Method for identifying patients

Abstract

The present invention relates to methods 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 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 methods for treating cancer patients who have a Nectin-4 copy number in a tumor of 4 of more.

Description

[0001] METHOD FOR IDENTIFYING PATIENTS TECHNICAL FIELD OF THE INVENTION The present invention relates to methods for identifying or selecting cancer patients 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 amplification. BACKGROUND OF THE INVENTION Nectin-4 is overexpressed in a number of different cancers and can serve as a therapeutic target for various anticancer agents. Enfortumab vedotin (EV) is an example of an approved Nectin-4 targeted therapeutic. Others, including the Nectin-4 targeted Bicycle BT8009, are in clinical development. Durable responses may however only be achieved in a subset of patients. An object of the invention is to provide a biomarker that is predictive of clinical response to treatment with a Nectin-4 targeted therapeutic to allow selection of patients that are more likely to respond to a Nectin-4 targeted therapy. The inventors have identified that patients having a Nectin-4 amplification (defined herein as a Nectin-4 copy number ratio to a control gene of 2 or more and / or a Nectin-4 copy number of 4 or more) in a tumor have improved outcomes when treated with Nectin- 4 targeted therapeutics. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 shows that Nectin-4 amplification predicts EV response in metastatic urothelial cancer (mUC). (A and B) Nectin-4 FISH image (green signals 5 Nectin-4; red signals 5 centromere 1, 1,000x oil immersion) and (A) corresponding immunohistochemical Nectin- 4 staining on Nectin-4 nonamplified and (B) Nectin-4-amplified urothelial cancers. The grey dashed box demonstrates the two patient cases. (C) Membranous Nectin-4 expression is significantly associated with FISH-detected Nectin-4 amplification in our EV-treated UC cohort (mUC-EV). Statistical significance (***P < .001) was determined using the Mann- Whitney U test. (D) Sankey plot of Nectin-4 amplification status in the 27 matched primary (PRIM) and metastatic (MET) samples. (E) Evolution of membranous Nectin-4 expression during metastatic spread in the eight Nectin-4-amplified PRIMs. (F) BOR on the mUC-EV cohort on the basis of Nectin-4 copy number status; BOR was available for n=65 patients. Nectin-4 amplification status is associated with both prolonged (G) PFS and (H) OS since EV therapy start compared with nonamplified tumors. (I) Nectin-4 amplification is not associated with OS in non–EV-treated mUC. The log-rank P value is shown. The dashed lines demonstrate median PFS and OS when reached. BOR, best overall response; EV, enfortumab vedotin; FISH, fluorescence in situ hybridization; OS, overall survival; MET, metastatic; PFS, progression-free survival. FIGURE 2 shows multivariable Cox Regression analyses in the multicentre Enfortumab Vedotin cohort. Significant P values are highlighted in bold. Abbreviations: CNV, copy number variation; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; PFS, progression-free survival. FIGURE 3 shows that Nectin-4 amplifications occur frequently across solid tumors. (A) The frequency of Nectin-4 amplifications (called by GISTIC 2.0) are depicted for 32 studies consisting of 10,712 samples / patients, with BLCA presenting the highest prevalence (17%). Positive correlation was observed between Nectin-4 copy number variation and mRNA level in both (B) Pan-Cancer Study and (C) TCGA-BLCA. Standard TCGA study abbreviations were used. BLCA, Bladder Urothelial Carcinoma; TCGA, The Cancer Genome Atlas. FIGURE 4 shows the baseline characteristics of the mUC-EV cohort. Significant p values are highlighted in bold. Abbreviations: ECOG, Eastern Cooperative Oncology Group; mUC-EV, metastatic urothelial cancer-enfortumab vedotin.aPearson’s chi-squared test; Wilcoxon rank-sum test; Fisher’s exact test. FIGURE 5 shows the baseline characteristics of (A) the mUC-Non-EV cohort and (B) the TCGA-BCLA cohort. Significant P values are highlighted in bold. Abbreviation: mUC- Non-EV, metastatic urothelial cancer-non enfortumab vedotin. TCGA-BCLA, The Cancer Genome Atlas - Bladder Cancer.aPearson’s chi-squared test; Wilcoxon rank-sum test. FIGURE 6 shows an illustration of copy number variation profiles derived by Illumina SNP arrays. Upper panel: Nectin-4 nonamplified tumor profile; lower panel: Nectin-4 amplified tumor profile. The Nectin-4 gene location on Chr.1 shows higher copy numbers in the amplified tumors. Chr.1, chromosome 1; SNP, single nucleotide polymorphisms. FIGURE 7 shows PFS (A) and OS (B) upon initiation of EV treatment stratified by presence of Nectin-4 gene amplification versus high membranous Nectin-4 protein expression without Nectin-4 gene amplification. EV, enfortumab vedotin; OS, overall survival; PFS, progression-free. survival. FIGURE 8 shows A) Disease-specific survival of n = 393 patients of the TCGA-BLCA cohort stratified by copy number alterations of Nectin-4 (data were missing for 14 patients). (B) Overall survival of n = 407 patients of the TCGA-BLCA cohort stratified by copy number alterations of Nectin-4. TCGA-BLCA, The Cancer Genome Atlas-bladder cancer. FIGURE 9 shows (A) Nectin-4 mRNA expression (log2 normalized RSEM values) in TCGA-BRCA cohort stratified by Nectin-4 copy number alterations (called by GISTIC 2.0). (B) Nectin-4 protein expression levels (Z-score scaled results from RPPA) in TCGA- BRCA cohort stratified by Nectin-4 copy number alterations (called by GISTIC 2.0). (C) Nectin-4 mRNA expression (log2 normalized RSEM values) in TCGA-LUAD cohort stratified by Nectin-4 copy number alterations (called by GISTIC 2.0). NS, not significant; RPPA, reverse-phase protein arrays; TCGA-BRCA, The Cancer Genome Atlas breast cancer; TCGALUAD; The Cancer Genome Atlas lung adenocarcinoma. FIGURE 10 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 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 11 shows that Nectin-4 amplifications occur relatively frequently in breast cancer / TNBC and lung cancer / NSCLC. Approximately one third of breast / TNBC and lung cancer / NSCLC patients in the BT8009-100 trial were identified as having Nectin-4 amplifications (Figure 11A). This corresponds closely with the frequency of Nectin-4 amplification observed in additional TNBC tumor samples (not part of the BT8009-100 cohort) (Figure 11B). FIGURE 12 shows that in a preliminary dataset, Nectin-4 gene amplifications may predict 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 12A). In the clinical dataset, all breast / TNBC and lung cancer / NSCLC patients with a Nectin-4 amplification (Ratio Nectin-4 copy number / CEN1 >=2.0) had stable disease (SD) or a partial response (PR) (Figure 12B). FIGURE 13 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 14 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 14A). Lung cancer / NSCLC (n=15): patients with Nectin-4 amplifications had an ORR of 40%, CBR of 80% and DCR of 100% (Figure 14B). FIGURE 15 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 15A). Lung cancer / NSCLC (Figure 15B) FIGURE 16 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 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 17 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. FIGURE 18 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 19 indicates the Nectin-4 protein expression levels for the patients of Figure 14. High Nectin-4 expression (H-score) is ^100. Top panel – breast / TNBC. Bottom panel – lung / NSCLC. FIGURE 20 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). 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 20A). Figure 20B shows a waterfall plot for EV naïve patients 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.

[0002] SUMMARY OF THE INVENTION In a first aspect, the present invention 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 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 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 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 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. In a sixth aspect, the present invention 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 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 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. 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. 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 in a tumor of 2 or more of the patient; and ii) administering to the patient a Nectin-4 targeted therapeutic. 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 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 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 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 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 in a tumor 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 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 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; 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: 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 and / or a Nectin-4 copy number ratio of 2 or more. In a seventeenth aspect, 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 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 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 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 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 / or a Nectin-4 copy number ratio of 2 in the tumor; and iii) administering to the patient a Nectin-4 targeted therapeutic. In a twenty-first aspect, 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 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 certain embodiments, the cancer is selected from urothelial cancer, bladder cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, lung adenocarcinoma or non–small cell lung cancer. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The inventors have surprisingly noted that in contrast to membranous Nectin-4 expression, Nectin-4 amplification is highly stable during metastatic spread and is predictive of enfortumab vedotin response in metastatic urothelial cancer (mUC), as reported in Klümper et al.2024. J Clin Oncol Apr 2024, as well as response to BT8009 in urothelial, breast and lung cancers (see Examples and Figures). Furthermore, the inventors have identified that a Nectin-4 amplification (defined herein as a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio (i.e. to a control gene) of 2 or more) in the tumor of a patient 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 urothelial cancer patients. The inventors have also identified that Nectin-4 amplifications occur frequently in other cancers, such as cholangiocarcinoma, hepatocellular carcinoma, breast cancer, lung adenocarcinoma and non–small cell lung cancer. The inventors have identified that whilst approximately 26% of metastatic urothelial carcinoma patients have Nectin-4 amplifications, Nectin-4 gene amplifications may predict a higher response rate to treatment with a Nectin-4 targeted therapeutic such as enfortumab vedotin (EV), and that 96% (27 of 28) of patients with Nectin-4 amplifications demonstrated objective responses to EV compared with only 32% (24 of 74) in the nonamplified subgroup (P < .001). Without wishing to be bound by theory, an increased Nectin-4 copy number may result in more stable long-term expression of Nectin-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 protein expression or Nectin-4 mRNA expression, particularly in urothelial cancer. Identifying and treating a patient with a Nectin-4 amplification As described herein, the inventors have identified that there is a particularly strong correlation between Nectin-4 copy number and / or copy number ratio, and the effectiveness of therapy with a Nectin-4 targeted therapeutic in metastatic urothelial carcinoma patients and in breast and lung cancer 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 urothelial carcinoma patients with tumors that have elevated levels of membrane 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. The inventors have also identified that Nectin-4 amplification is frequently observed in a number of other cancers. 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. The present invention provides methods 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 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 a tumor of the patient is 2 or more. As demonstrated in the present Examples, urothelial 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 / selected according to the 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 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 mroe. 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) administering to the patient a Nectin-4 targeted therapeutic. In a further one embodiment, the identification / selection methods of the invention may further comprise administering a Nectin-4 targeted therapeutic to the patient. The present invention thus 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 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 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 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 and / or a Nectin-4 copy number ratio of 2 or more. 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 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 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 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 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. 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 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 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; 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. "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 following administration of the Nectin-4 targeted therapeutic. 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 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 a corresponding treatment with a Nectin-4 targeted therapeutic. Administering a Nectin-4 targeted therapeutic to a patient (i.e. treating a patient) 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 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 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 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 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 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 ratio of 2 or more in the tumor. In further embodiments, a patient having 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 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. 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 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. 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 Nectin-4 copy number ratio 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: 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 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 / 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. 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 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%, 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 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. 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. 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 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, 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 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 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 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 ratio or 2 or more in 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. 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 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 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). 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 (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 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 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. 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 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 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 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 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 does not have a Nectin-4 copy number of 4 or more or a Nectin-4 copy number ratio of 2 or more. 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 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 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 with a Nectin-4 targeted therapeutic than a patient who does not have a Nectin-4 copy number of 4 or more in a tissue or a Nectin-4 copy number ratio of 2 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 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 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 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 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. 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 Nectin-4 copy number of 4 or more in a tumor of the patient and / or a 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 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. 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 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 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 more in a tumor, i.e. who receives corresponding treatment with a Nectin-4 targeted therapeutic. 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 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 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 urothelial cancer, bladder cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, lung adenocarcinoma or non–small cell lung cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is uterine cancer, endometrial cancer, ovarian cancer, gastrointestinal cancer, cervical cancer, head and neck cancer, 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 bladder cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is urothelial cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is lung cancer. In some embodiments, the cancer, solid tumor or advanced malignancy is breast 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. 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 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. Determining Nectin-4 copy number 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 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 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. 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 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 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 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 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 copy number of a gene or marker within chromosome 1, the 1q arm of chromosome 1, or 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. 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 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. Table 1 – list of genes found on chromosome 1 on the FoundationOne®CDx panel ^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^ ^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^ ^^^^^^^ ^ ^^" ^^ ^ ^^ ^^^$ #$^ ^^^^^ ^^ &1^1^^ !^^"######$^^$$^^#^^#$ ^^ ^#^$ ^^ ^ -)1^^-^ !^^"#####^^^#^#^One® 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 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 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 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 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; 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 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 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 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 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 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. The present invention also provides a method of suppressing or treating cancer 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; 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 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 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: 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 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 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 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. 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; 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 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. 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 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 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: 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. 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 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: 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 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 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 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 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 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 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 to 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- 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. 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 and / or if the SDHC copy number ratio in the tumor of the patient is 2 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 DDR2 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 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 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. 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. 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: 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 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. The present invention also provides a method comprising: i) identifying or 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. 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 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 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 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. 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. The present invention also provides a method of suppressing or treating cancer 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 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 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. 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 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. 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. 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. 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; 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. The present invention also provides methods of suppressing or treating cancer in a patient, 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 in the tumor and / or a DDR2 copy number ratio 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 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 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 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 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 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. The present invention also provides a method 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 and / or an SDHC copy number ratio 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 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. 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 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 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 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 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 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 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 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 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 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 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 a SDHC copy number of 4 or more in the tumor and / or an SDHC copy number ratio of 2 or more in the tumor. 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 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 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 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 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 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 and / or a Nectin-4 copy number ratio of 2 or more or more apply mutatis mutandis to the aspects of the invention described herein in which the copy number and / or copy number ratio of any one or more of the genes listed in Table 1, including SDHC and / or DDR2 is determined. The present invention is based on the observation that the Nectin-4 gene is frequently amplified in a number of cancers, including urothelial cancer, bladder cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, lung adenocarcinoma and non–small cell lung cancer. 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 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 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. 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 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 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 wider duplication event, for example tumor cells with aneuploidy e.g. chromosome 1 polysomy. The Nectin-4 copy number can be determined using standard techniques known to the skilled person for measuring copy number. 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- 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 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 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 (CISH or SISH) or fluorescence (FISH) miscroscopy, as appropriate). The skilled person will be able to count the number of sequences 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 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 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 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 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 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 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 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 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 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 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. 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. 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. 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: 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 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; 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; 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) 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. 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 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 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 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 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 tumor; and iii) 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; 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 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. 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. 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. 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 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 identified as having a Nectin-4 copy number of 4 or more. 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 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, 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 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 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, 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 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 copy number ratio of 2 or more. The examples demonstrate that having a Nectin-4 copy number ratio of 2 or more may 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: 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 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 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 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. 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 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 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 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 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 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 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 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 6 or more. 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, 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 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 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 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 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 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 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 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 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. 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 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 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). 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 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 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. In some embodiments, determining the Nectin-4 copy number of a tumor comprises determining the Nectin-4 copy number of more than one tumor cell. In some embodiments, determining the Nectin-4 copy number of a tumor may comprise determining the Nectin-4 copy number of a plurality of tumor cells. In some embodiments, determining the Nectin-4 copy number of a tumor comprises determining 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 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 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 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 80, at least 90 or at least 100 tumor cells may be determined at each region or location within a tumor or tumor sample. 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. 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 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 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. 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 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 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 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 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 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 the at least three cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold. 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 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 a 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: ^-Ala-Sar10-C1P[1Nal][dD]CiiM[HArg]DWSTP[HyP]WCiiiwherein Sar is sarcosine, 1Nal represents 1-naphthylalanine, HArg represents homoarginine, HyP represents hydroxyproline and Ci, Ciiand Ciiirepresent first, second and third cysteine residues.

[0003]

[0004] 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 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, 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 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 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 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 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. 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 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 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 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. 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 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 specific peptides via a N-(acid-PEG3)-N-bis(PEG3-azide) linker, having a structure as shown below. 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 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 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 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 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 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 3.5 mg / kg. 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. 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 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 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. 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 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 modifications that can be made to the provided peptides, ligands and related complexes are described in more detail herein. 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. 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 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 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 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 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 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 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- 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. 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 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. 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 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 upon target potency. 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, C^- disubstituted derivatives (for example, aminoisobutyric acid, Aib), and cyclo amino 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 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. 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 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 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 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-amino acids to stabilise ^-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 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: - 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 - 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), 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 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 Nectin-4 ADC (Araris Biotech AG), BA3361 (Himalaya Therapeutics; BioAtla Inc), BAT8007 (Bio-Thera Solutions Ltd), CAT-13 (Catalent Inc), enfortumab vedotin (Astellas 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 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) 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. 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. 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 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. In one embodiment, the ADC is BAT8007. This ADC is a topo-1 inhibitor (Exatecan) conjugated ADC with a cleavable linker. 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. 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 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 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, 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 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 targeted therapeutic is a T cell which comprises an engineered T cell receptor specific for Nectin-4. In one embodiment, the Nectin-4 targeted therapeutic is an NK cell which comprises a CAR specific for Nectin-4. EXEMPLIFICATION Example 1. Nectin-4 amplification is frequent in solid tumors and predicts Enfortumab Vedotin response in metastatic urothelial cancer Introduction The anti-Nectin-4 antibody-drug conjugate (ADC) enfortumab vedotin (EV) has been approved for previously treated patients with metastatic urothelial cancer (mUC). The combination of EV plus pembrolizumab (EV / P) was recently approved in metastatic, treatment-naïve and cisplatin-ineligible patients with mUC. More recently, in EV-302, this combination proved to be superior to platinum plus gemcitabine and defined a new standard of care in the first-line setting. EV is currently administered in an all-comer setting without rational biomarker- based patient selection although there is evidence that its target NECTIN-4 is heterogeneously expressed in urothelial cancer (UC) molecular subtypes. In addition, we recently showed that membranous NECTIN-4 expression frequently decreased during metastatic spread and correlates with EV response in patients with mUC. In light of other effective treatment alternatives such as trophoblast cell surface antigen 2 (TROP2)- or human epidermal growth factor receptor 2 (HER2)-directed ADC or fibroblast growth factor receptor inhibitors, a better understanding of the molecular basis for EV responses is urgently needed to improve the rational use of this effective drug for patients with mUC and to optimize its ongoing clinical development in earlier UC stages and other solid tumors. The relationship between copy number variation (CNV), mRNA, and protein expression has been known for decades. As a prime example, anti–HER2-targeted therapy conquered modern oncologic therapy of certain breast cancer subtypes and subsequently other entities in an unprecedented success story. The HER2-targeted ADC trastuzumab deruxtecan (T-DXd) proved to be effective in various HER2-expressing solid cancers, also mUC, with a close correlation with expression status. However, HER2-directed therapy is guided solely on the basis of biomarker testing that aims to identify HER2-overexpressing / ERBB2-amplified tumors. Unlike in this setting, anti–NECTIN-4 EV, whose therapeutic efficacy has been shown to depend on the expression of its target, is applied without previous tumor biomarker testing. Similar to HER2, whose expression is strongly linked to CNV of ERBB2, previous reports linked Nectin-4 gene expression to gains / amplifications of 1q23.3 - where the Nectin-4 gene is located - occurring in approximately 15%-20% of mUC22 with an enrichment of Nectin-4 amplifications in luminal molecular subtypes of mUC.23 Despite the frequency of Nectin-4 CNVs in mUC, to date, the link between Nectin-4 CNVs, membranous Nectin-4 protein expression, and especially the clinical potential of Nectin-4 CNVs to predict EV responses has not been assessed. Thus, we here assessed Nectin-4 CNVs and their association with membranous Nectin-4 protein expression in a multicentre cohort of n = 108 EV-treated patients with mUC and correlated the results with EV responses and outcomes. Furthermore, we confirmed the correlation of Nectin-4 CNVs, mRNA, and protein expression in a The Cancer Genome Atlas (TCGA) pan-cancer analysis and explored the prevalence of Nectin- 4 CNVs representing a potential tumor agnostic genomic biomarker to predict EV response in multiple cancer entities. Materials and methods TCGA Data CNV (Affymetrix single nucleotide polymorphism [SNP] 6.0 array data), transcriptome sequencing (RNA-Seq_v2, log2-transformed RNA-Seq by expectation maximization [RSEM] normalized values), and reverse phase protein arrays (RPPA, only for TCGA-BRCA) were downloaded via cBioPortal24 querying 10,712 samples / patients in a TCGA pan-cancer analysis including 32 studies. For the n = 408 bladder cancers from TCGA (TCGA-BLCA), clinical data (age, sex, outcomes) were downloaded from the University of California, Santa Cruz Xena browser. The TCGA Network calculated CNVs using GISTIC 2.0, and the following values were assigned: –2 = deep deletion; –1 = shallow deletion; 0 = diploid; 1 = gain; 2 = amplification. We retrospectively reviewed medical records of n = 108 EV-treated patients with mUC. All patients received EV as the standard of care. Treatment response was evaluated according to RECIST v.1.1 by site investigators. Progression-free survival (PFS) was defined as the time from EV initiation to radiologic or clinical progression or death from any cause. Representative formalin-fixed and paraffin-embedded (FFPE) tissue of the primary tumor (PRIM; transurethral resection of the bladder [TURB], cystectomy, or nephroureterectomy) and / or metastatic (MET) tissue was required for inclusion in our explorative biomarker study. When multiple tissue samples were available (matched PRIM 1 MET in n = 27), we considered the one closest to EV start for our outcome analyses. The study was approved by the ethical review board of the Friedrich-Alexander-University Erlangen-Nürnberg (approval numbers: 329_16B and 97_18Bc) and the Medical Faculty of the University of Bonn (approval number: 372 / 21). Our biomarker study conforms to REMARK guidelines. Non–EV-Treated mUC Cohort Whole-genome sequencing (WGS) was previously conducted on fresh-frozen metastatic biopsy samples from 116 patients with UC. These patients with mUC were enrolled in clinical trials (ClinicalTrials.gov identifiers: NCT01855477 and NCT02925234) for palliative systemic treatments, with none receiving EV (mUC-non- EV). Nectin-4 CNVs were assessed using GISTIC 2.0.28 Sufficient clinical information on outcomes was available for n = 103 patients. Nectin-4 Fluorescence In-Situ Hybridization The Nectin-4 fluorescence in situ hybridization (FISH) probe was purchased from Empire Genomics (Catalog No. Nectin-4-20-GR, Empire Genomics, Buffalo, NY). The probe is designed to specifically target and bind to the Nectin-4 gene (NCBI Gene ID: 81607). The probe consisted of a fluorescently labeled DNA probe that specifically binds to the Nectin-4 gene. All hybridizations were performed in an accredited specialized 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 Nectin-4 and CEN1 probes. Representative tumor areas for formal analysis were chosen by an experienced board- certified pathologist (ME; blinded to patient outcomes), and at least 50 nonoverlapping nuclei per sample were assessed. Green (Nectin-4) and red (CEN1) signals were manually quantified. The Nectin-4 / CEN1 ratio was calculated, and a ratio of ^2.0 qualified tumors as Nectin-4-amplified. Tumors with ratio values <2.0 were considered nonamplified. Furthermore, gene copy changes (^4 Nectin-4^gene copies per nucleus) without qualifying for an amplification (Nectin-4 / CEN1 ratio below <2.0) were considered as polysome tumors, and polysomy status was correlated with response to EV. Nectin-4 Immunohistochemistry Immunohistochemical staining of Nectin-4 was performed using a VENTANA BenchMark ULTRA autostainer (Ventana, Oro Valley, AZ), as previously described (Klumper N, Ralser DJ, Ellinger J, et al: Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with enfortumab vedotin resistance. Clin Cancer Res 29:1496-1505, 2023). The samples were categorized as negative (H-score, 0-14), weak (H-score, 15- 99), moderate (H-score, 100- 199), or strong (H-score, 200-300), as described previously. SNP Array DNA from the cryopreserved tumor specimen was isolated using the AllPrep DNA / RNA Micro Kit (#80284, Qiagen, Hilden, Germany) following the manufacturer’s instructions. Infinium Global Screening Array-24 v3.0 Kit (Illumina, San Diego, CA) was used according to the manufacturer’s protocol for the detection of Nectin-4 CNVs. Data were analyzed using GenomeStudio version 2.0.5 (Illumina) with cnvPartition CNV Analysis Plugin version 3.2.0 to identify CNV regions and estimate CNV values. CNV values of higher than two were considered as amplification. Statistical Analysis Statistical analysis was performed using R (Version 4.3.0), R Studio (Version 2023.03.11446), and GraphPad Prism (Version 9.4.0). Nectin-4 CNV was correlated with Nectin-4 mRNA (log2-transformed RSEM-normalized values) and membranous protein expression (H-score). Nonparametric Mann- Whitney test was used to compare two groups. For comparisons involving multiple groups, the nonparametric Kruskal-Wallis test was used. The predictive value of Nectin-4 amplification for response to EV was assessed by comparing best overall response (BOR), progression-free survival (PFS), and overall survival (OS) between Nectin-4-amplified and nonamplified tumors. To evaluate the survival after the start of EV treatment, univariable Kaplan-Meier regressions were performed, and significance was determined using the log-rank test. Multivariate Cox regression analyses were conducted to compare the prognostic value of Nectin-4 CNV with baseline patient characteristics (age, sex) and the Bellmunt risk factors (Eastern Cooperative Oncology Group >0, haemoglobin level <10 g / dL, and the presence of liver metastasis) 30 in relation to PFS and OS after EV initiation. All P values were calculated as two-sided, and a significance level of P < .05 was used to determine statistical significance. Results Nectin-4 Amplifications Predict Responses and Favorable Outcomes to EV in mUC We first established a Nectin-4 FISH assay to examine Nectin-4 CNVs. FISH images and corresponding IHC stainings for a Nectin-4 nonamplified UC lacking membranous Nectin-4 expression and a Nectin-4-amplified UC that demonstrates pronounced membranous Nectin-4 expression, respectively, are illustrated in Figures 1A and 1B. The Nectin-4 CNVs in these samples were validated using a SNP assay, which confirms the accuracy and specificity of our Nectin-4 FISH assay (Figure 6 only). Next, we used FISH to determine Nectin-4 CNV in our multicenter EV-treated mUC cohort (mUC- EV, n = 108). Twenty-eight of 108 samples (26%) showed Nectin-4 amplifications (Nectin-4 / CEN1 ratio ^2.0), consistent with amplification frequencies observed in the non–EV-treated metastatic biopsy mUC cohort (mUC-non-EV, 26%, 27 of 103). Regarding baseline characteristics, 25 of 28 patients with Nectin-4 amplifications were male (P = .043) and tended to be older (P = .20; Figure 4). In the mUC-non-EV cohort (Clinical-Trials.gov identifiers: NCT01855477 and NCT02925234), 27 of 27 patients with Nectin-4 amplification were male (P = .001), and again, there was a nonsignificant trend toward a higher frequency of Nectin-4 amplification in older patients with mUC (P = .069; Figure 5A). In TCGA-BLCA, there was a significant correlation between Nectin-4 amplification and older age (P = .013), and there was a nonsignificant trend toward higher amplification frequency in males (P = .15; Figure 5B). Next, we evaluated whether Nectin- 4 CNVs correlated with membranous Nectin-4 protein expression, the prerequisite for EV binding, known to be correlated with EV response. Nectin-4-amplified tumors demonstrated significantly enhanced membranous Nectin-4 expression (median H-score: 295;^IQR, 235-300) compared with Nectin-4 nonamplified tumors (median H-score, 90; IQR, 20-205; Figure 1C). In 27 matched primary (PRIM) and corresponding metastatic (MET) tumor tissues, Nectin-4 CNV was stable in 93% (25 of 27). Of eight Nectin-4- amplified PRIM with available matched MET, only one tumor lost Nectin-4 amplification during metastasis (Figure 1D). Membranous Nectin-4 expression of Nectin-4- amplified PRIM (median H-score, 290; range, 170-300) remained high in the corresponding MET (median H-score, 280; range, 20-300), except for the primary tumor, which lost its Nectin- 4 amplification (Figure 1E). In only 1 of 27 matched PRIM and MET pairs, Nectin-4 amplification was exclusive in the metastatic sample (Figure 1D). A total of 96% (27 of 28) patients with Nectin-4 amplification demonstrated an objective response (82%; partial response [PR] and 14% complete response [CR], one patient with stable disease [SD]) as BOR compared with 32% (including 3% with CR) of the Nectin-4 nonamplified tumors (Chi square P < .001; Figure 1F). Nectin-4 amplifications associated with prolonged PFS (Figure 1G) and OS (Figure 1H), with 90% 12-month survival rate and median OS not reached (95% CI, NR to NR) compared with 41% 12-month survival and a median OS of 8.8 months (95% CI, 6.1 to 14) for Nectin-4 nonamplified tumors. In multivariable Cox regression coadjusted for age, sex, and Bellmunt risk factors, Nectin-4 amplification status led to a 92% risk reduction for death compared with Nectin-4 nonamplified tumors (hazard ratio, 0.08 [95% CI, 0.02 to 0.34], P < .001; Table 1). In addition, Nectin-4 amplification was associated with prolonged PFS and OS compared with the patient subgroup of nonamplified tumors with strong membranous Nectin-4 expression (H-score ^200; Figure 7). Furthermore, we explored whether polysome gene copy changes per nucleus (copy number ^4.0) without qualifying for an amplification (Nectin-4 / CEN1 ratio below <2.0) correlated with EV response and found that five of eight polysome tumors demonstrated an PR / CR or SD with disease control >6 months. To rule out a prognostic bias of Nectin-4 CNVs, we assessed their prognostic impact in non–EV-treated UC patient cohorts. In the mUC-non-EV cohort, Nectin-4 amplifications were assessed via whole-genome DNA sequencing in 103 metastatic biopsy samples obtained before palliative systemic treatment. In this cohort, Nectin-4 amplifications were found in 26% of tumors and were not associated with OS (Figure 1I). In the TCGA-BLCA cohort of muscle-invasive bladder cancer, Nectin-4 amplifications were also not associated with disease-specific survival and OS (Figure 8A and B). Nectin-4 Amplification Occurs Frequently Across Entities In the TCGA Pan-Cancer cohort, Nectin-4 amplifications were observed in 25 of 32 cancer types including various solid entities with Nectin-4 amplification frequency > 5% (Figure 3A). The highest prevalence of Nectin-4 amplifications was found in bladder cancer (BLCA, 17%), cholangiocarcinoma (CHOL, 14%), hepatocellular carcinoma (LIHC, 12%), breast cancer (BRCA, 9%), and lung adenocarcinoma (LUAD, 7%). Nectin- 4-amplified samples or those with gains showed increased Nectin-4 mRNA levels compared with diploid samples (Figure 3B) on the pan-cancer level. In BLCA, BRCA, and LUAD - where EV is approved or in late-stage clinical development - Nectin-4 amplifications associated with increased Nectin-4 mRNA expression (Figure 3C; Figures 9A and 9C) and higher Nectin-4 protein levels in breast cancer (Figure 9B). Discussion The identification of biomarkers to predict response to targeted therapies is crucial to improve the management of patients with cancer. Here, we provide data from a multicentre mUC patient cohort highlighting Nectin-4 amplifications as genomic biomarkers to predict EV responses and favorable outcomes. Importantly, in the non–EV- treated patients with mUC, Nectin-4 amplifications have no impact on OS, suggesting that Nectin-4 amplifications are^neither indicating aggressive nor favorable tumor biology, strengthening its potential value as a pure predictive biomarker. Nectin-4 amplification was strongly associated with EV sensitivity (BOR, 96%). However, the response rate of 32% in the nonamplified subgroup is comparable with the expected outcomes (BOR app.40%) observed in real-world settings and the pivotal phase III EV-301 study.1,35,36 With a median OS of 12 months (95% CI, 9.7 to NR) in our mUC-EV cohort, our data confirm the clinical activity of EV in previously treated patients with mUC (e.g. EV-301, 12.9 months [95% CI, 10.6 to 15.2]). Therefore, EV again proves to be an effective drug in previously treated mUC also in the non-amplified context. We recently showed that membranous Nectin-4 protein expression is volatile and often (>50%) decreases during metastatic progression of mUC (Klumper et al.2023 ibid) By contrast, 88% of PRIM with Nectin-4 amplifications retains their Nectin-4 amplification and subsequently a stable high membranous Nectin-4 protein expression during metastatic progression. This is in line with previous studies demonstrating that early acquired genomic features including copy number alterations are rather stable during^ metastatic progression in comparison with parental primary tumors. Thus, treatment decisions for the metastatic stage could be based on Nectin-4 amplification status in primary tumor material, facilitating implementation into clinical trials. It is worth noting that this consideration does not apply to the assessment of membranous Nectin-4 protein expression, which decreases substantially during metastasis in UC without Nectin-4 amplifications. This difference could be explained by the inability of Nectin-4-amplified tumors to downregulate membranous expression of Nectin-4 at the transcriptional level. Because downregulation of the target is a known mechanism of resistance to ADCs, this could explain, at least in part, the exceptional and durable clinical efficacy of EV in Nectin-4-amplified tumors. Beside considerations of tissue choice for predictive biomarker testing, overcoming hurdles to implement biomarker tests into daily care is a major obstacle for biomarker-guided therapies. In the case of CNV assessment, a broad variety of cytogenetic and molecular techniques are available, including FISH / chromogenic in situ hybridization, SNP microarray, comparative genomic hybridization, multiplex ligation- dependent probe amplification, and sequencing methods like whole-exome or whole- genome sequencing. Among these options, FISH is the most frequently performed diagnostic assay to assess CNVs in clinical routine. Moreover, FISH as predictive biomarker assay has been proven to be a highly reproducible, easy-to-implement, fast, and cost-effective method in daily molecular pathology. Thus, we conclude that a Nectin-4 FISH assay could be quickly integrated into clinical trials and routine molecular pathology / daily patient care. Other biomarkers were described to be associated with EV response and outcomes. Jindal T, Zhang L, Jiang C, et al:. J Clin Oncol 41, 2023 (suppl 16; abstr 4573) (hereby incorporated by reference in its entirety) describes a comprehensive biomarker analysis within the UNITE study cohort, which comprised 303 patients receiving EV monotherapy with available next-generation sequencing data across 16 US sites. Among these patients, 207 had their tumor mutational burden (TMB) assessed and 146 had their PD-L1 status evaluated. Multivariate analysis revealed that alterations in ERBB2, KDM6A, and PIK3CA were associated with favorable treatment outcomes on EV. Conversely, patients with low TMB (<10 Mut / Mb) and high PD-L1 (CPS ^10) exhibited less favorable outcomes on EV. It is known that alterations in ERBB2 and KDM6A are overrepresented in luminal differentiated UC, which are known to be enriched for Nectin-4 amplification and increased Nectin-4 mRNA and protein expression. Therefore, the prognostic value of these genomic alterations may depend on luminal differentiation and concomitant higher Nectin-4 expression. Consistent with this, the absence of squamous differentiation has been shown to correlate with response to EV. In addition, the occurrence of skin toxicity after initiation of EV treatment has been reported to be associated with favorable outcomes of EV treatment. In the context of ADC precision oncology, it is well established from several clinical trials that ADC^response correlates with the respective target gene expression, for example, for HER2 and FOLR1-targeting ADC; we have demonstrated linear correlation also between membranous NECTIN-4 expression and EV response. Future biomarker analyses would therefore ideally need to integrate membranous Nectin-4 expression, Nectin-4 CNV, histomorphology, and further high throughput data to deepen our understanding of EV responsive tumors. Rational biomarker-guided therapy selection is urgently required to establish the optimal therapy sequence for patients with (m)UC. Consideration of Nectin-4 amplifications as predictive biomarkers could potentially rationalize drug development of Nectin-4 targeted therapeutics, including EV, BT7480 and BT8009 - also at earlier disease stages - by defining the patient subgroup with the highest chance of durable benefit. In this context, a strategic focus on biomarker-guided trials could greatly enhance our understanding of the potential of EV or other anti–Nectin-4-targeted therapies and open new avenues to optimize treatment and improve outcomes in patients with (m)UC. A wide range of surface targets, such as HER2 or TROP2, are present in different types of cancers, and there has been a growing interest to expand the use of ADC beyond specific cancer types in a tumor-agnostic fashion. Of note, in our TCGA Pan-Cancer analysis, Nectin-4 amplifications can be found in 5%-10% of breast cancer and non–small cell lung cancer, both tumor types with a high impact on all-cancer mortality, which are currently being evaluated for EV response in the multicohort phase II EV-202 trial (ClinicalTrials.gov identifier: NCT04225117) and for BT8009 response in the multicohort phase I / II BT8009- 100 trial (ClinicalTrials.gov identifier: NCT04561362). Thus, Nectin-4 CNV may be a valuable predictive biomarker to streamline clinical development of Nectin-4-targeted therapies in tumor entities beyond UC. The frequent occurrence of Nectin-4 amplifications across solid cancer types could thus pave the way for basket trial designs studying the efficacy of EV, BT7480 or BT8009 on the basis of Nectin-4 CNV status in a tumor- agnostic study framework, similar to the phase II DESTINYPanTumor02 trial which assessed anti-HER2 ADC T-DXd in HER2-expressing solid tumors. Although our study certainly has important strengths, its main limitation is the use of a retrospectively assembled patient cohort, which consists of both archived primary (TURB, cystectomy or nephroureterectomy) and metastatic tumor specimens with varying ranges between tumor sampling and start of EV treatment. Therefore, our data are hypothesis-generating and prospective confirmation in larger, biomarker-driven trials is mandatory. As the combination of EV / P is the new standard of care in the first-line treatment of mUC, the predictive value of Nectin-4 amplification in this new treatment setting should be further investigated. In addition, our study does not include correlative data on Nectin-4 CNVs and responses to EV in other cancer entities, as mUC is the only approved standard-of care setting for EV to date. In conclusion, our study suggests that Nectin-4 amplification is a simple, valuable, and easy-to-implement predictive biomarker for EV in patients with mUC. EV is an ADC comprising an antibody that targets the Nectin-4 receptor on the surface of tumor cells, that is conjugated to the tubulin inhibitor monomethyl auristatin E (MMAE). Our study therefore also suggests that Nectin-4 amplification may similarly be a predictive biomarker in patients with mUC for treatment with other therapeutic agents that target cytotoxic agents to tumor cells via the Nectin-4 receptor (i.e. other Nectin-4 targeted therapeutics), such as other ADCs or Bicycle Drug Conjugates (BDCs) such as BT8009, or Bicycle TICAs® such as BT7480. The frequent occurrence of Nectin-4 amplifications in other cancer types also suggests that this biomarker is a promising candidate with broader applicability for clinical development of Nectin-4-targeted ADCs and other Nectin-4 targeted conjugates comprising cytotoxic agents (e.g. MMAE), such as other ADCs or Bicycle Drug Conjugates (BDCs) such BT8009, in a tumor-agnostic context. Example 2. Assessment of patients with / without a Nectin-4 amplification and response to a Nectin-4 targeted therapeutic Materials and methods FISH 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 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-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) 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. Immunohistochemistry (IHC) IHC was performed as described in WO 2022 / 038158. 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 Nectin-4 amplification using the FISH assay described herein. 1 breast / TNBC sample and 3 lung cancer / NSCLC samples failed QC and were not 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 BT8009-100 have Nectin-4 amplifications (Figure 11A). This corresponds well to data gathered from other TNBC samples not on BT8009-100 (Figure 11B) 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 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 12A). All patients identified as having a Nectin-4 amplification had a partial response or stable disease (Figure 12B). Patients with amplifications are more likely to respond to treatment with the Nectin-4 targeted therapeutic BT8009 (Figures 13-18). Nectin-4 amplification status is a better predictor of response to a Nectin-4 targeted therapeutic than measuring Nectin-4 protein expression by IHC. Although there is a higher frequency of Nectin-4 protein expression (H-score ^100) for both breast / 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 16). Of the 37 response evaluable patients with Nectin-4 amplification status, all of the 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 17). 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 had stable disease (square) or a partial response (circle) (Figure 18). 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 having a Nectin-4 copy number of 4 or more according to the methods of the invention. Figure 19 provides a similar observation – it indicates the Nectin-4 protein expression levels for the patients of Figure 14. 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. 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 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. 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 20A). 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 20B).

Claims

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 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, 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 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; 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: 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: i) determining Nectin-4 copy number in a tumor of the patient; andii) 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.

7. The method of any one of claims 1 to 4, 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.

8. The method of any one of 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.

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 or 2 or more in a tumor, and / or 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.

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.

11. 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.

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.

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.

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 and / or a Nectin-4 copy number ratio of 2 or more.

15. The method of any one of claims 7 to 14, wherein the volume of a solid tumor is maintained or reduced following administration of the Nectin-4 targeted therapeutic.

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.

17. 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.

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 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: 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. 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 and / or a Nectin-4 copy number ratio of 2 or more.

21. The method of any one of claims 16 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 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 baseline measurement, optionally wherein the SLD decreases by up to 20% when compared to a baseline measurement, optionally wherein the SLD decreases by up to30% when compared to a baseline measurement, and / or wherein the SLD increases by less than 5 mm.

22. The method of any one of claims 16 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 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 wherein the SLD decreases by 90% or more when compared to a baseline measurement.

23. The method of any one of claims 16 to 22, wherein administration of the Nectin-4 targeted therapeutic results in disappearance of the tumor.

24. The method of any one of claims 16 to 23, 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, 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 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.

26. 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 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: 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 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.

29. 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 identified as having a Nectin-4 copy number of 4 or more and / or a Nectin-4 copy number ratio of 2 or more.

30. The method of 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 Nectin-4 copy number of 4 or more in the tumor.

31. 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, atleast 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 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 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.

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).

36. 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 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- derived cell-free DNA is circulating tumor DNA (ctDNA).

38. The method of claim 36, wherein the sample is a urine sample.

39. 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 in situ hybridisation (CIS) or silver-enhanced in situ hybridisation (SISH).

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 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.

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.

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 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, bladder cancer, cholangiocarcinoma, hepatocellular carcinoma, breast cancer, lung adenocarcinoma or non–small cell lung cancer.

48. The method of claim 47, wherein the cancer is locally advanced or metastatic urothelial cancer.

49. The method of any one of claims 1 to 48, wherein the Nectin-4 targeted therapeutic comprises a peptide ligand specific for Nectin-4 that comprises (a) a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and (b) a molecular scaffold that forms covalent bonds with the at least three cysteine residuesof the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold.

50. The method of any one of claims 1 to 49, wherein the Nectin-4 targeted therapeutic is a Bicycle drug conjugate® (BDC) or Bicycle TICA® specific for Nectin-4.

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

52. The method of claim 51, wherein the Nectin-4 targeted therapeutic is BT8009, wherein BT8009 is administered intravenously: (a) weekly at a dose of 5 mg / m2; or (b) on days 1 and 8 of a 21-day treatment cycle at a dose of 6 mg / m253. The method of any one of claims 1 to 48, wherein the Nectin-4 targeted therapeutic is an antibody drug conjugate.

54. The method of claim 53, 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.

55. The method of claim 54, 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.

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