-oncology based therapies. In some embodiments, a patient having NSCLC has previously received platinum-based therapy with or without immunotherapy or single-agent immunotherapy (if not platinum eligible) as a first-line 5 treatment for advanced or metastatic NSCLC. In some embodiments, the patient has received at least 1 but no more than 3 prior lines of systemic therapy for advanced or metastatic NSCLC. In some embodiments, the patient does not have mixed small-cell lung cancer (SCLC) and NSCLC histology. In some embodiments, the cancer, solid tumor or advanced malignancy is urothelial 10 cancer. In some embodiments, the cancer is a stage one cancer, i.e. a small tumor that hasn’t spread beyond its organ. In some embodiments, the cancer is a stage two cancer, i.e. a tumor that has grown more deeply into surrounding tissue and may have spread into lymph nodes close to the tumor. In one embodiment, the cancer is a stage three cancer, i.e. 15 a larger tumor that has started to spread into surrounding tissues and cancer cells are found in nearby lymph nodes. In one embodiment, the cancer is a stage four cancer, i.e. the cancer has spread from where it started to another body organ, for example, from the lung to the liver. Stage 4 cancer is also known as secondary or metastatic cancer. In some embodiments, treating a patient identified according to the methods of the present 20 invention may prevent or delay progression of the cancer, e.g. from stage two to stage three, and / or from stage three to stage four. In some embodiments, a patient has not previously received MMAE-based therapy. Determining Nectin-4 copy number 25 In certain embodiments, the methods of the invention require the Nectin-4 copy number of a tumor to be determined. Determining the Nectin-4 copy number of a tumor refers to determining the Nectin-4 gene copy number or the Nectin-4 DNA copy number, and these terms can be used interchangeably herein. As discussed in more detail below, the Nectin-4 copy number can be determined 30 directly e.g. by measuring Nectin-4 copy number in a sample comprising genetic material from a tumor. In one embodiment, the Nectin-4 copy number can be determined by

[0050] 26

[0051] measuring the Nectin-4 copy number. Furthermore, the Nectin-4 copy number can be determined indirectly (or predicted) by measuring the copy number of one or more surrogate markers which are associated with the Nectin-4 gene, and thus which would also typically be duplicated in the event of a Nectin-4 gene duplication. 5 Thus, in certain embodiments, Nectin-4 copy number in a tumor can be determined by measuring any suitable marker indicative for the presence of a copy of a Nectin-4 gene in genomic DNA. The Nectin-4 gene is located on chromosome 1 within the 1q23.3 chromosomal region (defined as the chromosomal region Chr1: 160,500,001 – 165,500,000). Measuring the chromosome 1 copy number (or more particularly the copy 10 number of any gene or segment of the 1q or 1p arm of chromosome 1), optionally the 1q arm of chromosome 1 (or more particularly, the copy number of any gene or segment within the 1q arm of chromosome 1), optionally the 1q23.3 copy number (or more particularly, the copy number of any gene or segment within the 1q23.3 chromosomal region) in a tumor may thus allow the Nectin-4 copy number to be determined. Thus, in 15 one embodiment, the Nectin-4 copy number can be determined by measuring the chromosome 1 copy number (or more particularly the copy number of any gene or segment of the 1q or 1p arm of chromosome 1), optionally the 1q arm of chromosome 1 (or more particularly, of any gene or segment within the 1q arm of chromosome 1), optionally the 1q23.3 copy number in the tumor (or more particularly, the copy number of any gene or 20 segment within the 1q23.3 chromosomal region). It is therefore apparent that the Nectin-4 copy number can be determined (or predicted) by measuring the copy number of a surrogate marker for the Nectin-4 gene. In one embodiment, the Nectin-4 copy number can be determined by measuring the copy number of a gene or marker on chromosome 1, optionally a gene or marker on the 1q arm 25 of chromosome 1, optionally a gene or marker within the 1q23.3 chromosomal region. It is within the capabilities of the skilled person to identify genes or markers on chromosome 1, the 1q arm of chromosome 1 or within the 1q23.3 chromosomal region e.g. based on publicly available reference genomes. In one embodiment, the Nectin-4 copy number can be determined by measuring the 30 copy number of a gene or marker within chromosome 1, the 1q arm of chromosome 1, or

[0052] 27

[0053] the 1q23.3 chromosomal region that co-segregates with the Nectin-4 gene during a gene duplication event. In one embodiment, the gene or marker is located within 2 cM of the Nectin-4 gene. In one embodiment, the gene or marker is located within 1 cM of the Nectin-4 gene. 5 In one embodiment, the gene or marker is located within 2 Mb of the Nectin-4 gene. In one embodiment, the gene or marker is located within 500 kb of the Nectin-4 gene. In one embodiment, the gene or marker is located within 400 kb of the Nectin-4 gene. In one embodiment, the gene or marker is located within 300 kb of the Nectin-4 gene. Some standard cancer CDx panels include genes on chromosome 1, which may be 10 amplified together with Nectin-4 in the event of a Nectin-4 duplication. A number of genes found on chromosome 1 which are included in the FoundationOne®CDx panel and their positions on chromosome 1 is provided in Table 1 below. In one embodiment, the Nectin-4 copy number can be determined by measuring the copy number of one or more of the genes listed in Table 1. 15 Table 1 – list of genes found on chromosome 1 on the FoundationOne®CDx panel start_position end_position hgnc_symbol ensembl_gene_id2555639 2565382 TNFRSF14 ENSG00000157873 8004404 8026309 ERRFI1 ENSG00000116285 11106535 11262556 MTOR ENSG00000198793 15836095 15940456 SPEN ENSG00000065526 17018664 17054151 SDHB ENSG00000117118 23557926 23559501 ID3 ENSG00000117318 26693236 26782104 ARID1A ENSG00000117713 32292083 32333635 HDAC1 ENSG00000116478 36466043 36483278 CSF3R ENSG00000119535 39895428 39902256 MYCL ENSG00000116990 43337818 43354466 MPL ENSG00000117400 45329163 45340893 MUTYH ENSG00000132781 46246461 46278480 RAD54L ENSG00000085999 46557407 46616843 MKNK1 ENSG00000079277 50960745 50974634 CDKN2C ENSG00000123080 58776845 58784048 JUN ENSG00000177606 64833223 65067754 JAK1 ENSG00000162434 77944055 77979110 FUBP1 ENSG00000162613 114704469 114716771 NRAS ENSG00000213281 117606048 117628389 TENT5C ENSG00000183508

[0054] 28

[0055] 119507198 119515054 HSD3B1 ENSG00000203857 119911553 120100779 NOTCH2 ENSG00000134250 156815636 156881850 NTRK1 ENSG00000198400 161314381 161363206 SDHC ENSG00000143252 162631373 162787405 DDR2 ENSG00000162733 193121983 193254815 CDC73 ENSG00000134371 203305491 203309602 BTG2 ENSG00000159388 204422628 204494805 PIK3C2B ENSG00000133056 204516379 204558120 MDM4 ENSG00000198625 206470476 206496889 IKBKE ENSG00000263528 226061851 226072019 H3-3A ENSG00000163041 226360210 226408154 PARP1 ENSG00000143799 241497511 241519799 FH ENSG00000091483 243488233 243851079 AKT3 ENSG00000117020 By way of reference, the Nectin-4 gene, which is not found in the FoundationOne® CDx panel, is situated at positions 161070998-161089558 of chromosome 1, and has the ensemble gene id ENSG00000143217. The present invention also provides a method of identifying or selecting a cancer 5 patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of the patient and ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the copy number of one or more of the genes listed in Table 1 in the 10 tumor of the patient is 4 or more and / or if the copy number ratio of one or more of the genes listed in Table 1 in the tumor of the patient is 2 or more. The present invention also provides a method comprising administering to a patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy 15 number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor. The present invention also provides a method comprising: i) identifying or selecting a patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 or 2 or more in a tumor; and 20 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising:

[0056] 29

[0057] i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; ii) selecting the patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more 5 of the genes listed in Table 1 of 2 or more in a tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) detecting the copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor of a patient and / or the copy number ratio or one or more of the 10 genes listed in Table 1 of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; and 15 ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a copy number of one or more of the genes listed in Table 1 of 4 or more and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more. The present invention also provides a method of suppressing or treating cancer in a 20 patient comprising administering to a patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor. The present invention also provides a method of suppressing or treating cancer in a 25 patient comprising: i) identifying or selecting a patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor; and ii) administering to the patient a Nectin-4 targeted therapeutic. 30 The present invention also provides a method of suppressing or treating cancer in a patient comprising:

[0058] 30

[0059] i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; ii) selecting the patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more 5 of the genes listed in Table 1 of 2 or more in a tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method of suppressing or treating cancer in a patient comprising: i) detecting the copy number of one or more of the genes listed in Table 1 of 4 10 or more in a tumor of a patient and / or the copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method of suppressing or treating cancer in a patient comprising: 15 i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a copy number of one or more of the genes listed in Table 1 of 4 or more and / or a copy number ratio of one or more of the genes listed in Table 1 20 of 2 or more. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising administering to a patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number 25 ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: i) identifying or selecting a patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of 30 one or more of the genes listed in Table 1 of 2 or more in a tumor; and ii) administering to the patient a Nectin-4 targeted therapeutic.

[0060] 31

[0061] The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; 5 ii) selecting the patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for maintaining or reducing the 10 volume of a solid tumor in a patient comprising: i) detecting the copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor of a patient and / or the copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 15 The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 20 identified as having a copy number of one or more of the genes listed in Table 1 of 4 or more and / or a copy number ratio of one or more of the genes listed in Table 1 or 2 or more. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient comprising administering to a patient 25 a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient comprising:

[0062] 32

[0063] i) identifying or selecting a patient having a copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor; and ii) administering to the patient a Nectin-4 targeted therapeutic. 5 The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient comprising: i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; ii) selecting the patient having a copy number of one or more of the genes 10 listed in Table 1 of 4 or more in a tumor and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient comprising: 15 i) detecting the copy number of one or more of the genes listed in Table 1 of 4 or more in a tumor of a patient and / or the copy number ratio of one or more of the genes listed in Table 1 of 2 or more in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or 20 the progression free survival time of a cancer patient comprising: i) determining the copy number of one or more of the genes listed in Table 1 in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a copy number of one or more of the genes listed in Table 1 of 25 4 or more and / or a copy number ratio of one or more of the genes listed in Table 1 of 2 or more. SDHC and DDR2 are two genes which are located within the 1q23.3 chromosomal region which are found in close proximity to the Nectin-4 gene. SDHC and DDR2 copy number and Nectin-4 copy number have been shown to be highly correlated in WO 30 2022 / 038158, the contents of which is hereby incorporated by reference in their entirety. In one embodiment, the Nectin-4 copy number can be determined by measuring the DDR2

[0064] 33

[0065] copy number. In one embodiment, the Nectin-4 copy number can be determined by measuring the SDHC copy number. SDHC is also known by the following aliases, each of which is equivalent to SDHC: Succinate Dehydrogenase Complex Subunit C; CYB560; Succinate 5 Dehydrogenase Complex, Subunit C, Integral Membrane Protein, 15kD; Succinate Dehydrogenase Cytochrome B560 Subunit, Mitochondrial; Succinate-Ubiquinone Oxidoreductase Cytochrome B Large Subunit; Succinate Dehydrogenase Cytochrome B; Large Subunit Of Cytochrome B; CYBL; SDH3; Succinate Dehydrogenase Complex, Subunit C, Integral Membrane Protein, 15kDa; Succinate Dehydrogenase Complex 10 Subunit C Integral Membrane Protein 15kDa; Succinate Dehydrogenase Integral Membrane Subunit; Succinate Dehydrogenase Cytochrome B560 Subunit; Cytochrome B Large Subunit Of Complex II; Integral Membrane Protein CII-3b; Integral Membrane Protein CII-3; QPs-1; PGL3; QPS1; SDHC; CybL; and QPsl. DDR2 is also known by the following aliases, each of which is equivalent to15 DDR2: Discoidin Domain Receptor Tyrosine Kinase 2; TKT; Discoidin Domain- Containing Receptor Tyrosine Kinase 2; Discoidin Domain Receptor Family, Member 2; Discoidin Domain-Containing Receptor 2; Receptor Protein-Tyrosine Kinase TKT; CD167 Antigen-Like Family Member B; Tyrosine-Protein Kinase TYRO 10; Discoidin Domain Receptor 2; EC 2.7.10.1; NTRKR3; TYRO 10; Neurotrophic Tyrosine Kinase, Receptor- 20 Related 3; Neurotrophic Tyrosine Kinase Receptor Related 3; Cell Migration-Inducing Protein 20; Migration-Inducing Gene 16 Protein; Hydroxyaryl-Protein Kinase; CD167b Antigen; EC 2.7.10; MIG20a; WRCN; and DDR2. In some embodiments, the Nectin-4 copy number is determined by measuring the Nectin-4, SDHC and / or DDR2 DNA copy number in the tumor. 25 The present invention also provides a method of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining SDHC copy number in a tumor of the patient and ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the SDHC copy number in the tumor of the patient is 4 or more 30 and / or if the SDHC copy number ratio in the tumor of the patient is 2 or more.

[0066] 34

[0067] The present invention also provides a method of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining DDR2 copy number in a tumor of the patient and ii) identifying or selecting the patient for treatment with a Nectin-4 targeted 5 therapeutic if the DDR2 copy number in the tumor of the patient is 4 or more and / or if the DDR2 copy number ratio in the tumor of the patient is 2 or more. The present invention also provides a method comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor 10 of 2 or more. The present invention also provides a method comprising: i) identifying or selecting a patient having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 15 The present invention also provides a method comprising: i) determining SDHC copy number in a tumor of a patient; ii) selecting the patient having an SDHC copy number of 4 or more in the tumor and / or an SDHC copy number ratio in a tumor of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 20 The present invention also provides a method comprising: i) detecting an SDHC copy number of 4 or more in a tumor of a patient and / or an SDHC copy number ratio of 2 or more in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: 25 i) determining SDHC copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having an SDHC copy number of 4 or more and / or an SDHC copy number ratio of 2 or more. The present invention also provides a method comprising administering to the 30 patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a

[0068] 35

[0069] DDR2 copy number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more. The present invention also provides a method comprising: i) identifying or selecting a patient having a DDR2 copy number in a tumor of 5 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) determining DDR2 copy number in a tumor of a patient; ii) selecting the patient having a DDR2 copy number of 4 or more in the tumor 10 and / or a DDR2 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) detecting a DDR2 copy number of 4 or more in a tumor of a patient and / or a DDR2 copy number ratio of 2 or more in a tumor of a patient; and 15 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) determining DDR2 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a DDR2 copy number of 4 or more and / or a DDR2 copy 20 number ratio of 2 or more. The present invention also provides a method of suppressing or treating cancer in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or more. 25 The present invention also provides a method of suppressing or treating cancer in a patient, comprising: i) selecting a patient having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 30 The present invention also provides a method of suppressing or treating cancer in a patient, comprising:

[0070] 36

[0071] i) detecting an SDHC copy number of 4 or more in a tumor of the patient and / or an SDHC copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method of suppressing or treating cancer in a 5 patient comprising: i) determining SDHC copy number in a tumor of the patient; ii) selecting a patient having an SDHC copy number of 4 or more in the tumor and / or an SDHC copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 10 The present invention also provides methods of suppressing or treating cancer in a patient, comprising: i) determining SDHC copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having an SDHC copy number of 4 or more in the tumor and / or an 15 SDHC copy number ratio of 2 or more in the tumor. The present invention also provides a method of suppressing or treating cancer in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a DDR2 copy number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more. 20 The present invention also provides a method of suppressing or treating cancer in a patient, comprising: i) selecting a patient having a DDR2 copy number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 25 The present invention also provides a method of suppressing or treating cancer in a patient, comprising: i) detecting a DDR2 copy number of 4 or more in a tumor of the patient and / or a DDR2 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 30 The present invention also provides a method of suppressing or treating cancer in a patient comprising:

[0072] 37

[0073] i) determining DDR2 copy number in a tumor of the patient; ii) selecting a patient having a DDR2 copy number of 4 or more in the tumor and / or a DDR2 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 5 The present invention also provides methods of suppressing or treating cancer in a patient, comprising: ii) determining DDR2 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a DDR2 copy number of 4 or more in the tumor and / or a 10 DDR2 copy number of 2 or more in the tumor. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or 15 more. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient comprising: i) selecting a patient having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or more; and 20 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) detecting an SDHC copy number of 4 or more in a tumor of the patient and / or an SDHC copy number ratio of 2 or more in a tumor of the patient; and 25 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining SDHC copy number in a tumor of the patient; ii) selecting the patient having an SDHC copy number of 4 or more in the 30 tumor and / or an SDHC copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic.

[0074] 38

[0075] The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining SDHC copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 5 identified as having an SDHC copy number of 4 or more in the tumor and / or an SDHC copy number ratio or 2 or more in the tumor. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a DDR2 copy 10 number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) selecting a patient having a DDR2 copy number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more; and 15 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) detecting a DDR2 copy number of 4 or more in a tumor of the patient and / or a DDR2 copy number ratio of 2 or more in a tumor of the patient; and 20 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining DDR2 copy number in a tumor of the patient; ii) selecting the patient having a DDR2 copy number of 4 or more in the tumor 25 and / or a DDR2 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method of suppressing or treating cancer in a patient comprising: i) determining DDR2 copy number in a tumor of the patient; and

[0076] 39

[0077] ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a DDR2 copy number of 4 or more and / or a DDR2 copy number ratio of 2 or more. The present invention also provides a method for increasing survival time and / or 5 the progression free survival time of a cancer patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or more. The present invention also provides a method for increasing survival time and / or 10 the progression free survival time of a cancer patient, comprising: i) selecting a patient having an SDHC copy number in a tumor of 4 or more and / or an SDHC copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or 15 the progression free survival time of a cancer patient, comprising: i) detecting an SDHC copy number of 4 or more in a tumor of the patient and / or an SDHC copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or 20 the progression free survival time of a cancer patient, comprising: i) determining SDHC copy number in a tumor of the patient; ii) selecting the patient having an SDHC copy number of 4 or more in the tumor and / or an SDHC copy number of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 25 The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) determining SDHC copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having an SDHC copy number of 4 or more in the tumor and / or an 30 SDHC copy number ratio of 2 or more in the tumor.

[0078] 40

[0079] The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a DDR2 copy number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor 5 of 2 or more. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) selecting a patient having a DDR2 copy number in a tumor of 4 or more and / or a DDR2 copy number ratio in a tumor of 2 or more; and 10 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) detecting a DDR2 copy number of 4 or more in a tumor of the patient and / or a DDR2 copy number ratio of 2 or more in a tumor of the patient; and 15 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) determining DDR2 copy number in a tumor of the patient; ii) selecting the patient having a DDR2 copy number of 4 or more in the tumor 20 and / or a DDR2 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising i) determining DDR2 copy number in a tumor of the patient; and 25 ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a DDR2 copy number of 4 or more in the tumor and / or a DDR2 copy number ratio of 2 or more in the tumor. Embodiments of the present invention which discuss identifying or selecting patients on the basis of a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy 30 number ratio of 2 or more apply mutatis mutandis to the aspects of the invention described

[0080] 41

[0081] herein in which the copy number and / or copy number ratio of any one or more of the genes listed in Table 1, SDHC and / or DDR2 is determined. The present invention is based on the observation that the Nectin-4 gene is frequently amplified in urothelial cancer, breast cancer, particularly TNBC, and lung 5 cancer, particularly NSCLC. In some embodiments, the Nectin-4 copy number is 4 or more. In some embodiments, the Nectin-4 copy number ratio is or 2 or more. In some embodiments, the Nectin-4 copy number is 4 or more and the Nectin-4 copy number ratio is 2 or more. In some embodiments, the Nectin-4 copy number is 4 or more but the Nectin-4 copy number 10 ratio is not 2 or more. In some embodiments, the Nectin-4 copy number ratio is 2 or more but the Nectin-4 copy number is not 4 or more. In the course of making the present invention, the inventors have identified that both patients with a Nectin-4 amplification, and patients with Nectin-4 polysomy, are more likely to respond to treatment with a Nectin-4 targeted therapeutic. In the retrospective 15 analysis reported in the Examples, selecting patients who have a Nectin-4 amplification, and patients who have Nectin-4 polysomy improves ORR relative to unselected patients, as well as relative to selecting patients on the basis of high Nectin-4 expression (H-score >158) or positive tumor proportion score (TPS > 1) when measured by IHC. In particular, for certain indications selecting patients who have a Nectin-4 20 amplification and patients who have Nectin-4 polysomy has been shown to provide the highest observed ORR, and / or to capture the highest proportion of patients who responded to treatment. Thus, in certain embodiments, it may be advantageous to select both patients with a Nectin-4 amplification and patients with Nectin-4 polysomy. Applying a threshold for identifying patients for treatment that captures both of these groups of patients, may 25 allow the greatest number of patients who are likely to response to treatment to be identified, and / or may allow the patients who are most likely to response to treatment to be identified. In particular, and as shown in the Examples, in some instances applying selection criteria which includes thresholds that allow both of these patient groups to be captured may be particularly beneficial compared to using a threshold that captures only 30 one of these groups of patients, for example a threshold that only captures patients with a Nectin-4 amplification whilst excluding patients with Nectin-4 polysomy, or vice-versa.

[0082] 42

[0083] At a population level, applying selection criteria which includes thresholds that allow both of these patient groups to be captured may thus allow the identification or selection of the greatest number of patients who are most likely to respond to treatment with a Nectin-4 targeted therapeutic for treatment, and / or the patient groups that are captured to have an 5 increased ORR. Thus, in some embodiments, the present invention provides methods in which patients are identified or selected on the basis of having a Nectin-4 copy number ratio of 2 or more or a Nectin-4 copy number of 4 or more. Put another way, the present invention provides methods in which patients are identified or selected on the basis of a particular threshold which includes both patients who have a Nectin-4 copy number ratio 10 of 2 or more and patients who have a Nectin-4 copy number of 4 or more. The present invention thus provides a method of identifying or selecting cancer patients for treatment with a Nectin-4 targeted therapeutic comprising identifying or selecting patients for treatment with a Nectin-4 targeted therapeutic who have a tumor Nectin-4 copy number of 4 or more or a tumor Nectin-4 copy number ratio of 2 or more. 15 In some embodiments, the Nectin-4 copy number is 5 or more. In some embodiments, the Nectin-4 copy number is 6 or more. In some embodiments, the Nectin-4 copy number is 7 or more. In some embodiments, the Nectin-4 copy number is 8 or more. In particular, the inventors have identified that patients with Nectin-4 polysomy who have a Nectin-4 copy number of 6 or more respond to treatment with a Nectin-4 20 targeted therapeutic. Thus, in one embodiment, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 6 or more. In a further embodiment, the Nectin-4 copy number ratio is 2 or more, or the Nectin-4 copy number is 6 or more. 25 In one embodiment the present invention provides a method of identifying or selecting cancer patients for treatment with a Nectin-4 targeted therapeutic comprising identifying or selecting patients for treatment with a Nectin-4 targeted therapeutic who have a tumor Nectin-4 copy number of 6 or more or a tumor Nectin-4 copy number ratio of 2 or more. 30 The Nectin-4 gene amplification may have occurred as part of a larger duplication event. In some embodiments, the tumor has a duplication of the 1q23.3 chromosomal

[0084] 43

[0085] region. In some embodiments, the tumor has a duplication of the 1q arm of chromosome 1. In some embodiments, the tumor has duplication of chromosome 1. In some embodiments, the tumor has chromosome 1 polysomy. In some embodiments, the patient has a whole genome duplication (i.e. within the tumor). A tumor which has a Nectin-4 5 copy number of 4 or more, and thus which may have greater susceptibility to treatment with a Nectin-4 targeted therapeutic as discussed elsewhere herein, is, thus, a tumor in which cells in the tumor are confirmed to have a copy number of Nectin-4 of 4 or higher. This, therefore, includes tumors in which cells have a local amplification of the region of the Nectin-4 gene, and tumors which have a Nectin-4 copy number of 4 or more due to a 10 wider duplication event, for example tumor cells with aneuploidy e.g. chromosome 1 polysomy. In one embodiment, the cancer is TNBC or breast cancer, and patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number ratio is 15 2 or more, or the Nectin-4 copy number is 6 or more. In one embodiment, the cancer is TNBC or breast cancer, and patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number ratio is 2 or more. In one embodiment, the cancer is TNBC or breast cancer, and patients may be identified or selected for treatment with a 20 Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 5.13 or more. In some embodiments, Nectin-4 copy number ratio and / or Nectin-4 copy number are measured by FISH. In one embodiment, the cancer is muscle invasive bladder cancer (MIBC), in particular EV-naïve MIBC. In some embodiments, patients may be identified or selected 25 for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number ratio is 2 or more, or the Nectin- 4 copy number is 6 or more. In some embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 5.6 or more. In some 30 embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the

[0086] 44

[0087] Nectin-4 copy number is 5 or more. In some embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 5 or more relative to genome ploidy. In some embodiments, patients may be identified or selected 5 for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 6 or more. In some embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 6 or more relative to genome ploidy. In some embodiments, 10 patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 7 or more. In some embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 7 or more irrespective of genome 15 wide ploidy. In some embodiments, the cancer is NSCLC. In some embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number ratio is 2 or more, or the Nectin-4 copy number is 6 or more. In some embodiments, patients may 20 be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number ratio is 2 or more. In some embodiments, patients may be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number is 4.8 or more. In some embodiments, patients may 25 be identified or selected for treatment with a Nectin-4 targeted therapeutic (or a Nectin-4 targeted therapeutic may be administered to a patient) if the Nectin-4 copy number ratio is 2.2 or more. The Nectin-4 copy number can be determined using standard techniques known to the skilled person for measuring copy number. 30 In certain embodiments, particularly embodiments in which the Nectin-4 copy number is determined in a cellular sample (e.g. a tumor tissue sample or in CTCs), Nectin-

[0088] 45

[0089] 4 copy number can be determined using an in-situ hybridisation (ISH) assay. Examples of in-situ hybridisation assays include chromogenic in situ hybridisation (CISH), silver- enhanced in-situ hybridisation (SISH) (a variation of CISH) and fluorescence in-situ hybridisation (FISH). CISH, SISH and FISH involve the use of labelled oligonucleotide 5 probes with a high degree of sequence complementarity to specific chromosomal DNA sequences. CISH typically utilises probes labelled with biotin or digoxigenin and cognate labelled chromogenic enzyme (e.g. streptavidin or an anti-digoxigenin antibody conjugated to horseradish peroxidase (HRP)); diamimobenzidine (DAB) is subsequently added to the sample and HRP converts DAB into an insoluble brown product). SISH typically utilises 10 probes labelled with dinitrophenol (DNP) and an anti-DNP antibody conjugated to HRP; silver acetate, hydroquinone and hydrogen peroxide are subsequently added to the sample and HRP catalyses the polymerisation of silver in the presence of hydrogen peroxide. FISH utilises probes labelled with a fluorescent label. Binding of the probes to chromosomal DNA sequences can typically be detected using microscopy (e.g. bright field 15 (CISH or SISH) or fluorescence (FISH) miscroscopy, as appropriate). The skilled person will be able to count the number of sequences (identified by the ISH method) which are or which are surrogates for the Nectin-4 gene within a cell, thereby to determine the Nectin-4 copy number of the tumor. In certain embodiments, Nectin-4 copy number can be determined using array 20 comparative genomic hybridisation (array CGH). Array CGH detects differences between a control and test DNA. The DNA is labelled with a fluorescent dye (test DNA labelled with a first colour and control DNA with a second colour) and applied to a microarray on a slide. Labelled probes are then applied to the array – the fluorescence ratio of the test and control hybridisation signals is determined at different positions along the genome, which 25 provides information on the relative copy number of the sequences in the test genome and control genome. In certain embodiments, Nectin-4 copy number can be determined using an SNP array. Briefly, a SNP array comprises a large number of probes which are capable of identifying heterozygous genes within the genome. In a standard diploid sample, at a 30 heterozygous locus the maternal and paternal sequences would be expected to be present in approximately similar proportions. In the event of a duplication of a genomic region (for

[0090] 46

[0091] example, in the event of a duplication of the 1q23.3 region, or a part thereof, which comprises the Nectin-4 gene) in chromosome 1 (e.g. paternal chromosome 1), the signal for one allele (e.g. the paternal allele) at a heterozygous locus for a SNP located within the duplicated region would be expected to increase relative to the signal for the other allele at 5 that locus (e.g. a maternal allele), thus allowing an increase in copy number to be detected. In certain embodiments, Nectin-4 copy number can be determined using next- generation sequencing (NGS) technologies. (NGS) technologies, also known as high- throughput sequencing technologies, allow for sequencing of DNA and RNA much more quickly and cheaply than the previously used Sanger sequencing. In some embodiments, a 10 NGS technology is Illumina (Solexa) sequencing, which simultaneously identifies DNA bases, as each base emits a unique fluorescent signal, and adds them to a nucleic acid chain. In some embodiments, a NGS technology is Roche 454 sequencing, which is based on pyrosequencing, a technique which detects pyrophosphate release, again using fluorescence, after nucleotides are incorporated by polymerase to a new strand of DNA. In 15 some embodiments, a NGS technology is Ion Torrent: Proton / PGM sequencing, which measures the direct release of H+ (protons) from the incorporation of individual bases by DNA polymerase. The copy number of a gene, for example, the Nectin-4 copy number, refers to the total number of copies of the gene, for example, the Nectin-4 gene, in a tumor cell. As 20 discussed above, a variety of amplification / duplication events may have occurred in a tumor cell for a tumor to have a Nectin-4 copy number of 4 or more, including chromosome 1 aneuploidy and a more localised amplification of the Nectin-4 gene within chromosome 1. In one embodiment, the present invention provides a method of identifying or 25 selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the Nectin-4 copy number in the tumor of the patient is 4 or more. In one embodiment, the present invention provides a method comprising 30 administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more.

[0092] 47

[0093] In one embodiment, the present invention provides a method comprising: i) identifying or selecting a patient having a Nectin-4 copy number in a tumor of 4 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 5 In a one embodiment, the present invention provides a method comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 10 In one embodiment, the present invention provides a method comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. In one embodiment, the present invention provides a method comprising: 15 i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more. In one embodiment, the present invention provides a method of suppressing or treating cancer in a patient comprising administering to the patient a Nectin-4 targeted 20 therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more. In one embodiment, the present invention provides a method of suppressing or treating cancer in a patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more; 25 and ii) administering to the patient a Nectin-4 targeted therapeutic. In one embodiment, the present invention provides a method of suppressing or treating cancer in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient; 30 and ii) administering to the patient a Nectin-4 targeted therapeutic.

[0094] 48

[0095] In one embodiment, the present invention provides a method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the 5 tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. In one embodiment, the present invention provides a method of suppressing or treating cancer in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; and 10 ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more. In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 15 copy number in a tumor of 4 or more. In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more; and 20 ii) administering to the patient a Nectin-4 targeted therapeutic. In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient; and 25 ii) administering to the patient a Nectin-4 targeted therapeutic. In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the 30 tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic.

[0096] 49

[0097] In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 5 identified as having a Nectin-4 copy number of 4 or more. In one embodiment, the present invention provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more. 10 In one embodiment, the present invention provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 15 In one embodiment, the present invention provides a method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 20 In one embodiment, the present invention provides a method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor; and 25 iii) administering to the patient a Nectin-4 targeted therapeutic. In one embodiment, the present invention provides a method for increasing survival time and / or the progression free survival of a cancer patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 30 identified as having a Nectin-4 copy number of 4 or more.

[0098] 50

[0099] It is also possible to determine the copy number ratio of a gene, for example, the Nectin-4 copy number ratio, in a tumor. Typically, this can be done by determining the copy number of a gene of interest in a cell (for example, the Nectin-4 gene or a gene listed in Table 1), and determining the copy number of at least one reference or control gene or 5 marker. In some embodiments, the reference or control gene may be within chromosome 1, for example, the chromosome 1 centromere region (CEN1). Dividing the copy number of the gene of interest, for example, the Nectin-4 copy number, by the copy number of the reference or control gene or marker provides the copy number ratio. In certain embodiments, the copy number ratio of a gene of interest, for example, 10 the Nectin-4 gene to the chromosome 1 centromere (the copy number ratio) is 1. Typically, when the copy number ratio is 1 but the copy number of the gene of interest (e.g. the Nectin-4 gene) is 3 or greater, this suggests that a wider duplication event has taken place, e.g. that the tumor may have chromosome 1 polysomy or whole genome duplication (as in such events, both the gene of interest (e.g. Nectin-4) and a reference gene 15 or marker within chromosome 1 would both have been duplicated, so the ratio between the copy number of the gene of interest (e.g. Nectin-4) and the copy number of the reference gene or marker remains unchanged). Thus, in certain embodiments, the tumor may have a Nectin-4 copy number of 4 or more, and yet may only have a Nectin-4 copy number ratio of 1. Without wishing to be bound by theory, tumors having such aneuploidy events and 20 having a Nectin-4 copy number of 4 or more may still be more susceptible to treatment with Nectin-4 targeted therapeutic agents according to the methods of the invention, and the examples demonstrate that a patient with an aneuploidy event that resulted in a Nectin- 4 copy number of 6 responded well to treatment with BT8009. In certain embodiments, the copy number ratio of a gene of interest, for example, 25 the Nectin-4 copy number ratio is 2 or more. Without wishing to be bound by theory, this suggests that the Nectin-4 gene and / or a limited portion of chromosome 1 (e.g. the 1q23.3 region) has undergone a gene duplication event within chromosome 1, but that overall the tumor remains diploid for chromosome 1; whilst the number of copies of Nectin-4 may have increased following the gene duplication event, the number of copies of a reference or 30 control region within chromosome 1, such as CEN1, would be unchanged. Thus, in certain embodiments, the tumor may have a Nectin-4 copy number of 4 or more and a Nectin-4

[0100] 51

[0101] copy number ratio of 2 or more. The examples demonstrate that having a Nectin-4 copy number ratio of 2 or more may be particularly informative for patient selection. The present invention thus provides a method of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: 5 i) determining Nectin-4 copy number ratio in a tumor of the patient; and ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the Nectin-4 copy number ratio in the tumor of the patient is 2 or more. The present invention provides methods comprising administering to a 10 patient a Nectin-4 targeted therapeutic wherein the patient has been selected for having a Nectin-4 copy number ratio in a tumor of 2 or more. The present invention also provides methods comprising: i) identifying or selecting a patient having a Nectin-4 copy number ratio in a tumor of 2 or more; and 15 ii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides a method comprising: i) determining Nectin-4 copy number ratio in a tumor of a patient; ii) selecting the patient having a Nectin-4 copy number ratio of 2 or more in the tumor; and 20 iii) administering to the patient a Nectin-4 targeted therapeutic. The present invention also provides methods comprising: i) detecting a Nectin-4 copy number ratio of 2 or more in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 25 The present invention also provides methods comprising: i) determining Nectin-4 copy number ratio in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number ratio of 2 or more. In particular embodiments, patients having a Nectin-4 copy number ratio of 2 or 30 more may have a cancer that is more likely to be suppressed or treated with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number ratio of 2 or

[0102] 52

[0103] more in a tumor, and / or that is more likely to maintain its volume or reduce in volume following administration of the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number ratio of 2 or more in a tumor, and / or the patient identified or selected for treatment with a Nectin-4 may be more likely to have an increased survival 5 time following initiation of treatment with the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number ratio of 2 or more in a tumor, and / or wherein the patient identified or selected for treatment with a Nectin-4 targeted therapeutic may be more likely to have an increased progression free survival time (PFS) following initiation of treatment with the Nectin-4 targeted therapeutic than a patient who does not have a 10 Nectin-4 copy number ratio of 2 or more in a tumor. Thus, the present invention provides corresponding methods for suppressing or treating cancer in a patient, maintaining or reducing the volume of a solid tumor in a patient and / or increasing survival time and / or the progression free survival time of a cancer patient, wherein the patient is identified and / or selected on the basis of having a Nectin-4 15 copy number ratio of 2 or more. In some embodiments, the tumor has copy number ratio of 3 or more. In some embodiments, the tumor has a copy number ratio of 4 or more. In certain embodiments, the tumor has an increased ratio of a gene (e.g. the Nectin- 4 gene) relative to the genome level ploidy of the tumor (a copy number ploidy ratio of 20 greater than 1). For example, a tumor may have undergone a whole genome duplication event, whilst the Nectin-4 gene may also have been amplified beyond and in addition to the whole genome duplication event. Thus, by way of representative embodiment, the ploidy of the tumor may be 2, whilst the tumor may have a Nectin-4 copy number of 6; in such an event, the tumor would have a tumor ploidy ratio of 3. In certain embodiments, the tumor 25 may have a Nectin-4 copy number ploidy ratio of 2 or more. In certain embodiments, the tumor may have a Nectin-4 copy number ploidy ratio of 3 or more. In certain embodiments, the tumor may have a Nectin-4 copy number ploidy ratio of 4 or more. In certain embodiments, the tumor may have a Nectin-4 copy number ploidy ratio of 5 or more. In certain embodiments, the tumor may have a Nectin-4 copy number ploidy ratio of 30 6 or more.

[0104] 53

[0105] In certain embodiments, the tumor is not associated with, does not have or is not characterised by elevated Nectin-4 protein and / or mRNA expression. In other words, in certain embodiments, the tumor does not have elevated Nectin-4 protein and / or mRNA expression (despite having a Nectin-4 copy number of at least 4). In some embodiments, 5 the patient identified or selected according to the methods of the present invention having a Nectin-4 copy number of 4 or more does not have a tumor which is associated with elevated Nectin-4 protein (e.g. as measured by IHC) and / or mRNA expression. In some embodiments, the patient identified or selected according to the methods of the present invention having a Nectin-4 copy number of 4 or more has a tumor which is not associated 10 with elevated Nectin-4 protein and / or mRNA expression. In certain embodiments, the patient is not identified or selected by determining the level of Nectin-4 protein and / or mRNA expression in the tumor. In certain embodiments, a step of determining the level of Nectin-4 protein and / or mRNA expression is not performed. In certain embodiments, an IHC assay to determine the level of Nectin-4 15 protein in the tumor is not performed. Tumor sample The Nectin-4 copy number of a tumor can be determined by determining Nectin-4 copy number in genetic material from a tumor, such as genomic DNA. This can be 20 performed using any sample which contains genetic material from a tumor, for example genomic tumor DNA. Thus, reference to determining Nectin-4 copy number in a tumor is not limited to methods which determine the Nectin-4 copy number in a tumor tissue sample, but rather refers more broadly to methods which allow the Nectin-4 copy number in a tumor to be determined e.g. by determining the Nectin-4 copy number in a sample 25 containing tumor DNA. In some embodiments, the sample is a tumor tissue sample (e.g. a tumor biopsy) obtained from the patient. In some embodiments, the sample is a liquid biopsy (e.g. a blood sample) or other liquid sample e.g. urine, sputum, saliva, alveolar lavage, ascites, pleural effusion or breast milk. In some embodiments, the sample is a blood sample and 30 the Nectin-4 copy number is determined in circulating tumor cells (CTCs). In some embodiments, Nectin-4 copy number is determined in tumour-derived cell-free DNA in a

[0106] 54

[0107] non-tumor sample, e.g. a liquid sample. In some embodiments, the sample is a blood sample, urine, sputum, saliva, alveolar lavage, ascites, pleural effusion or breast milk. In one embodiment, the tumor-derived cell-free DNA is in a blood sample i.e. is circulating tumor DNA (ctDNA). In one embodiment, the tumor-derived cell-free DNA is found in 5 any other biological sample or bodily fluid e.g. urine. In some embodiments, two or more samples may be obtained from a patient. In some embodiments, two or more tumor tissue samples may be obtained from a patient, for example, two or more tumor tissue samples within the same tumor or two or more tumor tissue samples from different tumors, e.g. a first tumor tissue sample from a primary tumor 10 and a second tumor tissue sample from a tumor metastasis. In some embodiments, a tumor tissue sample and a non-tumor tissue sample may be obtained from a patient. In some embodiments, determining Nectin-4 copy number in the tumor comprises determining Nectin-4 copy number in a tumor tissue sample derived or obtained from the patient. In some embodiments, the tumor tissue sample is a sample from a primary tumor. 15 In some embodiments, the tumor tissue sample is a sample from a secondary tumor, e.g. a tumor metastasis. In some embodiments, the patient has urothelial cancer. In some embodiments, the urothelial cancer is locally advanced, muscle invasive or metastatic urothelial cancer. In some embodiments, the tumor tissue sample is an at least pathologically confirmed stroma 20 invasive urothelial carcinoma. In some embodiments, the patient has urothelial cancer. In some embodiments, the urothelial cancer is non-invasive urothelial cancer. In some embodiments, the tumor tissue sample is a papillary non-invasive tumor. In some embodiments, determining Nectin-4 copy number in the tumor comprises 25 determining Nectin-4 copy number in tumor cells in a liquid sample derived or obtained from the patient, for example a blood sample, urine, sputum, saliva, alveolar lavage, ascites sample, pleural effusion or breast milk. In some embodiments, determining Nectin-4 copy number in the tumor comprises determining Nectin-4 copy number in circulating tumor cells (CTCs). 30 In some embodiments, determining Nectin-4 copy number in the tumor comprises determining Nectin-4 copy number in tumor-derived cell-free DNA in a non-tumor sample

[0108] 55

[0109] obtained from the patient. In one embodiment, the sample is a blood sample and the tumor-derived cell-free DNA is circulating tumor DNA (ctDNA). In one embodiment, the sample is a urine sample. A tumor which has a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy 5 number ratio of 2 or more comprises a cell or cells which have a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more. Detecting the presence of a cell or cells which has a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more indicates that the tumor has a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more. 10 In some embodiments, determining the Nectin-4 copy number of a tumor (or copy number ratio) comprises determining the Nectin-4 copy number (or copy number ratio) of more than one tumor cell. In some embodiments, determining the Nectin-4 copy number (or copy number ratio) of a tumor may comprise determining the Nectin-4 copy number (or copy number ratio) of a plurality of tumor cells. In some embodiments, determining the 15 Nectin-4 copy number (or copy number ratio) of a tumor comprises determining the Nectin-4 copy number (or copy number ratio) of at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 tumor cells. In some embodiments, determining the Nectin-4 copy number of a tumor comprises 20 determining the Nectin-4 copy number at two or more regions or locations within a tumor or tumor sample. For example, if the Nectin-4 copy number is determined in a plurality of tumor cells in a first region within a tumor or tumor sample and it is identified that the cells within that region are heterogeneous for having a Nectin-4 copy number of 4 or more, it may be beneficial to determine the Nectin-4 copy number at a second region or location 25 within a tumor or tumor sample. The Nectin-4 copy number of more than one tumor cell may be determined. In some embodiments, the Nectin-4 copy number of a plurality of tumor cells may be determined at each region or location of the tumor or tumor sample. In some embodiments, the Nectin-4 copy number of at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 60, at least 70, at least 30 80, at least 90 or at least 100 tumor cells may be determined at each region or location within a tumor or tumor sample.

[0110] 56

[0111] In some embodiments, determining the Nectin-4 copy number of a tumor comprises determining the Nectin-4 copy number (or copy number ratio) across more than one tumor cell. In other words, determining the Nectin-4 copy number (or copy number ratio) may comprise determining the total number of copies of Nectin-4 in more than one tumor cell. 5 In some embodiments, determining the Nectin-4 copy number (or copy number ratio) of a tumor may comprise determining the Nectin-4 copy number across a plurality of tumor cells. In some embodiments, determining the Nectin-4 copy number (or copy number ratio) of a tumor comprises determining the Nectin-4 copy number (or copy number ratio) across at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at 10 least 45, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 tumor cells. In some embodiments, determining the Nectin-4 copy number of a tumor comprises determining the average Nectin-4 copy number of more than one tumor cell. By way of representative example, determining the Nectin-4 copy number of a tumor may comprise 15 determining the total number of copies of the Nectin-4 gene across a number of cells, and dividing the total number of copies of the Nectin-4 gene by the number of cells analysed. In some embodiments, the average Nectin-4 copy number of more than one tumor cell is 4 or more. In some embodiments, the average Nectin-4 copy number in the tumor is 4 or more. Notably, by calculating e.g. the average Nectin-4 copy number in the tumor cells 20 within a tumor it is possible to detect a non-integer value for the Nectin-4 copy number. Furthermore, in certain embodiments the average Nectin-4 copy number in the tumor may be less than 4, despite the tumor comprising cells which have a Nectin-4 copy number of 4 or more. This may occur, for example, if the tumor is heterogeneous and not all cells within the tumor have a Nectin-4 copy number of 4 or more (for example, if only 50% of 25 the measured cells have a Nectin-4 copy number of 4 and the remaining 50% of the cells have a normal diploid Nectin-4 copy number, the average Nectin-4 copy number may be calculated to be 3. However, such a tumor may be considered to have a Nectin-4 copy number of 4 or more as it comprises cells within it which comprise a Nectin-4 copy number of 4 or more. 30 In some embodiments, determining the Nectin-4 copy number ratio may comprise determining the total number of copies of the Nectin-4 gene and the total number of copies

[0112] 57

[0113] of a reference gene (e.g. CEN1) across a number of cells, and dividing the total number of copies of the Nectin-4 gene by the total number of copies of the reference gene. In some embodiments, determining the Nectin-4 copy number of a tumor comprises determining the proportion of tumor cells which have a Nectin-4 copy number of 4 or 5 more. In some embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the tumor cells (e.g. tumor cells in a tumor, tumor sample, in a region or location within a tumor or tumor sample, or in a liquid sample which have been analysed for Nectin-4 copy number) have a Nectin-4 copy 10 number of 4 or more. As discussed above, if the tumor cells are heterogeneous for having a Nectin-4 copy number of 4 or more, in certain embodiments the detection may be repeated e.g. in a further region or location within a tumor or a tumor sample. Nectin-4 targeted therapeutic 15 In one embodiment, the Nectin-4 targeted therapeutic is a Bicycle Drug Conjugate® (BDC) or a Bicycle TICA®, i.e. a BDC or a Bicycle TICA® specific for Nectin-4. Both BDCs and Bicycle TICAs® comprise Bicycle® molecules. Bicycle® molecules typically comprise a binding moiety comprising a peptide ligand tethered to a 20 small molecule scaffold by active groups on at least three residues within the peptide ligand, typically cysteine residues or a derivative thereof. Bicycle molecules comprise a peptide ligand specific for Nectin-4 that comprises (a) a polypeptide comprising at least three residues comprising active groups, separated by at least two loop sequences, and (b) a molecular scaffold that forms covalent bonds with the at least three residues of the 25 polypeptide comprising active groups such that at least two polypeptide loops are formed on the molecular scaffold. Optionally, the residue comprising an active group is a cysteine residue or a derivative thereof. Thus, in certain embodiments, a BDC comprises (a) a polypeptide comprising at least three cysteine residues (or derivatives thereof), separated by at least two loop sequences, and (b) a molecular scaffold that forms covalent bonds with 30 the at least three cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold.

[0114] 58

[0115] BDCs comprise such Bicycle molecules conjugated to one or more drug molecules typically a cytotoxic agent, via a linker and are specific for a binding target. BDCs (which may also be referred to as Bicycle toxin conjugates if conjugated to a cytotoxic agent) which target Nectin-4 specifically bind to Nectin-4. BDCs which target Nectin-4 have 5 been described previously, for example, in WO 2019 / 243832 and WO 2019 / 243833, and the peptide ligands and Bicycle toxin conjugates which are disclosed therein are incorporated herein by reference. In one embodiment, the BDC which targets Nectin-4 is BT8009. BT8009 is referred to as BCY8245 in WO 2019 / 243832 and WO 2019 / 243833. The term “BT8009” as used herein is a BDC having the structure as shown below, or a10 pharmaceutically acceptable salt thereof, wherein the molecular scaffold is (l,1’,l’’(l,3,5- triazinane-l,3,5-triyl)triprop-2-en-l-one (TATA), and the peptide ligand comprises the amino acid sequence: β-Ala-Sar10-CiP[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiiiwherein Sar is sarcosine, 1Nal represents 1-naphthylalanine, HArg represents 15 homoarginine, HyP represents hydroxyproline and Ci, Ciiand Ciiirepresent first, second and third cysteine residues.

[0116] 59

[0117] In some embodiments, BT8009 is administered to a patient once every day. In some embodiments, BT8009 is administered to a patient once every 2, 3, 4, 5, 6, or 7 days. In some embodiments, BT8009 is administered to a patient once every week, or weekly. In some embodiments, BT8009 is administered to a patient once every two weeks. In some 5 embodiments, BT8009 is administered as a liquid formulation or a liquid unit dosage form. In some embodiments, a treatment cycle is 4 weeks, i.e., a 28-day treatment cycle. In some embodiments, BT8009 is administered weekly on a 28-day treatment cycle, for example, on days 1, 8, 15, and 22. In some embodiments, BT8009 is administered once every two weeks on a 28-day cycle, for example, on days 1 and 15. In some embodiments, 10 BT8009 is administered as a liquid formulation or a liquid unit dosage form. In some embodiments, a treatment cycle is 3 weeks, i.e., a 21-day treatment cycle. In some embodiments, BT8009 is administered in week 1 and week 2, but not in week 3, of a 21-day treatment cycle. In some embodiments, BT8009 s administered on days 1 and 8 of a 21-day treatment cycle. In some embodiments, BT8009 is administered once 15 weekly of a 21-day treatment cycle. In some embodiments, BT8009 administered on days 1, 8, and 15 of a 21-day treatment cycle. In some embodiments, BT8009 is administered as a body surface area (BSA)-based dose, which is expressed in units of mg / m2, such as any of the doses discussed herein. A dose in units of mg / m2 refers to a dose (in mg) that is administered per m2 of the body 20 surface area (BSA) of a patient. A BSA-based dose (in mg / m2) may be determined by dividing a dose (in mg) by the BSA of a patient. The skilled person will be aware of models and formula that may be used to estimate or determine the BSA of a patient based on factors such as the height and weight of the patient. In some embodiments, BSA may be estimated using the Dubois Formula for BSA Dosing (0.007184x (Height(cm))^0.725 25 x(Weight(kg))^0.425 or the Monteller Formula for BSA Dosing (square root [(Height (cm) x Weight (kg)) / 3600]). In some embodiments, a patient may have a BSA of 1.37 m2to 2.3 m2. In some embodiments, the patient may have a BSA of 1.37 m2to 1.69 m2. In some embodiments, the patient may have a BSA of 1.69 m2to 1.84 m2. In some embodiments, the patient may 30 have a BSA of 1.84 m2to 1.96 m2. In some embodiments, the patient may have a BSA of 1.96 m2to 2.3 m2.

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[0119] In some embodiments, BT8009 is administered at a dose (measured by the amount of the API: BT8009) of about 1-20 mg / m2. In some embodiments, BT8009 is administered at a dose of about 2-15 mg / m2. In some embodiments, BT8009 is administered at a dose of about 2-10 mg / m2. In some embodiments, BT8009 is administered at a dose of about 2 5 mg / m2, 3 mg / m2, 4 mg / m2, 5 mg / m2, 6 mg / m2, 7 mg / m2, 8 mg / m2, 9 mg / m2, or 10 mg / m2. In some embodiments, a BT8009 is administered at a dose of about 2.5 mg / m2, 3.5 mg / m2, 4.5 mg / m2, 5.5 mg / m2, 6.5 mg / m2, 7.5 mg / m2, 8.5 mg / m2, or 9.5 mg / m2. In one particular embodiment, BT8009 is administered at a dose of about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of 10 about 5 mg / m2. In another particular embodiment, BT8009 is administered at a dose of about 6-9 mg / m2, optionally at a dose of about 7-8 mg / m2, optionally at a dose of about 7.5 mg / m2or 6 mg / m2. In some embodiments, BT8009 is administered at a dose of about 4-8 mg / m2, optionally at a dose of about 5-7 mg / m2, optionally at a dose of about 6 mg / m2. In some embodiments, BT8009 is administered to the patient weekly at a dose of 15 about 2-10 mg / m2, optionally at a dose of about 2.5-7.5 mg / m2, optionally at a dose of about 4-6 mg / m2, optionally at a dose of 5 mg / m2. In some embodiments, BT8009 is administered to the patient on days 1 and 8 of a 21-day treatment cycle at a dose of about 4-8 mg / m2, optionally at a dose of 5-7 mg / m2, optionally at a dose of about 6 mg / m2. 20 As used herein, the term “Bicycle® tumor targeted immune agonists (Bicycle TICAs®) specific for Nectin-4” refers to Bicycle ® tumor targeted immune agonists (TICAs) that bind specifically to Nectin-4. Various Bicycle® tumor targeted immune agonists (TICAs) specific for Nectin-4 have been described previously, for example, in US 2019 / 0307836, WO 2019 / 193328, US 2021 / 0040154, WO 2021 / 019244, and WO 25 2021 / 019246, the content of each of which is incorporated herein by reference in its entirety. In one embodiment, the Bicycle TICA® is BT7480. BT7480 is referred to as BCY11863 in US 2021 / 0040154, WO 2021 / 019244, and WO 2021 / 019246. The term “BT7480” is a Bicycle® tumor targeted immune agonist (TICA), which is heterotandem bicyclic peptide complex consisting of a Nectin-4 specific peptide linked to two CD 137 30 specific peptides via a N-(acid-PEG3)-N-bis(PEG3-azide) linker, having a structure as shown below.

[0120] 63

[0121] In some embodiments, BT7480 is administered at a dose of up to about 10 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.002 mg / kg to about 7.5 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.02 mg / kg to about 7.5 mg / kg. In some embodiments, BT7480 is administered at a dose of 5 about 0.05 mg / kg to about 7.5 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.1 mg / kg to about 7.5 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.15 mg / kg to about 7.5 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.02 to about 6 mg / kg, about 0.05 to about 6 mg / kg, about 0.15 to about 6 mg / kg, about 0.3 to about 6 mg / kg, about 0.6 to about 6 10 mg / kg, about 1.3 to about 6 mg / kg, or about 2.6 to about 6 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.002 mg / kg, about 0.006 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.15 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.0 mg / kg, about 2.6 mg / kg, about 3.0 mg / kg, about 3.5 mg / kg, about 3.9 mg / kg, about 4.25 mg / kg, about 5.0 mg / kg, about 5.75 mg / kg, about 6.0 mg / kg, about 6.5 15 mg / kg, about 7.0 mg / kg, or about 7.5 mg / kg. In some embodiments, BT7480 is administered at a dose of about up to about 7.5 mg / kg, about 0.002 to about 7.5 mg / kg, about 0.01 to about 7.5 mg / kg, about 0.1 to about 7.5 mg / kg, about 0.3 to about 7.5 mg / kg, about 0.6 to about 6.0 mg / kg, about 1.3 to about 5.5 mg / kg, about 2.6 to about 5.75 mg / kg, or about 2.6 to about 5.0 mg / kg, or about 3.0 to 20 about 4.0 mg / kg. In some embodiments, BT7480 is administered at a dose of about 2.0 to about 4.0 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.3 mg / kg to about 5.0 mg / kg, about 0.3 to about 3.5 mg / kg, about 0.3 to about 2.6 mg / kg, about 0.6 25 mg / kg to about 5.0 mg / kg, about 0.6 to about 3.5 mg / kg, about 0.6 to about 2.6 mg / kg, about 1.3 mg / kg to about 5.0 mg / kg, about 1.3 to about 3.5 mg / kg, or about 1.3 to about 2.6 mg / kg. In some embodiments, BT7480 is administered at a dose of about 0.3 to about 3.5 mg / kg, about 0.6 to about 3.5 mg / kg, about 1.3 to about 3.5 mg / kg, or about 2.6 to about 30 3.5 mg / kg.

[0122] 65

[0123] In some embodiments, BT7480 is administered at a dose of about 0.3 mg / kg, about 0.6 mg / kg, about 1.3 mg / kg, about 2.6 mg / kg, or about 3.5 mg / kg. In some embodiments, BT7480 is administered at a dose of about 2.6 mg / kg. In some embodiments, BT7480 is administered at a dose of about 3.5 mg / kg. 5 In some embodiments, BT8009 or BT7480 are administered by an IV injection. In some embodiments, BT8009 or BT7480 is administered by an IV infusion. In some embodiments, the IV infusion is over about 5 to about 30 minutes. In some embodiments, the IV infusion is over about 30 to about 60 minutes. In some embodiments, an IV infusion is over about 55 to about 75 minutes. In some embodiments, an IV infusion is over about 10 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, or about 90 minutes. In some embodiments, an IV infusion is over about 60 minutes. In some embodiments, an IV infusion is over about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours. Reference 15 to “is over” in the context of IV infusion means that the IV infusion lasts for the specified length of time. It will be appreciated that Nectin-4 targeted therapeutics may comprise Bicycle peptide ligands or modified derivatives thereof. In some embodiments, modified derivatives include functional fragments, derivatives and variants. 20 Fragments of amino acid sequences include deletion variants of such sequences wherein one or more, such as at least 1, 2, 3, 4 or 5 amino acids are deleted. Deletion may occur at the C- terminus or N-terminus of the reference sequence or within the reference sequence. Derivatives of amino acid sequences include modified sequences including 25 sequences which are modified in vivo or ex vivo. Many different protein modifications are known to those skilled in the art and include modifications to introduce new functionalities to amino acid residues, modifications to protect reactive amino acid residues or modifications to couple amino acid residues to chemical moieties such as reactive functional groups on linkers for attachment to such amino acid residues. Exemplary 30 modifications that can be made to the provided peptides, ligands and related complexes are described in more detail herein.

[0124] 66

[0125] Derivatives of amino acid sequences include addition variants of such sequences wherein one or more, such as at least 1, 2, 3, 4, or 5 amino acids are added or introduced into the reference sequence. Addition may occur at the C- terminus or N-terminus of the reference sequence or within the reference sequence. 5 Variants, derivatives and fragments of the aforementioned amino acid sequences typically retain at least some of the activity / functionality of the reference sequence. In a preferred embodiment, the variants, derivatives and fragments substantially retain their biological function(s) as described herein. Thus, in one embodiment the variants, derivatives and fragments retain the binding specificity of the reference sequence i.e. the 10 ability to specifically bind to a biological target such as Nectin-4. In one such embodiment, the variants, derivatives and fragments bind to the same epitope as the reference sequence. In another embodiment, the variants, derivatives and fragments retain the binding affinity of the reference sequence. Preferably, variants, derivatives and fragments of a reference sequence have increased / improved activity / functionality when compared to the reference 15 sequence. Examples of such suitable modified derivatives include one or more modifications selected from: N-terminal and / or C-terminal modifications; replacement of one or more amino acid residues with one or more non-natural amino acid residues (such as replacement of one or more polar amino acid residues with one or more isosteric or 20 isoelectronic amino acids; replacement of one or more non-polar amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of a spacer group; replacement of one or more oxidation sensitive amino acid residues with one or more oxidation resistant amino acid residues; replacement of one or more amino acid residues with one or more replacement amino acids, such as an alanine, replacement of one or more 25 L-amino acid residues with one or more D-amino acid residues; N-alkylation of one or more amide bonds within the bicyclic peptide ligand; replacement of one or more peptide bonds with a surrogate bond; peptide backbone length modification; substitution of the hydrogen on the alpha-carbon of one or more amino acid residues with another chemical group; modification of amino acids such as cysteine, lysine, glutamate / aspartate and 30 tyrosine with suitable amine, thiol, carboxylic acid and phenol-reactive reagents so as to functionalise said amino acids; and introduction or replacement of amino acids that

[0126] 67

[0127] introduce orthogonal reactivities that are suitable for functionalisation, for example azide or alkyne-group bearing amino acids that allow functionalisation with alkyne or azide- bearing moieties, respectively. In one embodiment, the modified derivative comprises an N-terminal and / or C- 5 terminal modification. In a further embodiment, wherein the modified derivative comprises an N-terminal modification using suitable amino-reactive chemistry, and / or C-terminal modification using suitable carboxy-reactive chemistry. In a further embodiment, said N- terminal or C-terminal modification comprises addition of an effector group, including but not limited to a cytotoxic agent, a radiochelator or a chromophore. 10 In a further embodiment, the modified derivative comprises an N-terminal modification. In a further embodiment, the N-terminal modification comprises an N- terminal acetyl group. In this embodiment, the N-terminal residue is capped with acetic anhydride or other appropriate reagents during peptide synthesis leading to a molecule which is N-terminally acetylated. This embodiment provides the advantage of removing a 15 potential recognition point for aminopeptidases and avoids the potential for degradation of the bicyclic peptide. In an alternative embodiment, the N-terminal modification comprises the addition of a molecular spacer group which facilitates the conjugation of effector groups and retention of potency of the bicyclic peptide to its target. 20 In a further embodiment, the modified derivative comprises a C-terminal modification. In a further embodiment, the C-terminal modification comprises an amide group. In this embodiment, the C-terminal residue is synthesized as an amide during peptide synthesis leading to a molecule which is C-terminally amidated. This embodiment provides the advantage of removing a potential recognition point for carboxypeptidase and 25 reduces the potential for proteolytic degradation of the bicyclic peptide. In one embodiment, the modified derivative comprises replacement of one or more amino acid residues with one or more non-natural amino acid residues. In this embodiment, non-natural amino acids may be selected having isosteric / isoelectronic side chains which are neither recognised by degradative proteases nor have any adverse effect 30 upon target potency.

[0128] 68

[0129] Alternatively, non-natural amino acids may be used having constrained amino acid side chains, such that proteolytic hydrolysis of the nearby peptide bond is conformationally and sterically impeded. In particular, these concern proline analogues, bulky sidechains, Cα-disubstituted derivatives (for example, aminoisobutyric acid, Aib), and cyclo amino 5 acids, a simple derivative being amino-cyclopropylcarboxylic acid. In one embodiment, the modified derivative comprises the addition of a spacer group. In a further embodiment, the modified derivative comprises the addition of a spacer group to the N-terminal cysteine and / or the C-terminal cysteine. In one embodiment, the modified derivative comprises replacement of one or more 10 oxidation sensitive amino acid residues with one or more oxidation resistant amino acid residues. In a further embodiment, the modified derivative comprises replacement of a tryptophan residue with a naphthylalanine or alanine residue. This embodiment provides the advantage of improving the pharmaceutical stability profile of the resultant bicyclic peptide ligand. 15 In one embodiment, the modified derivative comprises replacement of one or more charged amino acid residues with one or more hydrophobic amino acid residues. In an alternative embodiment, the modified derivative comprises replacement of one or more hydrophobic amino acid residues with one or more charged amino acid residues. The correct balance of charged versus hydrophobic amino acid residues is an important 20 characteristic of the bicyclic peptide ligands. For example, hydrophobic amino acid residues influence the degree of plasma protein binding and thus the concentration of the free available fraction in plasma, while charged amino acid residues (in particular arginine) may influence the interaction of the peptide with the phospholipid membranes on cell surfaces. The two in combination may influence half-life, volume of distribution and 25 exposure of the peptide drug, and can be tailored according to the clinical endpoint. In addition, the correct combination and number of charged versus hydrophobic amino acid residues may reduce irritation at the injection site (if the peptide drug has been administered subcutaneously). In one embodiment, the modified derivative comprises replacement of one or more 30 L-amino acid residues with one or more D-amino acid residues. This embodiment is believed to increase proteolytic stability by steric hindrance and by a propensity of D-

[0130] 69

[0131] amino acids to stabilise β-turn conformations (Tugyi et al. (2005) PNAS, 102(2), 413– 418). In one embodiment, the modified derivative comprises removal of any amino acid residues and substitution with alanines, such as D-alanines. This embodiment provides the 5 advantage of identifying key binding residues and removing potential proteolytic attack site(s). It should be noted that each of the above-mentioned modifications serve to deliberately improve the potency or stability of the peptide. Further potency improvements based on modifications may be achieved through the following mechanisms: 10 - Incorporating hydrophobic moieties that exploit the hydrophobic effect and lead to lower off rates, such that higher affinities are achieved; - Incorporating charged groups that exploit long-range ionic interactions, leading to faster on rates and to higher affinities (see for example Schreiber et al., Rapid, electrostatically assisted association of proteins (1996), Nature Struct. Biol. 3, 427-31); and 15 - Incorporating additional constraint into the peptide, by for example constraining side chains of amino acids correctly such that loss in entropy is minimal upon target binding, constraining the torsional angles of the backbone such that loss in entropy is minimal upon target binding and introducing additional cyclisations in the molecule for identical reasons. (for reviews see Gentilucci et al., Curr. Pharmaceutical Design, (2010), 20 16, 3185-203, and Nestor et al., Curr. Medicinal Chem (2009), 16, 4399-418). In some embodiments, the Nectin-4 targeted therapeutic is an antibody drug conjugate. Antibody drug conjugates comprise an antibody which specifically binds to a target ligand (i.e. Nectin-4 in the case of the present invention) and a cytotoxic agent, typically wherein the antibody and the cytotoxic agent are connected by a linker (e.g. a 25 linker which is susceptible to proteolytic cleavage). A large number of Nectin-4 targeted ADCs are in development. These include 9MW2821 (Mabwell (Shanghai) Bioscience), ADC2204 (Hangzhou Adcoris BioPharma Co., Ltd; Lunan Pharmaceutical Group Co.Ltd), ADRX-0706 (Adcentrx Therapeutics), Anwita Biosciences anti-Nectin-4-ATI020 ADC (Anwita Biosciences), Araris Biotech 30 Nectin-4 ADC (Araris Biotech AG), BA3361 (Himalaya Therapeutics; BioAtla Inc), BAT8007 (Bio-Thera Solutions Ltd), CAT-13 (Catalent Inc), enfortumab vedotin (Astellas

[0132] 70

[0133] Pharma Inc; Pfizer Inc; Seagen Inc.), ETx-22 (Eli Lilly and Company; Loxo Oncology, Inc.), ETX-ATACs (Emergence Therapeutics AG; Heidelberg Pharma; Eli Lilly and Company; Loxo Oncology, Inc.; Mablink), HLX44 (Shanghai Henlius Biotech, Inc.), Innate Pharma Nectin-4 ADC / IPH45 (Innate Pharma), JS114 (Shanghai Junshi Bioscience 5 Co., Ltd), LY4052031 (Eli Lilly and Company), Novarock Biotherapeutics Nectin 4 ADC (Novarock Biotherapeutics; CSPC Pharmaceutical Group Limited), NTX-1105 (Nectin Therapeutics), OBI-904 (OBI Pharma), SHR-A2102 (Jiangsu HengRui Pharmaceutical Co., Ltd; Shanghai Hengrui Pharmaceutical Co., Ltd.) or SYS6002 (CSPC Megalith Biopharmaceutical; Corbus Pharmaceuticals Inc) 10 In some embodiments, the antibody drug conjugate is 9MW2821, ADC2204, ADRX-0706, Anwita Biosciences anti-Nectin-4-ATI020 ADC, Araris Biotech Nectin-4 ADC, BA3361, BAT8007, CAT-13, enfortumab vedotin, ETx-22, ETX-ATACs, HLX44, Innate Pharma Nectin-4 ADC / IPH45, JS114, LY4052031, Novarock Biotherapeutics Nectin 4 ADC, NTX-1105, OBI-904, SHR-A2102 or SYS6002. 15 In one embodiment, the ADC is CRB-701 / SYS6002. This ADC is an MMAE- conjugated ADC with a valine-citrulline cleavable linker. Optionally, CRB-701 / SYS6002 is administered at a dose of 3.6 mg / kg. Optionally, CRB-701 / SYS6002 is administered at a dose of 4.5 mg / kg. Optionally, CRB-701 / SYS6002 is administered once every three weeks. 20 In one embodiment, the ADC is 9MW2821. This ADC is an MMAE-conjugated ADC with a valine-citrulline cleavable linker. Optionally, 9MW2821 is administered at a dose of 1.25 mg / kg. Optionally, 9MW2821 is administered at a dose of 1.5 mg / kg. Optionally, 9MW2821 is administered on days 1, 8 and 15 of a 28-day cycle. In one embodiment, the ADC is LY4101174 / ETx-22. This ADC is a topo-1 25 inhibitor (Exatecan) conjugated ADC with a maleimide-beta glucuronide poly-sarcosine. Optionally, LY4101174 / ETx-22 is administered once every two weeks, or once every three weeks. In one embodiment, the ADC is ADRX-0706. This ADC is a tubulin inhibitor (AP052) conjugated ADC with a cleavable linker. 30 In one embodiment, the ADC is BAT8007. This ADC is a topo-1 inhibitor (Exatecan) conjugated ADC with a cleavable linker.

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[0135] In one embodiment, the ADC is IPH45. This ADC is a topo-1 inhibitor (Exatecan) conjugated ADC with a cleavable linker. In one embodiment, the ADC is LY4052031. This ADC is a topo-1 inhibitor (Exatecan) conjugated ADC with a cleavable linker. 5 In one embodiment, the ADC is enfortumab vedotin (EV). This ADC is an MMAE conjugated ADC with a valine-citrulline cleavable linker and is licensed in the treatment of metastatic urothelial carcinoma (mUC). In one embodiment, EV is administered intravenously on days 1, 8 and 15 of a 28-day treatment cycle at a dose of 1.25 mg / kg. In one embodiment, the Nectin-4 targeted therapeutic is a radioligand. A 10 radioligand comprises a ligand component that specifically binds to a target on the surface of a cell (i.e. Nectin-4 in the context of the present invention) and a radioactive isotope. A radioligand thus allows the targeted administration of a radioactive isotope to a cancer cell. The component that specifically binds to the target can be any targeting compound, for example an antibody or a fragment thereof that binds specifically to Nectin-4, or a Bicycle 15 molecule specific for Nectin-4. Radioisotopes typically used in radioligands include Y-90, H-3, C-11, Lu-177, Ac-225, Ra-223, In-111, I-131 and I-125. In one embodiment, the Nectin-4 targeted therapeutic is a T-cell engager. A T-cell engager is a bi-specific molecule such as a monoclonal antibody or a Bicycle TICA (e.g. BT7480) that can direct a patient’s immune system, more specifically cytotoxic T-cells, 20 against cancer cells. T-cell engagers comprise two separate binding domains (for example single-chain variable fragments (scFvs)). One of the binding domains binds specifically to a component on the surface of a cytotoxic immune cell such as a T-cell, for example the CD3 receptor, and the other binding domain binds specifically to an antigen on the surface of a tumor cell. Thus, a T-cell engager specific for Nectin-4 comprises a binding domain 25 that binds specifically to Nectin-4 on the surface of a tumor cell, thereby recruiting a T-cell to the cancer cell and allowing the T-cell to exert cytotoxic activity on the tumor cell. In one embodiment, the Nectin-4 targeted therapeutic is a cell-therapy. In one embodiment, the Nectin-4 targeted therapeutic is a CAR-T cell which comprises a chimeric antigen receptor (CAR) specific for Nectin-4. In one embodiment, the Nectin-4 30 targeted therapeutic is a T cell which comprises an engineered T cell receptor specific for

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[0137] Nectin-4. In one embodiment, the Nectin-4 targeted therapeutic is an NK cell which comprises a CAR specific for Nectin-4. EXEMPLIFICATION 5 Example 1. Assessment of patients with / without a Nectin-4 amplification and response to a Nectin-4 targeted therapeutic Materials and methods FISH 10 The NECTIN4 fluorescence in situ hybridization (FISH) probe was purchased from Empire Genomics (Catalog No. NECTIN4-20-GR, Empire Genomics, Buffalo, NY). The probe is designed to specifically target and bind to the NECTIN4 gene (NCBI Gene ID: 81607). The probe consisted of a fluorescently labeled DNA probe that specifically binds to the NECTIN4 gene. All hybridizations were performed in an accredited specialized 15 laboratory for clinical molecular pathology (accredited according to DIN EN ISO / IEC 17020) using a standard protocol. The slides were analyzed using a fluorescence microscope equipped with appropriate filter sets to detect the fluorescence signal from NECTIN4 and CEN1 probes. Representative tumor areas for formal analysis were chosen by an experienced board- 20 certified pathologist (ME; blinded to patient outcomes), and at least 50 nonoverlapping nuclei per sample were assessed. Green (NECTIN4) and red (CEN1) signals were manually quantified. The NECTIN4 / CEN1 ratio was calculated, and a ratio of ≥2.0 qualified tumors as NECTIN4-amplified. Tumors with ratio values <2.0 were considered nonamplified. Furthermore, gene copy changes (≥4 NECTIN4 gene copies per nucleus) 25 without qualifying for an amplification (NECTIN4 / CEN1 ratio below <2.0) were considered as polysome tumors, and polysomy status was correlated with response to BT8009. Tumors with a ratio <2.0 and NECTIN4 copy number ≥6 were polysomic, while those with a copy number between 3-6 had a gain. 30 Immunohistochemistry (IHC) IHC was performed as described in WO 2022 / 038158.

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[0139] Results A total of 46 patients with breast cancer / TNBC (n=23) or lung cancer / NSCLC (n=19) enrolled in the BT8009-100 trial were screened for whether or not they had a 5 Nectin-4 amplification using the FISH assay described herein (a total of 38 breast cancer patients (32 TNBC, 6 HR+ / HER2-negative), median 6 prior lines of therapy were enrolled in the BT8009-100 trial and treated with BT8009, 23 of whom were tested for Nectin-4 amplification (19 TNBC, 4 non-TNBC – HR+ / HER2-negative)). 1 breast / TNBC sample and 3 lung cancer / NSCLC samples failed QC and were not 10 included in analysis for Nectin-4 amplification vs. non-amplification. 1 breast / TNBC patient and 4 lung cancer / NSCLC patients (including 1 patient with Nectin-4 amplification) were response non-evaluable and were not included in response calculations. Approximately one third of breast / TNBC and lung cancer / NSCLC patients on 15 BT8009-100 have Nectin-4 amplifications (Figure 2A). This corresponds well to data gathered from other TNBC samples not on BT8009-100 (Figure 2B) and tested with the same FISH assay. Here a Nectin-4 amplification is classified as CN ratio ≥2. Nectin-4 amplifications may predict a higher response rate in breast / TNBC and lung cancer / NSCLC patients. In response evaluable patients (22 breast / TNBC patients and 20 15 lung cancer / NSCLC patients), patients with a Nectin-4 amplification had a higher PR rate (confirmed PR and unconfirmed PR) than the overall cohorts (Figure 3A). Among the 7 patients with Nectin-4 amplified breast cancer (1 HR+ / HER2-negative, 6 TNBC), 4 patients (3 TNBC, 1 HR+ / HER2-negative) achieved a PR. All patients identified as having a Nectin-4 amplification had a partial response or stable disease (Figure 3B). 25 Patients with amplifications are more likely to respond to treatment with the Nectin-4 targeted therapeutic BT8009 (Figures 4-7). As of a later data cut, prolonged responses were seen in breast cancer / TNBC patients with Nectin-4 amplification who responded. One TNBC patient with Nectin-4 polysomy (Nectin-4 copy number ≥6, ratio Nectin-4:CEN1 <2.0) had a confirmed PR and 30 was the only responder among 16 patients who were not Nectin-4 amplified. Of the TNBC patients with Nectin-4 amplifications, three had a PR and three had SD. All three patients

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[0141] with TNBC and Nectin-4 amplification who achieved a PR had previously received sacituzumab govitecan treatment. Of the eight breast cancer patients with a Nectin-4 amplification and / or polysomy, the ORR was 62.5% (5 / 8). Among TNBC patients the ORR was 57.1% (4 / 7). Duration and response and change from baseline in tumor size in 5 efficacy evaluable patients with breast cancer who were treated with BT8009 and tested for Nectin-4 amplification are shown in Figure 12A. Overall response rates for the breast cancer cohort are shown in Figure 12B. Nectin-4 amplification status is a better predictor of response to a Nectin-4 targeted therapeutic than measuring Nectin-4 protein expression by IHC in breast cancer / TNBC and 10 lung cancer / NSCLC. Although there is a higher frequency of Nectin-4 protein expression (H-score ≥100) for both breast cancer / TNBC and lung cancer / NSCLC, response data shows that Nectin-4 amplifications predict a higher response rate in breast / TNBC and lung cancer / NSCLC compared to measuring Nectin-4 protein expression (Figure 7). Of the 37 response evaluable patients with Nectin-4 amplification status, all of the 15 patients who had a partial response had a Nectin-4 copy number ≥4, and all patients with a Nectin-4 amplification had SD or PR (Figure 8). Surprisingly, patients with and without Nectin-4 amplifications have a range of Nectin-4 protein expression levels. Breast / TNBC and lung / NSCLC patients with low levels of Nectin-4 expression (H-score <100) who have tumors with Nectin-4 amplification 20 had stable disease (square) or a partial response (circle) (Figure 9). Partial responses are not observed in patients with lower Nectin-4 protein expression levels who do not have a Nectin-4 amplification. This suggests that there may be a sub-set of cancer patients who do not have high Nectin-4 protein expression who may nevertheless benefit from treatment with a Nectin-4 targeted therapeutic – these patients can be identified on the basis of 25 having a Nectin-4 copy number of 4 or more according to the methods of the invention. Figure 10 provides a similar observation – it indicates the Nectin-4 protein expression levels for the patients of Figure 5. Nectin-4 expression (H-score) is ≥100. Nectin-4 amplification status is shown to be a far superior indication of therapeutic response compared to Nectin-4 expression. 30 A total of 76 patients with urothelial cancer enrolled in the BT8009-100 trial were screened for whether or not they had a Nectin-4 amplification using the FISH assay

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[0143] described herein. 5 samples failed QC and were not included in analysis for Nectin-4 amplification vs non-amplification. 13 patients did not have histology for muscle invasive tissue. 52 / 58 patients were response evaluable. 24 / 58 patients on BT8009-100 have Nectin-4 amplifications. 5 Nectin-4 amplifications may predict a higher response rate in urothelial cancer. In response evaluable patients, patients with a Nectin-4 amplification had a higher ORR than patients who did not have a Nectin-4 amplification (Figure 11A). Overall patients with a Nectin-4 amplification showed a greater degree of tumor shrinkage compared to patients who did not have a Nectin-4 amplification (Figure 11B). 10 Example 2. Optimisation of thresholds to maximise patient benefit for treatment with a Nectin-4 targeted therapeutic Biomarker thresholds for measuring Nectin-4 copy number, copy number ratio and 15 protein expression were investigated. FISH, NGS and immunohistochemistry (IHC) analyses were carried out on samples from patients in the BT8009-100 clinical trial to evaluate biomarker thresholds, in order to better understand the overall response rate observed at different thresholds, the thresholds with the highest sensitivity and specificity (ROC) and thresholds that identify the most responders, and that do not exclude 20 responders. The goal was to identify thresholds which provide the maximum patient benefit. The suitability of a threshold can be measured in various ways. Sensitivity refers to how well a test identifies true positives, i.e. how well a biomarker cutoff correctly identifies patients that are responders. Specificity refers to how well a test identifies true25 negatives, i.e. how well a biomarker cutoff correctly identifies patients that are non- responders. A Receiver Operating Characteristic (ROC) curve plots the true positive frequency (sensitivity) against false positive frequency (1-specificity) at all individual data points. Younden’s J is calculated for all possible thresholds as J = sensitivity + specificity -1. The Younden Index (maximum J) on the ROC curve identifies the optimal biomarker 30 threshold where the combined false positive and false negative rate are at their lowest. Various thresholds were investigated:

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[0145] FISH - Nectin-4 copy number ratio (Nectin-4 / CEN1 ratio) ≥2; - Nectin-4 copy number ratio (Nectin-4 / CEN1 ratio) ≥2 or Nectin-4 copy number ≥6; and 5 - ROC identified cutoffs (Nectin-4 copy number ratio and Nectin-4 copy number). NGS - SDHC copy number ≥6; - SDHC copy number ≥5 relative to genome wide ploidy (threshold used in ERBB2 (HER2) companion diagnostic); and 10 - ROC identified cutoff (SDHC copy number irrespective of genome wide ploidy). IHC - Nectin-4 membrane TPS >1; and - ROC identified cutoff (Nectin-4 membrane H-score and TPS). As shown in Figure 13A-B, in TNBC / breast cancer, using Nectin-4 membrane H 15 score ≥158 as a cutoff identifies an ORR to treatment with BT8009 of 44%, compared to 18% unselected. Membrane TPS was found to be a poor predictor of response to treatment with BT8009. Using a Nectin-4 copy number ratio of ≥1.93 increased the ORR to 57%, and using a Nectin-4 copy number of ≥ 5.13 increased the ORR to 50% in selected patients (the copy number ratio cutoff of 1.93 identified the same patients as using a copy number 20 ratio ≥2) (Figure 13C-D). In a TNBC / breast cancer cohort, all biomarker assays revealed at least one cutoff that increased ORR compared to unselected patients. Using a threshold of Nectin-4 copy number ratio ≥ 2 or Nectin-4 copy number ≥6 in a FISH assay identified the highest selected ORR of 63% (see Figure 14). This threshold, which identifies patients with 25 Nectin-4 amplification and patients with polysomy is the only method that identified all responders in the cohort investigated (ROC cutoffs for IHC and NGS identified many but not all responders). In a limited EV-naïve MIBC cohort (administered BT80095 mg / m2weekly), FISH and NGS cutoffs increased ORR compared to unselected patients. Using a threshold of 30 Nectin-4 copy number ratio ≥ 2 or Nectin-4 copy number ≥6 in a FISH assay identified an ORR of 50% (see Figure 15). Using an ROC cutoff for Nectin-4 copy number of ≥5.6 in a

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[0147] FISH assay identified an ORR of 55%. An ROC cutoff for Nectin-4 copy number ratio ≥1.6 in a FISH assay identified the same patients as the Nectin-4 copy number ratio ≥2 or copy number ratio ≥6 threshold. The threshold of Nectin-4 copy number ≥2 using FISH identifies 56% of responders, whilst including patients with Nectin-4 copy number ≥6 5 identifies 67% of responders. In an NGS assay, SDHC copy number ≥6 copies (relative to ploidy – threshold of 7 in triploid, 8 for tetraploid etc.) identified an ORR of 67%, SDHC copy number of ≥5 (relative to genome ploidy – threshold of 6 in triploid, 7 in tetraploid etc.) identified an ORR of 80%. The ROC cutoff of SDHC copy number >7 irrespective of genome wide ploidy identified 63% of responders and an ORR of 83% (see Figure 15). 10 In the limited data for lung / NSCLC, using a Nectin-4 copy number ratio of ≥2 in a FISH assay identified an ORR of 40%. The same ORR was identified using an ROC Nectin-4 copy number cutoff of ≥4.8. An ROC identified Nectin-4 copy number ratio of ≥2.2 in the FISH assay identifies the highest ORR of 67%, and identified 100% of responders (see Figure 16). 15 In summary, in these limited data sets, FISH, IHC, and FMI all identify potential biomarker cutoffs that increase ORR over unselected in at least one indication, and may help to maximize patient benefit. In aggregate, based on current data, FISH with alternative cut points may provide the best unified approach to patient selection across tumor types investigated. 20 Example 3. Analysis of Nectin-4 copy number gain / amplification across various cancers The frequency of Nectin-4 amplification status across a range of cancer types within the 25 TCGA database was analysed. Raw data of gene level copy number data (Affymetrix single nucleotide polymorphism [SNP] 6.0 array) from the Absolute pipeline was downloaded from the Genomic Data Commons Data Portal. The frequency of NECTIN4 amplification was determined by 30 NECTIN4 copy number divided by mode of all genes’ copy number around the chromosome 1 centromere (p21.1 to q21.3) ≥ 2, or a NECTIN4 copy number ≥ 6.

[0148] 78 Triple Negative Breast cancer (TNBC) was selected by filtering Breast Cancer (BRCA) patients with ER, PR, and HER2 status based on PMID23000897. 5 Amplification frequency (%) for the different cancer types are shown in Figure 17. This confirms that the Nectin-4 gene is frequently amplified in a range of different cancers. Notably, TNBC, HR+ / HER2- breast cancer and other breast cancers were all found to have a high occurrence of Nectin-4 amplification (copy number ratio ≥ 2 or copy number ≥ 6).

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Claims

1. CLAIMS 1. A method of identifying or selecting a cancer patient for treatment with a Nectin-4 targeted therapeutic comprising: i) determining Nectin-4 copy number in a tumor of the patient and 5 ii) identifying or selecting the patient for treatment with a Nectin-4 targeted therapeutic if the Nectin-4 copy number in the tumor of the patient is 4 or more and / or if the Nectin-4 copy number ratio in the tumor of the patient is 2 or more.

2. A method comprising administering to a patient a Nectin-4 targeted therapeutic, 10 wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more.

3. A method comprising: i) identifying or selecting a patient having a Nectin-4 copy number in a tumor of 4 or 15 more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic.

4. A method comprising: i) determining Nectin-4 copy number in a tumor of a patient; 20 ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic.

5. A method comprising: 25 i) detecting a Nectin-4 copy number of 4 or more in a tumor of a patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of a patient; and ii) administering to the patient a Nectin-4 targeted therapeutic.

6. A method comprising: 30 i) determining Nectin-4 copy number in a tumor of the patient; and80ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more. 5 7. The method of any one of claims 1 to 6, wherein the patient identified or selected has a cancer that is more likely to be suppressed or treated with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. 10 8. The method of any one or claims 1 to 7, wherein the patient identified or selected has a cancer that is more likely to maintain its volume or reduce in volume following administration of the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. 15 9. The method of any one of claims 1 to 8, wherein the patient identified or selected is more likely to have an increased survival time following initiation of treatment with the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor, and / or 20 wherein the patient identified or selected for treatment with a Nectin-4 targeted therapeutic is more likely to have an increased progression free survival time (PFS) following initiation of treatment with the Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tumor or a Nectin-4 copy number ratio of 2 or more in a tumor. 25 10. A method of suppressing or treating cancer in a patient comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. 30 11. A method of suppressing or treating cancer in a patient, comprising:81i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic. 5 12. A method of suppressing or treating cancer in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 10 13. A method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 15 14. A method of suppressing or treating cancer in a patient comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 20 copy number ratio of 2 or more in the tumor.

15. The method of any one of claims 10 to 14, wherein the volume of a solid tumor in the patient is maintained or reduced following administration of the Nectin-4 targeted therapeutic. 25 16. A method for maintaining or reducing the volume of a solid tumor in a patient comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more. 308217. A method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more; and 5 ii) administering to the patient a Nectin-4 targeted therapeutic.

18. A method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a 10 Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic.

19. A method for maintaining or reducing the volume of a solid tumor in a patient, comprising: 15 i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 20 20. A method for maintaining or reducing the volume of a solid tumor in a patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 25 copy number ratio of 2 or more in the tumor.

21. The method of any one of claims 15 to 20, wherein the sum of the longest diameters (SLD) of up to five tumors in the patient increases by less than 20% when compared to a baseline measurement following administration of the Nectin-4 targeted 30 therapeutic, optionally wherein the SLD increases by less than 10% when compared to a baseline measurement, optionally wherein there is SLD is unchanged when compared to a83baseline measurement, optionally wherein the SLD decreases by up to 10% when compared to a baseline measurement, optionally wherein the SLD decreases by up to 20% when compared to a baseline measurement, optionally wherein the SLD decreases by up to 30% when compared to a baseline measurement, and / or wherein the SLD increases by less 5 than 5 mm.

22. The method of any one of claims 15 to 21, wherein the SLD decreases by 30% or more when compared to a baseline measurement following administration of the Nectin-4 targeted therapeutic, optionally wherein the SLD decreases by 40% or more when 10 compared to a baseline measurement, optionally wherein the SLD decreases by 50% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 60% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 70% or more when compared to a baseline measurement, optionally wherein the SLD decreases by 80% or more when compared to a baseline measurement, optionally 15 wherein the SLD decreases by 90% or more when compared to a baseline measurement.

23. The method of any one of claims 15 to 22, wherein administration of the Nectin-4 targeted therapeutic results in disappearance of the tumor. 20 24. The method of any one of claims 15 to 22, wherein the volume of the tumor is maintained or reduced for at least 6 weeks following administration of the Nectin-4 targeted therapeutic, optionally wherein the volume of the tumor is maintained or reduced for at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, 25 at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months following administration of the Nectin-4 targeted therapeutic.

25. A method for increasing survival time and / or the progression free survival time of a 30 cancer patient, comprising administering to the patient a Nectin-4 targeted therapeutic, wherein the patient has been selected for having a Nectin-4 copy number in a tumor of 4 or more and / or a Nectin-4 copy number ratio in a tumor of 2 or more.8426. A method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) selecting a patient having a Nectin-4 copy number in a tumor of 4 or more and / or a 5 Nectin-4 copy number ratio in a tumor of 2 or more; and ii) administering to the patient a Nectin-4 targeted therapeutic.

27. A method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: 10 i) detecting a Nectin-4 copy number of 4 or more in a tumor of the patient and / or a Nectin-4 copy number ratio of 2 or more in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic.

28. A method for increasing survival time and / or the progression free survival time of a 15 cancer patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; ii) selecting the patient having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. 20 29. A method for increasing survival time and / or the progression free survival time of a cancer patient, comprising: i) determining Nectin-4 copy number in a tumor of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic if the patient is 25 identified as having a Nectin-4 copy number of 4 or more in the tumor and / or a Nectin-4 copy number ratio of 2 or more in the tumor.

30. The method of claim any one of claims 25 to 29, wherein survival time and / or progression free survival time is increased compared to a patient who does not have a 30 Nectin-4 copy number of 4 or more in the tumor.8531. The method of claim 30, wherein survival time and / or progression free survival time of the patient is increased by at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at 5 least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months or at least 24 months compared to a patient who does not have a Nectin- 4 copy number of 4 or more in the tumor 32. The method of any one of claims 1 to 31, wherein the Nectin-4 copy number is 10 determined by measuring the chromosome 1 copy number, optionally the copy number of the 1q arm of chromosome 1, optionally the 1q23.3 copy number in the tumor.

33. The method of any one of claims 1 to 32, wherein the Nectin-4 copy number is determined by measuring the Nectin-4, SDHC and / or DDR2 DNA copy number in the 15 tumor.

34. The method of any one of claims 1 to 33, wherein determining Nectin-4 copy number in the tumor comprises determining Nectin-4 copy number in a tumor tissue sample. 20 35. The method of any one of claims 1 to 34, wherein determining Nectin-4 copy number in the tumor comprises determining Nectin-4 copy number in circulating tumor cells (CTCs). 25 36. The method of any one of claims 1 to 35, wherein determining Nectin-4 copy number in the tumor comprises determining Nectin-4 copy number in tumor-derived cell- free DNA in a non-tumor sample obtained from the patient.

37. The method of claim 36, wherein the sample is a blood sample, wherein the tumor- 30 derived cell-free DNA is circulating tumor DNA (ctDNA).

38. The method of claim 36, wherein the sample is a urine sample.8639. The method of any one of claims 1 to 38, wherein the Nectin-4 copy number is determined using fluorescence in-situ hybridisation (FISH), chromogenic situ hybridisation (CISH) or silver enhanced in situ hybridisation (SISH). 5 40. The method of any one of claims 1 to 38, wherein the Nectin-4 copy number is determined using a SNP array or by array CGH.

41. The method of any one of claims 1 to 38, wherein the Nectin-4 copy number is determined using next-generation sequencing (NGS) or Multiplex Ligation-dependent 10 Probe Amplification (MLPA).

42. The method of any one of claims 1 to 41, wherein the patient has a duplication of the 1q23.3 chromosomal segment. 15 43. The method of any one of claims 1 to 42, wherein the patient is identified and / or selected if the patient has a Nectin-4 copy number ratio of 2 or more in said tumor.

44. The method of any one of claims 1 to 41, wherein the tumor has chromosome 1 polysomy. 20 45. The method of any one of claims 1 to 44, wherein the tumor is not associated with elevated Nectin-4 protein and / or mRNA expression.

46. The method of any one of claims 1 to 45, wherein the method does not comprise 25 determining the level of Nectin-4 protein and / or mRNA expression in the tumor.

47. The method of any one of claims 1 to 46, wherein the cancer is urothelial cancer, uterine cancer, endometrial cancer, ovarian cancer, gastrointestinal cancer, cervical cancer, head and neck cancer, pancreatic cancer, thyroid cancer, colorectal cancer, thymoma, 30 sarcoma, renal clear cell carcinoma (RCC), prostate cancer, stomach cancer, breast cancer, optionally TNBC, HR+ / HER2- breast cancer or HR+ / HER2-low breast cancer, or lung cancer, optionally NSCLC, optionally wherein the NSCLC is non-squamous NSCLC or wherein the NSCLC is squamous NSCLC.8748. The method of claim 47, wherein the cancer is breast cancer or lung cancer, optionally wherein the breast cancer is HR+ / HER2- breast cancer, HR+ / HER2-low breast cancer or TNBC, or the lung cancer is NSCLC, optionally wherein the NSCLC is non- squamous NSCLC or wherein the NSCLC is squamous NSCLC. 5 49. The method of any one of claims 1 to 48, wherein the Nectin-4 targeted therapeutic is a Bicycle drug conjugate® (BDC) or Bicycle TICA® specific for Nectin-4.

50. The method of any one of claims 1 to 49, wherein the Nectin-4 targeted therapeutic 10 is BT8009 or BT7480.

51. The method of claim 50, wherein the Nectin-4 targeted therapeutic is BT8009, wherein BT8009 is administered intravenously: (a) weekly at a dose of 5 mg / m2; or 15 (b) on days 1 and 8 of a 21-day treatment cycle at a dose of 6 mg / m252. The method of any one of claims 1 to 51, wherein the Nectin-4 targeted therapeutic is an antibody drug conjugate. 20 53. The method of claim 52, wherein the antibody drug conjugate is 9MW2821, ADC2204, ADRX-0706, Anwita Biosciences anti-Nectin-4-ATI020 ADC, Araris Biotech Nectin-4 ADC, BA3361, BAT8007, CAT-13, Enfortumab vedotin, ETx-22, ETX-ATACs, HLX44, Innate Pharma Nectin-4 ADC / IPH45, JS114, LY4052031, Novarock Biotherapeutics Nectin 4 ADC, NTX-1105, OBI-904, SHR-A2102 or SYS6002. 25 54. The method of claim 53, wherein the antibody drug conjugate is EV, wherein EV is administered intravenously on days 1,8 and 15 of a 28-day treatment cycle at a dose of 1.25 mg / kg.88

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