Treatment of non-small cell lung cancer

Abstract

The present disclosure relates generally to methods and compositions for treating patients suffering from resectable non-small cell lung cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 496,200, filed April 14, 2023, and U.S. Provisional Application No. 63 / 509,408, filed June 21, 2023, each of which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] This disclosure relates in general to methods and compositions for treating patients with non-small cell lung cancer using durvalumab and platinum-based chemotherapy.

[0004] sequence list

[0005] This application includes a sequence list, which is submitted electronically and incorporated herein by reference in its entirety. The sequence list submitted with it is contained in an XML file named "23-0535-US-PRO2_SequenceListing.xml" created on May 26, 2023, and is 8,192 bytes in size. Background Technology

[0006] Lung cancer is a leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for over 80% of cases. Approximately 25%–30% of patients have resectable disease at diagnosis, and this proportion is expected to increase with the use of lung cancer screening programs. Surgery remains the primary treatment with a curative intent for eligible early-stage NSCLC patients. Nevertheless, many patients experience tumor recurrence within 5 years of surgery (approximately 30%–55%, depending on the disease stage at diagnosis), leading to a decline in health-related quality of life and increasing the likelihood of disease-related death. In neoadjuvant or adjuvant settings, chemotherapy is a recognized treatment strategy, but it provides only a modest improvement in 5-year survival of approximately 5% compared to surgery alone.

[0007] Lung cancer has been the most common cancer in the world for decades, with an estimated 1.8 million new cases in 2012 (accounting for 12.9% of all new cancers), and it was also the leading cause of cancer death in 2012, with 1.6 million deaths (accounting for 19.4% of cancer deaths; GLOBOCAN 2012). Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers (Pisters and Le Chevalier, “Adjuvant chemotherapy in completely resected non-small-cell lung cancer: J Clin Oncol. May 10, 2005; 23(14):3270-8). Despite advances in the diagnosis, imaging, staging, and treatment of NSCLC, the estimated 5-year overall survival (OS) remains low in European and American patients (11% and 17%, respectively; D'Addario et al., “Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up” Ann Oncol. May 2010; 21 Supplement 5:v116-9; Howlader et al., “SEER Cancer Statistics Review, 1975-2014”, National Cancer Institute. Bethesda, MD. April 2017).

[0008] For early-stage NSCLC, the primary treatment is curative surgery. Only about 30% of patients present with stage I to IIIA lung cancer; however, this percentage is expected to increase due to the implementation of lung cancer screening. Unfortunately, the 5-year survival rate for patients treated with surgery alone remains low, ranging from 67% (stage IA) to 23% (stage IIIA) (Mountain “Revisions in the international system for staging lung cancer.” Chest 1997;111:1710-7.).

[0009] Studies of adjuvant chemotherapy in NSCLC settings have demonstrated modest but clinically meaningful improvements in overall survival; perioperative platinum-based chemotherapy has shown a 5.4 percentage point improvement in survival compared to surgery alone, with grade 3 or higher toxicities observed in more than 60% of patients (Pignon et al., “Lung adjuvant cisplatin evaluation: apooled analysis by the LACE Collaborative Group.” J Clin Oncol 2008; 26:3552-9; Wakelee et al., “Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial.” Lancet Oncol 2017;18:1610-23).

[0010] Numerous studies have demonstrated the clinical benefits of neoadjuvant chemotherapy in early-stage NSCLC. However, despite these advances, new therapies are still needed to further improve the long-term outcomes for NSCLC patients who have undergone surgical resection. Summary of the Invention

[0011] This disclosure generally relates to methods for treating patients with resectable non-small cell lung cancer (NSCLC). This disclosure demonstrates that perioperative durvalumab combined with neoadjuvant chemotherapy significantly improves both pathological complete response (PCR) and event-free survival (EFS) in patients with resectable NSCLC.

[0012] In one aspect, this disclosure provides a method for treating a patient diagnosed with resectable non-small cell lung cancer (R-NSCLC), the method comprising administering to the patient a combination therapy comprising duvalumab and platinum-based chemotherapy.

[0013] In some embodiments, the drug is administered approximately every 14 to 28 days or approximately every 21 days. In some embodiments, the combination therapy is administered approximately every 14 to 28 days for approximately 3 to 6 cycles. In some embodiments, the combination therapy is administered approximately every 21 days (Q3W) for approximately 4 cycles. In some embodiments, the method further includes resection of the R-NSCLC after approximately 3 to 6 cycles of combination therapy. In some embodiments, the method further includes resection of the R-NSCLC after approximately 4 cycles of combination therapy. In some embodiments, the method further includes administering durvalumab to the patient approximately every 14 to 28 days after resection of the R-NSCLC for up to approximately twelve cycles. In some embodiments, the method further includes administering durvalumab to the patient approximately every 28 days (Q4W) after resection of the R-NSCLC for up to approximately twelve cycles.

[0014] In some implementations, the combination therapy comprises approximately 1000 mg to 2000 mg of durvalumab. In some implementations, the combination therapy comprises approximately 1500 mg of durvalumab.

[0015] On the other hand, this disclosure provides a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), the method comprising:

[0016] (i) The patient was given approximately 1500 mg of durvalumab and platinum-based chemotherapy approximately every 3 weeks (Q3W) for approximately 4 cycles;

[0017] (ii) surgical removal of R-NSCLC; and then

[0018] (iii) Administer approximately 1500 mg of durvalumab to the patient approximately every four weeks (Q4W) for at least approximately 12 weeks.

[0019] In some embodiments of the methods disclosed herein, the platinum-based chemotherapy is one or more of the following: carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, the platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of about 5 mg / mL / min to about 6 mg / mL / min, or about 75 mg / mL. 2 The cisplatin dose. In some embodiments, platinum-based chemotherapy also includes one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments, platinum-based chemotherapy comprises approximately 200 mg / m². 2 The dosage of paclitaxel is approximately 500 mg / m². 2 The dosage of pemetrexed is approximately 1250 mg / m². 2 Gemcitabine dosage.

[0020] In some embodiments of the methods disclosed herein, R-NSCLC is squamous cell carcinoma. In some embodiments, platinum-based chemotherapy includes: (i) carboplatin and paclitaxel; (ii) cisplatin and gemcitabine; and / or (iii) carboplatin and gemcitabine.

[0021] In some embodiments of the methods disclosed herein, R-NSCLC is non-squamous cell carcinoma. In some embodiments, platinum-based chemotherapy includes: (i) carboplatin and pemetrexed; and / or (ii) cisplatin and pemetrexed.

[0022] In some implementations of the methods disclosed herein, the patient does not have an EGFR mutation and / or an ALK translocation.

[0023] In some embodiments of the methods disclosed herein, resection of R-NSCLC occurs within approximately 10 weeks following approximately 3 to 6 cycles of combination therapy.

[0024] In some embodiments of the method disclosed herein, the method further includes postoperative radiation therapy. In some embodiments, postoperative radiation therapy is initiated approximately 8 weeks after resection of R-NSCLC. In some embodiments, duvalumab is initiated approximately 3 weeks after the end of postoperative radiation therapy.

[0025] In certain embodiments of the methods disclosed herein, the method results in one or more of the following: (i) an improvement in event-free survival (EFS) of at least about 13 months; (ii) an improvement in pathological complete response (pCR) of at least about 13%; and (iii) an improvement in major pathological response (mPR) of at least about 21%. In certain embodiments, the method improves one or more of EFS, pCR, mPR, DFS, and OS compared to the standard of care. In certain embodiments, the method improves one or more of EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy or platinum-based chemotherapy before or after surgery.

[0026] In one aspect, this disclosure provides a combination therapy comprising duvalumab and platinum-based chemotherapy for use in the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients in need.

[0027] In some implementations, the combination therapy is administered approximately every 14 to 28 days or approximately every 21 days. In some implementations, the combination therapy is administered approximately every 14 to 28 days for approximately 3 to 6 cycles. In some implementations, the combination therapy is administered approximately every 21 days (Q3W) for approximately 4 cycles. In some implementations, the combination therapy further includes resection of the R-NSCLC after approximately 3 to 6 cycles of combination therapy. In some implementations, the combination therapy further includes resection of the R-NSCLC after approximately 4 cycles of combination therapy. In some implementations, the combination therapy further includes administration of durvalumab to the patient approximately every 14 to 28 days after resection of the R-NSCLC for up to approximately twelve cycles. In some implementations, the combination therapy further includes administration of durvalumab to the patient approximately every 28 days (Q4W) after resection of the R-NSCLC for up to approximately twelve cycles.

[0028] In some implementations, the combination therapy comprises approximately 1000 mg to 2000 mg of durvalumab. In some implementations, the combination therapy comprises approximately 1500 mg of durvalumab.

[0029] In another aspect, this disclosure provides a combination therapy for use in treating subjects diagnosed with resectable non-small cell lung cancer (R-NSCLC), wherein the combination therapy comprises: administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every 3 weeks (Q3W) for approximately 4 cycles; and then administering approximately 1500 mg of durvalumab to the patient approximately every 4 weeks (Q4W) after surgical removal of the R-NSCLC for at least approximately 12 weeks.

[0030] In some embodiments of the combination therapy, the platinum-based chemotherapy is one or more of the following: carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, the platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of about 5 mg / mL / min to about 6 mg / mL / min, or about 75 mg / mL. 2 The cisplatin dose. In some embodiments, platinum-based chemotherapy also includes one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments of the combination therapy, platinum-based chemotherapy comprises approximately 200 mg / m². 2 The dosage of paclitaxel is approximately 500 mg / m². 2 The dosage of pemetrexed is approximately 1250 mg / m². 2 Gemcitabine dosage.

[0031] In some implementations of the combination therapy, R-NSCLC is squamous cell carcinoma. In some implementations, platinum-based chemotherapy includes: (i) carboplatin and paclitaxel; (ii) cisplatin and gemcitabine; and / or (iii) carboplatin and gemcitabine.

[0032] In some implementations of the combination therapy, R-NSCLC is non-squamous cell carcinoma. In some implementations, platinum-based chemotherapy includes: (i) carboplatin and pemetrexed; and / or (ii) cisplatin and pemetrexed.

[0033] In some implementations of the combination therapy, the patient does not have an EGFR mutation and / or an ALK translocation.

[0034] In some implementations of the combination therapy, resection of R-NSCLC occurs within approximately 10 weeks after approximately 3 to 6 cycles of combination therapy.

[0035] In some implementations, the combination therapy also includes postoperative radiation therapy. In some implementations, postoperative radiation therapy is initiated approximately 8 weeks after resection of R-NSCLC. In some implementations, duvalumab is initiated approximately 3 weeks after the end of postoperative radiation therapy.

[0036] In certain implementations of the combination therapy, the use of the combination therapy results in one or more of the following: (i) an improvement in event-free survival (EFS) of at least approximately 13 months; (ii) an improvement in pathological complete response (pCR) of at least approximately 13%; and (iii) an improvement in major pathological response (mPR) of at least approximately 21%. In certain implementations, the use of the combination therapy improves one or more of EFS, pCR, mPR, DFS, and OS compared to the standard of care. In certain implementations, the use of the combination therapy improves one or more of EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy or platinum-based chemotherapy before or after surgery.

[0037] In one aspect, this disclosure provides the use of a combination therapy comprising duvalumab and platinum-based chemotherapy for the manufacture of a medicament for the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients of need.

[0038] In some embodiments, the drug is administered approximately every 14 to 28 days or approximately every 21 days. In some embodiments, the drug is administered approximately every 14 to 28 days for approximately 3 to 6 cycles. In some embodiments, the drug is administered approximately every 21 days (Q3W) for approximately 4 cycles. In some embodiments, the use of the drug also includes resection of R-NSCLC after approximately 3 to 6 cycles of combination therapy. In some embodiments, the use of the drug also includes resection of R-NSCLC after approximately 4 cycles of combination therapy. In some embodiments, the use of the drug also includes administration of durvalumab to the patient approximately every 14 to 28 days after resection of R-NSCLC for up to approximately twelve cycles. In some embodiments, the use of the drug also includes administration of durvalumab to the patient approximately every 28 days (Q4W) after resection of R-NSCLC for up to twelve cycles.

[0039] In some embodiments of the drug, the drug comprises about 1000 mg to 2000 mg of durvalumab. In some embodiments, the drug comprises about 1500 mg of durvalumab.

[0040] On the other hand, this disclosure provides the use of duvalumab and platinum-based chemotherapy in the manufacture of a medicine for the treatment of resectable non-small cell lung cancer (R-NSCLC) in combination therapy, wherein the combination therapy comprises: administering about 1500 mg of duvalumab and platinum-based chemotherapy to the patient approximately every 3 weeks (Q3W) for about 4 cycles; surgical removal of R-NSCLC; and then administering about 1500 mg of duvalumab to the patient approximately every 4 weeks (Q4W) for at least about 12 weeks.

[0041] In some embodiments of the use of the drug, platinum-based chemotherapy is one or more of the following: carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of about 5 mg / mL / min to about 6 mg / mL / min, or about 75 mg / mL. 2 The cisplatin dose. In some embodiments of the use of the drug, platinum-based chemotherapy further includes one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments of the use of the drug, platinum-based chemotherapy comprises approximately 200 mg / m². 2 The dosage of paclitaxel is approximately 500 mg / m². 2 The dosage of pemetrexed is approximately 1250 mg / m². 2 Gemcitabine dosage.

[0042] In some embodiments of the use of the drug, R-NSCLC is squamous cell carcinoma. In some embodiments, platinum-based chemotherapy includes: (i) carboplatin and paclitaxel; (ii) cisplatin and gemcitabine; and / or (iii) carboplatin and gemcitabine.

[0043] In some embodiments of the use of the drug, R-NSCLC is non-squamous cell carcinoma. In some embodiments, platinum-based chemotherapy includes: (i) carboplatin and pemetrexed; and / or (ii) cisplatin and pemetrexed.

[0044] In some implementations of the drug’s use, the patient does not have an EGFR mutation and / or an ALK translocation.

[0045] In some implementations of the drug’s use, resection of R-NSCLC occurs within approximately 10 weeks following approximately 3 to 6 cycles of combination therapy.

[0046] In some embodiments of the use of the drug, the use also includes postoperative radiotherapy. In some embodiments, postoperative radiotherapy is initiated approximately 8 weeks after resection of R-NSCLC. In some embodiments, duvalumab is initiated approximately 3 weeks after the end of postoperative radiotherapy.

[0047] In certain embodiments of the use of the drug, the use of combination therapy results in one or more of the following: (i) an improvement in event-free survival (EFS) of at least about 13 months; (ii) an improvement in pathological complete response (pCR) of at least about 13%; and (iii) an improvement in major pathological response (mPR) of at least about 21%. In certain embodiments, the use of combination therapy results in one or more of EFS, pCR, mPR, DFS, and OS compared to the standard of care. In certain embodiments, the use of combination therapy results in one or more of EFS, pCR and mPR, DFS, and OS compared to platinum-based chemotherapy or platinum-based chemotherapy before or after surgery.

[0048] These and other features and advantages of this disclosure will be more fully understood from the following detailed description in conjunction with the appended claims. It should be noted that the scope of the claims is defined by the statements therein, and not by the specific discussion of the features and advantages listed in this specification. Attached Figure Description

[0049] The accompanying drawings are included to provide a further understanding of the methods and compositions of this disclosure. The drawings illustrate one or more embodiments of this disclosure and, together with this specification, serve to explain the principles and operation of this disclosure.

[0050] Figure 1A The study design of a phase 3, global, randomized, double-blind, placebo-controlled study according to this disclosure is shown. The protocol was modified during registration to exclude (1) patients with tumors classified as T4 for any reason other than size; (2) patients scheduled for lung resection; and (3) patients with documented EGFR / ALK abnormalities. †Ventana SP263 immunohistochemical assay. The CT protocol selection is determined by histological and investigator judgment. For non-squamous lesions: cisplatin + pemetrexed, or carboplatin + pemetrexed. For squamous lesions: carboplatin + paclitaxel or cisplatin + gemcitabine (or carboplatin + gemcitabine for patients with comorbidities or who, according to investigator judgment, cannot tolerate cisplatin). Postoperative radiotherapy (PORT) is permitted in accordance with each local guideline. All efficacy analyses reported in this article were performed on the mITT population, which included all randomized patients without documented EGFR / ALK abnormalities. AJCC, American Joint Committee on Cancer; BICR, Blinded Independent Central Review; DFS, Disease-Free Survival; EFS, Event-Free Survival; mITT, Modified Intention to Treatment; MPR, Major Pathological Response; pCR, Complete Pathological Response.

[0051] Figure 1B The CONSORT flowchart is displayed. Signed informed consent was received. †Efficacy endpoints were analyzed based on a modified cohort excluding patients with documented EGFR / ALK abnormalities. The safety analysis suite includes all randomized patients who received at least one dose of any study Tx. AE, Adverse Events; DCO, Data Cutoff; ITT, Intention to Treat; PD, Progressive Disease; Tx, Treatment.

[0052] Figure 2This figure shows event-free survival (EFS) in the modified intention-to-treat (mITT) cohort based on blinded independent central review (BICR). The data cutoff was November 10, 2022 (N=740). This figure shows EFS in patients in the modified intention-to-treat cohort (i.e., all randomized patients without documented EGFR / ALK abnormalities). EFS was defined as the time from randomization to the earliest of the following: (i) progressive disease that prevents surgery; (ii) progressive disease discovered and reported by the investigator during surgery in an attempt to prevent termination of surgery; (iii) local or distant recurrence using blinded independent central review according to the Solid Tumor Response Assessment Criteria version 1.1; or (iv) death from any cause. The median EFS follow-up for reviewed patients was 11.7 months (range: 0.0–46.1); EFS expiry date: 31.9%. P-values ​​were calculated using a stratified log-rank test, with a significance margin of 0.009899 (based on a total 5% α), calculated using the Lan-DeMets α-exhaustion function and the O'Brien Fleming boundary. CI, confidence interval; D, durvalumab; eCRF, electronic case report form; EFS, event-free survival; HR, hazard ratio; NR, not reached; PBO, placebo.

[0053] Figure 3 Event-free survival (EFS) according to blinded independent central review (BICR) is shown in the modified intention-to-treat (mITT) population. The data cutoff point was November 10, 2022 (N=740). Forest plot of EFS in pre-specified patient subgroups (where the size of the circles is proportional to the number of events in each subgroup, and the horizontal bars represent the 95% CI). EFS was defined as the time from randomization to the earliest of the following: (i) progressive disease that prevents surgery; (ii) progressive disease discovered and reported by the investigator during surgery in an attempt to prevent termination of surgery; (iii) local or distant recurrence using blinded independent central review according to the Solid Tumor Response Assessment Criteria version 1.1; or (iv) death from any cause. Race was determined based on eCRF self-reporting. †Determined using Ventana SP263 immunohistochemical assay. AJCC, American Joint Committee on Cancer; CI, confidence interval; D, durvalumab; ECOG PS, Eastern Cooperative Oncology Group performance status; eCRF, electronic case report form; EFS, event-free survival; HR, hazard ratio; NR, not reached; PBO, placebo; PD-L1, programmed cell death ligand 1; TC, tumor cells.

[0054] Figure 4AThe event-free survival (pre-specified subgroup analysis) of planned neoadjuvant platinum-based agents in the modified treatment intention group, as determined by blinded independent central review, is shown. Flexibility exists in the selection of neoadjuvant chemotherapy combinations. - Regardless of the planned platinum reagent, a clear and consistent EFS benefit was observed. Median and landmark estimates were calculated using the Kaplan-Meier method. HRs were calculated using a non-stratified Cox proportional hazard model. The CT protocol was selected based on histological and investigator judgment. For non-squamous lesions: cisplatin + pemetrexed, or carboplatin + pemetrexed. For squamous lesions: carboplatin + paclitaxel, or cisplatin + gemcitabine (or carboplatin + gemcitabine for patients with comorbidities or who, according to investigator judgment, cannot tolerate cisplatin). †HR <1 was favorable to group D relative to the PBO group. Results showed a significant and consistent EFS benefit regardless of the planned platinum agent. CI, confidence interval; D, duvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo.

[0055] Figure 4B The event-free survival (EFS) by disease stage, reviewed under blinded independent central review, is shown in the modified treatment intention-to-treat population (pre-specified subgroup analysis). The data cutoff point was November 10, 2022 (N=740). The top figure shows EFS in the subgroup of patients with stage II disease, and the bottom figure shows EFS in the subgroup of patients with stage III disease (at study baseline). EFS was defined as the time from randomization to the earliest of the following: (i) progressive disease that prevents surgery; (ii) progressive disease discovered and reported by the investigator during surgery in an attempt to prevent the termination of surgery; (iii) local or distant recurrence using blinded independent central review according to the Solid Tumor Response Assessment Criteria version 1.1; or (iv) death from any cause. CI, confidence interval; D, duvarulimab; EFS, event-free survival; HR, hazard ratio; PBO, placebo.

[0056] Figures 4C to 4E The data show event-free survival based on PD-L1 tumor cell expression in the modified treatment intention population, according to blinded independent central review (pre-specified subgroup analysis). The data cutoff point was November 10, 2022 (N=740). Figure 4C The study showed EFS in a subgroup of patients with PD-L1 tumor cell expression <1%. Figure 4D The study showed EFS in a subgroup of patients with PD-L1 tumor cell expression ranging from 1% to 49%, and... Figure 4EThe EFS (at study baseline) is shown in patients with PD-L1 tumor cell expression ≥50%. EFS is defined as the time from randomization to the earliest of the following: (i) progressive disease that prevents surgery; (ii) progressive disease identified and reported by the investigator during surgery in an attempt to prevent surgical termination; (iii) local or distant recurrence reviewed using blinded independent centers according to the Solid Tumor Response Evaluation Criteria version 1.1; or (iv) death from any cause. CI, confidence interval; D, duvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo; PD-L1, programmed cell death-ligand-1; TC, tumor cells.

[0057] Figures 4F to 4G The data show event-free survival (pre-specified subgroup analysis) in the modified treatment intention population, as determined by blinded independent central review of tumor histology. The data cutoff date was November 10, 2022 (N=740). Figure 4F EFS was shown in a subgroup of patients with squamous cell carcinoma histology, and Figure 4G EFS (at study baseline) is shown in the subgroup of patients with non-squamous tumor histology. EFS was defined as the time from randomization to the earliest of the following: (i) progressive disease that prevents surgery; (ii) progressive disease discovered and reported by the investigator during surgery in an attempt to prevent termination of the procedure; (iii) local or distant recurrence using blinded independent central review according to the Solid Tumor Response Evaluation Criteria version 1.1; or (iv) death from any cause. CI, confidence interval; D, durvalbumin; EFS, event-free survival; HR, hazard ratio; PBO, placebo.

[0058] Figure 5The final analysis of pathological responses based on center review is presented in the modified treatment intention-to-treat population. The data cutoff point was November 10, 2022 (N=740). The left panel shows pCR. The right panel shows MPR. pCR is defined as the absence of viable tumor cells after complete evaluation of the resected lung cancer sample and all sampled regional lymph nodes. MPR is defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer sample. To qualify for pathological evaluation, patients were required to receive three cycles of neoadjuvant study therapy according to the protocol, followed by in-process surgery, and unevaluable patients were classified as non-responders. No formal statistical tests were performed in the final analysis of complete pathological responses (data cutoff, November 10, 2022; n=740 [data shows]); statistical significance was achieved in the interim analysis (data cutoff, January 14, 2022; n=402), where p-values ​​were calculated using the stratified Cochran-Mantel-Haenszel test, significance boundary = 0.000082, calculated using the Lan-DeMets α exhaustion function and O'Brien Fleming boundary.

[0059] Figure 6 The final analysis of pathological responses based on central review is presented in the modified intention-to-treat population. The data cutoff point was November 10, 2022 (N=740). Forest plots are pCRs in pre-specified patient subgroups (where the size of the circles is proportional to the number of patients in each subgroup, and the horizontal bars represent the 95% CI). Statistical significance was achieved in the interim analysis (data cutoff point, January 14, 2022; n=402), where p-values ​​were calculated using the stratified Cochran-Mantel-Haenszel test, significance boundary = 0.000082, calculated using the Lan-DeMets α exhaustion function and the O'Brien Fleming boundary. Race was determined based on eCRF self-reporting. †Determined using Ventana SP263 immunohistochemical assay. AJCC stands for American Joint Committee on Cancer, ECOG PS for Eastern Cooperative Oncology Group performance status, eCRF for Electronic Case Report Form, PD-L1 for Programmed Cell Death Ligand 1, and TC for Tumor Cells.

[0060] Figures 7A to 7B This presents an interim analysis of pathological responses based on central review in the modified intention-to-treat (mITT) population. The data cutoff point was January 14, 2022 (N=402). Figure 7A Display pCR, and Figure 7BThis interim analysis shows the MPR in the pCR interim cohort (the top approximately 400 patients in the mITT cohort who had the opportunity to undergo surgery and a full central pathology evaluation for pCR [including patients ineligible for surgery]). pCR was defined as the absence of any viable tumor cells after a fully evaluated resected lung cancer sample and all sampled regional lymph nodes. MPR was defined as ≤10% viable tumor cells in the primary lung tumor after a fully evaluated resected lung cancer sample. To qualify for pathology evaluation, patients underwent three cycles of neoadjuvant study therapy according to the protocol, and ineligible patients were classified as nonresponders. Statistical significance was achieved in this interim analysis (N=402). P-values ​​were calculated using the stratified Cochran-Mantel-Haenszel test, with a significance margin of 0.000082, calculated using the Lan-DeMets α exhaustion function and the O'Brien Fleming margin. CI, confidence interval; D, durvalumab; MPR, primary pathological response; PBO, placebo; pCR, complete pathological response.

[0061] Figure 8 Subgroup analyses of major pathological responses (MPRs) in the central review population, based on a modified treatment intention-to-treat cohort, are presented. The data cutoff point was November 10, 2022 (N=740). The figure shows a forest plot of MPRs in pre-specified patient subgroups (where the size of the circles is proportional to the number of patients in each subgroup, and the horizontal bars represent 95% confidence intervals). MPR was defined as ≤10% viable tumor cells in the primary lung tumor after fully evaluable resection of a lung cancer sample. To qualify for pathological evaluation, patients were required to have received three cycles of neoadjuvant study therapy according to the protocol, and non-evaluable patients were classified as non-responders. Race was determined based on eCRF self-reporting. †Determined using Ventana SP263 immunohistochemical assay. AJCC, American Joint Committee on Cancer; D, durvalumab; ECOG PS, Eastern Cooperative Oncology Group performance status: eCRF, electronic case report form; MPR, major pathological response; PBO, placebo; PD-L1, programmed cell death ligand 1; TC, tumor cells.

[0062] Figure 9The modified treatment intention group is shown. The data cutoff point was November 10, 2022 (N=740). Pathological regression was summarized based on patients with evaluable RVT%. The waterfall plot shows the pathological regression of primary tumors in group D (left) and group PBO (right). Black stars indicate patients with signs of cancer present in any examined lymph nodes or whose lymph nodes are not evaluable. pCR is defined as the absence of any viable tumor cells after complete evaluation of the resected lung cancer sample and all sampled regional lymph nodes. MPR is defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer sample. D, durvalbumin; MPR, major pathological response; PBO, placebo; pCR, complete pathological response; RVT, residual viable tumor.

[0063] Figure 10 This shows the most frequently reported adverse events (AEs) from the Phase 3 study. (Security Analysis Set). DCO = November 10, 2022. The data shown represents adverse events (AEs) reported at a frequency of ≥10% in group D throughout the study period, spanning from the first dose of study Tx (D / PBO / CT) to the earliest of the following: the last dose of study Tx or surgery + 90 days (date of last dose of D / PBO / CT / surgery, +90 days); the date of DCO; or the date of the first subsequent dose of anticancer Tx. † Two patients (n=1 / group) experienced decreased appetite, resulting in death (grade 5); fatal events in group D were assessed by the investigator as potentially related to study Tx. Six patients had grade 5 COVID-19 events (Group D, n=5; PBO, n=1); all COVID-19 deaths were assessed by the investigators as being unrelated to study Tx (Note: COVID-19 is generalized to the grouping term that includes the preferred terms 'COVID-19' and 'COVID-19 pneumonia').

[0064] Those skilled in the art will understand that the elements in the accompanying drawings are shown for simplicity and clarity and are not necessarily drawn to scale. For example, the dimensions of some elements in the drawings may be enlarged relative to other elements to aid in understanding the embodiments of this disclosure. Detailed Implementation

[0065] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide those skilled in the art with general definitions of many terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise stated, the following terms have the meanings assigned to them hereinafter.

[0066] As used herein, the terms “comprise” and “include” and their variations (e.g., “comprises”, “comprising”, “includes”, and “including”) will be understood to indicate that a group of stated components, features, elements, or steps is included, but does not exclude any other components, features, elements, or steps. Any of the terms “comprise”, “substantially constitutes”, and “consisting of” may be replaced by any of the other two terms while retaining their ordinary meaning.

[0067] As used herein, unless the context clearly indicates otherwise, the singular forms “a / kind” and “the / said” include multiple referents.

[0068] As used in this article, “one or more species” can refer to a selection from a group.

[0069] The percentages disclosed herein may differ quantitatively from the disclosed values ​​by ±10%, 20%, or 30%, and remain within the range intended for disclosure.

[0070] Unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, unless the context otherwise expressly indicates otherwise, values ​​expressed herein as ranges may be assumed to be any specific value or subrange within the range stated in different embodiments of this disclosure, up to one-tenth of the unit of the lower limit of that range.

[0071] As used herein, ranges and quantities can be expressed as “about” a specific value or range. The term “about” also includes precise quantities. For example, “about 5%” means “about 5%” as well as “5%”. The term “about” can also refer to ±10% of a given value or range of values. Thus, about 5% also means, for example, 4.5%-5.5%. Additionally, “about” or “substantially comprises” can mean a range of up to ±10%. Furthermore, particularly with respect to biological systems or processes, these terms can mean a value of up to one order of magnitude or up to five times. When a specific value or composition is provided in this application and claims, unless otherwise stated, the meaning of “about” or “substantially comprises” should be assumed to be within an acceptable margin of error for that specific value or composition. Unless the context clearly indicates otherwise, all numerical values ​​provided herein are modified by the term “about”.

[0072] As described herein, unless otherwise specified, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer value within the range listed, and, where appropriate, its fractions (such as one-tenth and one-hundredth of an integer).

[0073] Units, prefixes, and symbols are represented in their internationally recognized (SI) form. Numerical ranges include the values ​​that define that range. Unless otherwise indicated, nucleotide sequences are written from left to right with a 5' to 3' orientation. Amino acid sequences are written from left to right with an amino-to-carboxyl orientation. The headings provided herein are not intended to limit the various aspects of this disclosure, which can be obtained by referring to the entire specification. Therefore, the terms that are immediately defined below are more fully defined by reference to the entire specification.

[0074] As used herein, the terms “or” and “and / or” can describe multiple components that are combined or mutually exclusive. For example, “x, y and / or z” can refer to “x” alone, “y” alone, “z” alone, “x, y and z”, “(x and y) or z”, “x or (y and z)” or “x or y or z”.

[0075] This disclosure generally relates to methods for treating patients with resectable non-small cell lung cancer (R-NSCLC). This disclosure demonstrates that perioperative durvalumab combined with neoadjuvant chemotherapy significantly improves both pathological complete response and event-free survival in patients with resectable NSCLC.

[0076] As used in this disclosure, unless otherwise stated, all technical and scientific terms should be understood to have the same meaning as commonly understood by one of ordinary skill in the art. Unless the context requires otherwise, singular terms should include plural forms and plural terms should include singular forms.

[0077] In one aspect, this disclosure provides a method for treating a patient diagnosed with resectable non-small cell lung cancer (R-NSCLC), the method comprising administering a combination therapy to the patient comprising duvalumab and platinum-based chemotherapy.

[0078] In one aspect, this disclosure provides a method for treating a subject identified as having resectable non-small cell lung cancer (R-NSCLC), the method comprising administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every 3 weeks (Q3W) for approximately 4 cycles; surgical removal of the R-NSCLC; and then administering approximately 1500 mg of durvalumab to the patient approximately every 4 weeks (Q4W) for at least approximately 12 weeks.

[0079] In one aspect, this disclosure provides a combination therapy comprising duvalumab and platinum-based chemotherapy for use in the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients in need.

[0080] In one aspect, this disclosure provides a combination therapy for use in treating a subject diagnosed with resectable non-small cell lung cancer (R-NSCLC), wherein the combination therapy comprises: administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every 3 weeks (Q3W) for approximately 4 cycles; and then administering approximately 1500 mg of durvalumab to the patient approximately every 4 weeks (Q4W) after surgical removal of the R-NSCLC for at least approximately 12 weeks.

[0081] In one aspect, this disclosure provides a combination therapy formulated for use in treating a subject diagnosed with resectable non-small cell lung cancer (R-NSCLC), wherein the combination therapy comprises: administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every 3 weeks (Q3W) for approximately 4 cycles; and then administering approximately 1500 mg of durvalumab to the patient approximately every 4 weeks (Q4W) after surgical removal of the R-NSCLC for at least approximately 12 weeks.

[0082] In one aspect, this disclosure provides the use of a combination therapy comprising duvalumab and platinum-based chemotherapy for the manufacture of a medicament for the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients of need.

[0083] In one aspect, this disclosure provides the use of duvalumab and platinum-based chemotherapy in the manufacture of a medicament for the treatment of resectable non-small cell lung cancer (R-NSCLC) in combination therapy, wherein the combination therapy comprises: administering about 1500 mg of duvalumab and platinum-based chemotherapy to a patient approximately every 3 weeks (Q3W) for about 4 cycles; surgical removal of R-NSCLC; and then administering about 1500 mg of duvalumab to the patient approximately every 4 weeks (Q4W) for at least about 12 weeks.

[0084] As used herein, the terms “treat,” “treatment,” or “treating,” when used in the context of treating cancer, refer to reducing disease pathology, reducing or eliminating disease symptoms, promoting increased survival, and / or reducing discomfort. For example, treatment can refer to the ability of a therapy to reduce disease symptoms, signs, or causes when administered to a subject. Treatment also refers to alleviating or reducing at least one clinical symptom and / or inhibiting or delaying the progression of symptoms and / or preventing or delaying the onset of the disease or illness.

[0085] As used herein, the terms “subject,” “individual,” or “patient” refer to any subject for whom diagnosis, prognosis, or treatment is desired, particularly mammalian subjects. Mammal subjects include, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, etc. The term “patient” can refer to a human.

[0086] In one aspect, this disclosure provides a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC). In some embodiments, the patient with R-NSCLC is newly diagnosed. In some embodiments, the patient with R-NSCLC is previously untreated. In some embodiments, the patient with R-NSCLC is histologically or cytologically documented as having stage II or III cancer (according to the American Joint Committee on Cancer Staging Manual, 8th edition). In some embodiments, the patient with R-NSCLC is histologically or cytologically documented as having stage IIA to selected [N2] stage IIIB cancer (according to the American Joint Committee on Cancer Staging Manual, 8th edition). In some embodiments, the patient with R-NSCLC is newly diagnosed, previously untreated, and histologically or cytologically documented as having resectable NSCLC (stage IIA to selected [N2] stage IIIB, according to the American Joint Committee on Cancer Staging Manual, 8th edition). In some implementations, patients with R-NSCLC have resectable stage IIA to select (i.e., N2) IIIB disease (according to the 8th edition of the IASLC Staging Manual in Thoracic Oncology 2016). In some implementations, subjects with R-NSCLC are candidates for planned lobectomy, sleeve resection, or bilobectomy at the time of enrollment.

[0087] In some implementations, the PD-L1 status of the patient's R-NSCLC is determined prior to treatment. In some implementations, the patient's R-NSCLC has <1% PD-L1 tumor cell expression (i.e., less than 1% of tumor cells express PD-L1). In some implementations, the patient's R-NSCLC has 1%–49% PD-L1 tumor cell expression. In some implementations, the patient's R-NSCLC has ≥50% PD-L1 tumor cell expression. In some implementations, the patient's tumor PD-L1 expression status is determined using a Ventana PD-L1 (SP263) immunohistochemical (IHC) assay applied to formalin-fixed paraffin-embedded tissue samples.

[0088] In some implementations, R-NSCLC is squamous cell carcinoma. In some implementations, R-NSCLC is non-squamous cell carcinoma. In some implementations, the tumor EGFR and ALK status of the patient's R-NSCLC is determined prior to treatment. In some implementations, the patient does not have EGFR mutations and / or ALK translocations. In some implementations, EGFR / ALK testing is not required for patients with Kirsten rat sarcoma (KRAS) mutations in their tumors, and ALK testing is not required for patients with squamous cell carcinoma.

[0089] As used herein, the term "dulvarumab" refers to an antibody that selectively binds to PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors. The duvalumab antibody is disclosed in U.S. Patent No. 9,493,565 (referred to as "2.14H9OPT"), which is incorporated herein by reference in its entirety. The crystallizable fragment (Fc) domain of duvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to complement component C1q and the Fcγ receptor responsible for mediating antibody-dependent cell-mediated cytotoxicity ("ADCC"). In some embodiments, the triple mutation refers to an IgG1 Fc region containing the L234F / L235E / P331S triple mutation (EU No.; see also US 9,493,565). Duvalumab alleviates PD-L1-mediated inhibition of human T-cell activation in vitro and inhibits tumor growth in xenograft models via a T-cell-dependent mechanism. The amino acid sequence of duvalumab is as follows:

[0090]

[0091] As used herein, the term "platinum-based chemotherapy" refers to chemotherapeutic agents containing elemental platinum. Platinum-based chemotherapy has been used to treat many different types of cancer. In some embodiments, platinum-based chemotherapy refers to chemotherapy treatment comprising at least one of one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, platinum-based chemotherapy may also refer to chemotherapy treatment comprising at least one or more of triplatinum tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In some embodiments, platinum-based chemotherapy further includes one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments, platinum-based chemotherapy includes carboplatin and paclitaxel. In some embodiments, platinum-based chemotherapy includes cisplatin and gemcitabine. In some embodiments, platinum-based chemotherapy includes carboplatin and gemcitabine. In some embodiments, platinum-based chemotherapy includes carboplatin and pemetrexed. In some embodiments, platinum-based chemotherapy comprises cisplatin and pemetrexed. In some embodiments, platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of approximately 5 mg / mL / min to 6 mg / mL / min. In some embodiments, platinum-based chemotherapy comprises approximately 75 mg / mL / min. 2 The cisplatin dose. In some implementations, platinum-based chemotherapy comprises approximately 200 mg / m². 2 The dosage of paclitaxel. In some implementations, platinum-based chemotherapy comprises approximately 500 mg / m².2 The dosage of pemetrexed. In some implementations, platinum-based chemotherapy contains approximately 1250 mg / m². 2 Gemcitabine dosage.

[0092] In some implementations, the combination therapy may be neoadjuvant durvalumab and neoadjuvant chemotherapy. In some implementations, the combination therapy may be perioperative durvalumab and neoadjuvant chemotherapy. In some implementations, the combination therapy may include neoadjuvant durvalumab, neoadjuvant chemotherapy, and adjuvant durvalumab.

[0093] In some implementations, the combination therapy includes administering approximately 1000 mg to approximately 2000 mg of duvalumab every 14 to 28 days prior to surgery for up to 3 to 6 cycles to remove resectable NSCLC, followed by administering approximately 1000 mg to approximately 2000 mg of duvalumab every 14 to 28 days post-surgery for up to 12 cycles. In some implementations, the combination therapy includes administering approximately 1500 mg of duvalumab every three weeks (Q3W) prior to surgery for up to 4 cycles to remove resectable NSCLC, followed by administering approximately 1500 mg of duvalumab every four weeks (Q4W) post-surgery for up to 12 cycles. In some implementations, the combination therapy includes administering an amount of duvalumab determined by the patient's weight. For example, if a patient’s weight drops to 30 kg or less [≤30 kg], the patient should receive a weight-based dose of durvalumab [or placebo] equivalent to about 20 mg / kg approximately every 3 weeks or every 4 weeks until the weight improves to >30 kg, at which point the patient should begin a fixed dose of durvalumab about 1500 mg [or placebo] approximately every 3 weeks or every 4 weeks.

[0094] In some embodiments, duvalumab may be provided as a 500 mg vial solution for infusion after dilution. In some embodiments, the solution contains 50 mg / mL duvalumab, 26 mM histidine / histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% w / v polysorbate 80; it has a pH of 6.0 and a density of 1.054 g / mL. In some embodiments, a dose of approximately 1500 mg (for patients weighing >30 kg) can be administered using an IV bag containing 0.9% (w / v) saline or 5% (w / v) dextran, wherein the final duvalumab concentration is between 1 mg / mL and 15 mg / mL, and delivered via an IV administration device having a 0.2 μm or 0.22 μm filter. In some embodiments, the amount of duvalumab is determined by the patient's weight. For example, if a patient's weight drops to ≤30 kg, a weight-based administration of 20 mg / kg can be given using a selected IV bag, resulting in a final concentration between 1 mg / mL and 15 mg / mL. In some implementations, the standard infusion time is 1 hour (±10 minutes); however, if there are interruptions, the total permissible time at room temperature must not exceed 8 hours.

[0095] In one aspect, this disclosure provides a method for treating a subject diagnosed with resectable non-small cell lung cancer (R-NSCLC), the method comprising (i) administering durvalumab and platinum-based chemotherapy to the patient at approximately 1000 mg to 2000 mg every 14 to 28 days for approximately 3 to 6 cycles; (ii) surgically removing the R-NSCLC; and then (iii) administering durvalumab at approximately 1000 mg to 2000 mg every 14 to 28 days for at least approximately 12 weeks.

[0096] In some implementations, following surgery to remove resectable NSCLC, patients should begin durvalumab administration when clinically feasible and approximately 10 weeks after the surgery. A minimum of approximately 3 weeks is recommended between surgery to remove resectable NSCLC and the initiation of durvalumab treatment (and if necessary, the first postoperative scan must be performed before the initiation of adjuvant therapy and postoperative radiation therapy). Complete postoperative wound healing must occur after any surgery.

[0097] In some implementations, the surgical removal of resectable NSCLC should occur approximately 40 days from the last administration of durvalumab.

[0098] In some implementations, procedures for removing resectable NSCLC include pulmonary resection, lobectomy, segmentectomy or wedge resection, sleeve resection, or bilobectomy. Pulmonary resection is a procedure that removes the entire lung and may be necessary if the mass is close to the center of the chest cavity. Lobectomy removes one or more of the five affected lobes of the lung (three in the right lung and two in the left lung) and removes the entire lobe containing the tumor. Segmentectomy or wedge resection removes only a portion of a lobe (i.e., a segment or wedge) and may be used if the patient does not have sufficient normal lung function to tolerate the removal of the entire lobe. In addition to the surrounding lobes, sleeve resection involves removing a portion of the bronchus and then rejoining the healthy ends of the bronchus together. In some implementations, procedures for removing resectable NSCLC include anatomical pulmonary resection of the NSCLC. In some implementations, open thoracotomy or video-assisted thoracoscopic surgery may be performed depending on the physician's expertise. In some implementations, anatomical resection preserving the lung (sleeve lobectomy) is preferred over pulmonary resection if anatomically appropriate and margin-negative resection is achieved. In some implementations, locally extending T3 and T4 tumors may require complete resection of the involved structures with margin-negative features.

[0099] In some implementations, patients may receive postoperative radiation therapy (PORT) after surgery to remove resectable NSCLC. PORT may be administered within approximately 8 weeks post-surgery. In some implementations, adjuvant duvalumab may be initiated no more than approximately 3 weeks after the completion of PORT. In some implementations, adjuvant duvalumab may be initiated no more than approximately 10 weeks post-surgery. In some implementations, PORT is permitted for patients instructed according to local guidelines. In some implementations, PORT may include, but is not limited to, doses ranging from 50 Gy to 60 Gy, administered at 1.8 Gy to 2 Gy fractions, 5 fractions per week, for patients with a positive borderline disease (R1). In some implementations, PORT may include, but is not limited to, doses ranging from 60 Gy to 66 Gy, administered at 1.8 Gy to 2 Gy fractions, 5 fractions per week. In some implementations, intensity-modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3D-CRT) is permitted.

[0100] In some implementations, the success of a treatment is determined by an improvement in pathological complete response (pCR) compared to the standard of care.

[0101] In some implementations, the success of a treatment is determined by an improvement in major pathological response (mPR) compared to the standard of care.

[0102] In some implementations, the success of a treatment is determined by an improvement in event-free survival (EFS) compared to the standard of care, such as neoadjuvant chemotherapy, including neoadjuvant platinum-based chemotherapy.

[0103] Therefore, treatment success can be defined as an increase in EFS, pCR, DFS, OS, and / or mPR in patients treated with (i) neoadjuvant durvalumab and neoadjuvant chemotherapy compared to patients treated with neoadjuvant chemotherapy alone; or (ii) perioperative durvalumab and neoadjuvant chemotherapy compared to patients treated with neoadjuvant chemotherapy alone; or (iii) neoadjuvant durvalumab, neoadjuvant chemotherapy, and adjuvant durvalumab compared to patients treated with neoadjuvant chemotherapy alone.

[0104] In some implementations, the success of the treatment is determined by an improvement of at least approximately 13% in pathological complete response (pCR) compared to the standard of care. In some implementations, the success of the treatment is determined by an improvement of at least approximately 21% in major pathological response (mPR) compared to the standard of care. In some implementations, the success of the treatment is determined by an improvement of at least approximately 13 months in event-free survival (EFS) compared to standard of care.

[0105] In some implementations, the use of combination therapy improves one or more of EFS, pCR, mPR, DFS, and OS compared to the standard of care. In some implementations, the use of combination therapy improves one or more of EFS, pCR and mPR, DFS, and OS compared to platinum-based chemotherapy or platinum-based chemotherapy before or after surgery.

[0106] As used herein, the term “Standard of Care” (SoC) may refer to one or more of the following:

[0107] 1) Carboplatin + Paclitaxel: Carboplatin AUC 6 (mg / mL / min) and Paclitaxel 200 mg / mL 2 It is administered via IV infusion on day 1 of each 3-week cycle, for a total of 4 cycles (for squamous cell carcinoma histology).

[0108] 2) Cisplatin + Gemcitabine: Cisplatin 75mg / m² 2 The treatment lasted for four cycles, administered via IV infusion on day 1 of each three-week cycle, along with gemcitabine 1250 mg / m². 2The cisplatin is administered via IV infusion on days 1 and 8 of each 3-week cycle, for a total of 4 cycles (for squamous cell carcinoma histology). In cases of adverse tolerability, patients may switch from cisplatin to carboplatin at any point during the study period (assuming eligibility for switching therapy). In patients with comorbidities or who, in the investigator's judgment, cannot tolerate cisplatin, carboplatin AUC 5 (mg / mL / min) may be administered from cycle 1.

[0109] 3) Pemetrexed + Cisplatin: Pemetrexed 500mg / m² 2 And cisplatin 75mg / m 2 The drug is administered via IV infusion on day 1 of each 3-week cycle for 4 cycles (for non-squamous histology). In cases of adverse tolerability, patients may switch from cisplatin to carboplatin at any point during the study period (assuming eligibility for switching therapy). In patients with comorbidities or who, in the investigator's judgment, cannot tolerate cisplatin, carboplatin AUC 5 (mg / mL / min) may be administered from cycle 1.

[0110] 4) Pemetrexed + Carboplatin: Pemetrexed 500mg / m² 2 Carboplatin AUC 5 (mg / mL / min) was administered via IV infusion on day 1 of each 3-week cycle for 4 cycles (for non-squamous tumor histology).

[0111] As used herein, the term “event-free survival” or “EFS” refers to the time from randomization to the first of the following: a) local or distant recurrence as determined by BICR using RECIST v1.1; b) death from any cause (event date is the date of death); c) PD that prevents surgery (event date is the date of the determination) or PD discovered and reported by the investigator during an attempt to prevent the termination of surgery (event date is the date of the first surgical attempt). Event-free survival can be analyzed using a log-rank test based on assessment using blinded independent central review (BICR) with RECIST v1.1 and pathological review stratified by disease stage (stage II vs. stage III) and by PD-L1 expression status on mITT (<1% vs. ≥1%). The p-value can be obtained from the stratified log-rank test using the Efron method (Hertz-Picciotto and Rockhill, “Validity and efficiency of approximation methods for tied survival times in Cox regression.” Biometrics 1997; 53(3): 1151-6.) used to handle ties.

[0112] As used herein, the terms “pathologically complete response” or “pathological CR” or “pCR” refer to the proportion of patients who, as assessed by a central pathology laboratory, have 0% residual viable tumor cells in all resected tissues (including primary lung injury and lymph nodes) after neoadjuvant therapy. Patients who are not evaluable according to central pathology assessment (this includes patients with R2 margin) or who do not have surgical samples may be considered non-pCR (e.g., pathology assessment is captured as “not evaluable” or “missing”, as appropriate). Central pathology assessment for pCR will be performed according to the recommended methods and definitions described in IASLC 2020 (Travis et al., “IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy.” J Thorac Oncol. 2020 May; 15(5):709-740. doi:10.1016 / j.jtho.2020.01.005). Analysis can be performed using the Cochran-Mantel-Haenszel (CMH) test, stratified by disease stage (stage II vs. stage III) and PD-L1 expression status (<1% vs. ≥1%). Treatment efficacy will be estimated by the proportional differences between treatment groups and their corresponding CI and p-values.

[0113] As used herein, the terms “disease-free survival” and “DFS” refer to the time from the date of surgery to the first date of disease recurrence as determined by BICR (local or distant) using RECIST 1.1 assessment, or the date of death from any cause (whichever comes first). Pathological confirmation from biopsy lesions may also be considered (if applicable). New primary malignancy confirmed by pathology is not considered a DFS event. Disease-free survival can be analyzed using a log-rank test based on BICR assessment using RECIST 1.1 and pathological review stratified by disease stage (stage II vs. stage III) and by PD-L1 expression status (<1% vs. ≥1%) on a modified correlation analysis set. The p-value can be obtained from the stratified log-rank test using the Efron method (Hertz-Picciotto and Rockhill 1997) for handling tie-breakers.

[0114] As used herein, the terms “major pathological response” and “mPR” refer to the proportion of patients with 10% or less residual viable tumor tissue in a primary lung tumor at the time of resection, as assessed by a central pathology laboratory. Patients who are not evaluable according to central pathology assessment (including those with a borderline R2) or who do not have surgical specimens may be considered to have non-mPR (e.g., the response is captured as “non-evaluable” or “missing,” as appropriate). Analysis can be performed using the CMH test, stratified by disease stage (stage II vs. stage III) and PDL1 expression status (<1% vs. ≥1%). Treatment efficacy can be estimated by the proportion differences between treatment groups and their corresponding CI and p-values.

[0115] As used herein, the terms “overall survival” and “OS” refer to the time from the date of randomization until death from any cause, regardless of whether the subject withdraws from randomized therapy or receives another anticancer therapy. Any patient whose death was unknown at the time of analysis will be reviewed based on the last recorded date of that patient’s known survival. Overall survival in the mITT population can be analyzed using the same methods described for EFS. Treatment effects can be estimated by HR and its corresponding CI. Kaplan-Meier plots can be presented by treatment group. Kaplan-Meier estimates of OS can be used for analysis to estimate the number of patients with OS at 12, 24, 36, 48, and 60 months.

[0116] Intention-to-Treat (ITT) Population: The ITT analysis set includes all randomized patients. Treatment groups are compared based on randomization to the study treatment, regardless of the actual treatment received. Patients who were randomized but subsequently did not continue receiving study treatment are included in the analysis within the treatment group to which they were randomized.

[0117] Modified Intent-to-Treat (mITT) cohort: mITT includes all patients in the ITT, excluding those whose tumors have EGFRm / ALK translocations. Unless otherwise stated, mITT is used for all efficacy analyses, including PRO. Treatment groups are compared based on randomized study treatment, regardless of the actual treatment received.

[0118] The resected population set: The resected set can consist of all patients in the ITT who underwent surgical resection after the neoadjuvant period, did not have an R2 margin, and whose first postoperative scan showed no evaluable disease (defined as no postoperative R2 margin and no RECIST evidence of disease).

[0119] Modified resection population set: The modified resection set may consist of all patients in the resection group, excluding those whose tumors have EGFRm / ALK translocations. Unless otherwise stated, this analysis set is used only for DFS. Treatment groups are compared based on randomized study treatment, regardless of the actual treatment received.

[0120] As used herein, the term "administration" means the provision, contact, and / or delivery of one or more compounds to achieve the desired effect through any suitable route. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, or intralesional injection), percutaneous, topical, oral, rectal, vaginal, nasal, ocular, inhalation, and implantation.

[0121] It should be understood that specific aspects of the specification described herein are not limited to the specific embodiments presented and may vary. It will also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting unless specifically defined herein. Furthermore, as those skilled in the art will recognize, the specific embodiments disclosed herein can be combined with other embodiments disclosed herein without limitation.

[0122] Without limiting this disclosure, many embodiments of this disclosure are described below for illustrative purposes.

[0123] Example

[0124] The following examples illustrate specific embodiments of this disclosure and their various uses. They are described for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0125] Example 1: Neoadjuvant / Adjuvant therapy for patients with resectable non-small cell lung cancer (R-NSCLC) Duvalumab

[0126] The AEGEAN (NCT03800134) study described in this article is a phase III, double-blind, placebo-controlled, multicenter international study evaluating perioperative (i.e., neoadjuvant and adjuvant) durvalumab plus neoadjuvant chemotherapy in patients with resectable stage II and III non-small cell lung cancer (R-NSCLC).

[0127] Although the primary treatment for early-stage non-small cell lung cancer (NSCLC [stages I to IIIA]) is curative surgery, the 5-year survival rate for patients treated with surgery alone remains low, ranging from 67% (stage IA) to 23% (stage IIIA) (Mountain 1997).

[0128] Early studies of immunotherapy in neoadjuvant settings have shown promising clinical activity and acceptable safety profiles in patients with resectable NSCLC (Forde et al., “Neoadjuvant PD-1 blockadein resectable lung cancer.” N Engl J Med 2018; 378:1976-86; Shu et al., “Neoadjuvant atezolizumab + chemotherapy in patients with resectable non-small cell lung cancer (NSCLC).” Poster presented at ASCO Annual Meeting 2018.). Combining chemotherapy with durvalumab before surgery may have clinical benefit over chemotherapy + placebo. Therefore, in this phase III study, we investigated whether administering durvalumab + platinum-based chemotherapy before surgery, followed by further administration of durvalumab after surgery, could improve activity and thus improve long-term clinical outcomes in patients with resectable NSCLC.

[0129] patient

[0130] The study enrolled approximately 1300 patients and randomized approximately 800 eligible patients. Eligible patients had newly diagnosed, previously untreated, histologically or cytologically documented resectable NSCLC (stage IIA to select [N2] stage IIIB, according to the American Joint Committee on Cancer [AJCC] Manual of Cancer Staging, 8th edition). Patients were randomized 1:1 to receive duvalumab plus platinum-based chemotherapy before surgery, followed by duvalumab after surgery (Group 1; intravenous platinum-based chemotherapy plus duvalumab every three weeks (four cycles) before surgery, followed by intravenous duvalumab every four weeks (12 cycles) after surgery), or to receive placebo plus platinum-based chemotherapy before surgery, followed by placebo after surgery (Group 2; intravenous platinum-based chemotherapy plus placebo every three weeks (four cycles) before surgery, followed by intravenous placebo every four weeks (12 cycles) after surgery). Patients were also stratified by disease stage (stage II vs. stage III) and PD-L1 expression status (<1% vs. ≥1%).

[0131] Patients had resectable (stage IIA to select [i.e., N2] IIIB) disease (according to the 8th edition of the IASLC Staging Manual in Thoracic Oncology 2016) and were candidates for planned lobectomy, sleeve resection, or bilobectomy at the time of enrollment. At screening, patients were considered capable of complete surgical resection of primary NSCLC through a multidisciplinary evaluation including a thoracic surgeon who has performed lung cancer surgery as a major part of their practice. Additional inclusion criteria included age 18 years or older; Eastern Cooperative Oncology Group performance status of 0 or 1; estimated life expectancy ≥12 weeks; documented tumor PD-L1 status (e.g., assessed in a central laboratory using VENTANA SP263 immunohistochemistry); and ≥1 previously unirradiated lesion meeting the RECIST v1.1 target lesion criteria.

[0132] A T4 tumor is only eligible if it is defined as T4 based solely on its size (greater than 7 cm); any other reason for T4 (e.g., adhesion to any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina) is considered ineligible.

[0133] The nodule status is investigated using whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) combined with contrast-enhanced computed tomography (CT). If the PET / CT scan is positive in the mediastinum, or if the scan is negative but a T>3cm, central tumor, or clinical N1 (cN1) is present, biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy is recommended to confirm the nodule status. At staging, forced brain magnetic resonance imaging (MRI; preferred) or brain CT using IV contrast agent is performed.

[0134] The patient has not been previously exposed to immune-mediated therapies, including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.

[0135] The tumor PD-L1 status of patients was confirmed prior to randomization using Ventana PD-L1 (SP263) immunohistochemical (IHC) assays on paraffin-embedded tissue samples fixed in formalin, with the tests performed by a central laboratory.

[0136] EGFR and ALK status were also confirmed during screening. EGFR / ALK testing was not required for patients with Kielston rat sarcoma (KRAS) mutations in their tumors, nor was ALK testing required for patients with squamous cell carcinoma. In the modified treatment intention-to-treat population, patients with documented EGFR / ALK abnormalities were excluded from the efficacy analysis (N=740).

[0137] If the planned surgery is a lobectomy, sleeve resection, or bilateral lobectomy, the patient is considered suitable for inclusion, as determined by the attending surgeon based on baseline findings. The patient is deemed to have adequate cardiac and pulmonary function based on a multidisciplinary assessment. Pre- or post-bronchodilator FEV1 is 1.0 L, and the postoperative predictive value is >40%. These cutoff values ​​are used to evaluate resection candidates, guided by the results of cardiopulmonary exercise testing, as outlined in the European Society for Medical Oncology (ESMO) guidelines on pre-treatment risk assessment. FEV1 and DLCO testing are required to assess pulmonary function prior to resection.

[0138] Table 1. Baseline characteristics and planned treatment in the modified treatment intention group.

[0139]

[0140]

[0141] Table 2. Representativeness of Research Participants .

[0142]

[0143] Table 3. Patient Management and Treatment Summary in the Modified Treatment Intention Group .

[0144]

[0145] Table 4. Baseline characteristics of the treatment intention group

[0146]

[0147]

[0148] Table 5. Summary of adverse events in the safety analysis .

[0149]

[0150] Study design and treatment

[0151] Approximately 800 patients with resectable NSCLC (stage IIA to selected stage IIIB; squamous or non-squamous) were randomized in a 1:1 ratio to receive duvalumab plus platinum-based chemotherapy before surgery, followed by duvalumab after surgery (Group 1), or placebo plus platinum-based chemotherapy before surgery, followed by placebo after surgery (Group 2). Patients were stratified by disease stage (stage II vs. stage III) and programmed cell death ligand-1 (PD-L1) expression status (<1% vs. ≥1%).

[0152] Patients received four cycles of duvarulimab or placebo plus platinum-based chemotherapy (every 3 weeks [Q3W]) followed by surgery to remove NSCLC. Surgery consisted of lobectomy, sleeve resection, or bilobectomy, as determined by the attending surgeon based on baseline findings. Patients whose planned surgery at enrollment included lung resection, segmentectomy, or wedge resection at eligibility assessment were ineligible for this study. All patients were staged and managed according to the National Comprehensive Cancer Network 2020 guidelines (version 1.2021). Surgery was expected to be performed within 40 days of administration.

[0153] Patients were initiated with duvalumab or placebo within 10 weeks of surgery, concurrently with clinical feasibility (except for patients receiving postoperative radiotherapy, who were initiated within 8 weeks postoperatively; duvalumab / placebo was administered within 3 weeks of the end of postoperative radiotherapy). Patients randomized before surgery to receive duvalumab plus platinum-based chemotherapy received an additional 12 cycles of duvalumab 1500 mg every 4 weeks (Q4W), while patients randomized before surgery to receive placebo plus platinum-based chemotherapy received an additional 12 cycles of placebo Q4W.

[0154] Treatment and Duration of Treatment: Patients received 1500 mg duvalumab or placebo via intravenous (IV) infusion for up to 4 cycles Q3W before surgery and up to 12 cycles Q4W after surgery, unless unacceptable toxicity was present, consent was withdrawn, or another interruption criterion was met. If a patient's weight (WT) decreased to 30 kg or less (≤30 kg), the patient received WT-based dosing at an equivalent of 20 mg / kg duvalumab [or placebo] Q3W or Q4W after consultation between the investigator and the investigational physician / medical scientist until WT improved to >30 kg, at which point the patient began a fixed dosing of 1500 mg duvalumab [or placebo] Q3W or Q4W.

[0155] Standard of Care (SoC): Based on tumor histology and investigator's judgment, patients receive one of the following four SoC regimens as part of their treatment regimen prior to surgery. For squamous tissue, the choice is carboplatin plus paclitaxel or cisplatin plus gemcitabine (or carboplatin plus gemcitabine for patients with comorbidities or who, in investigator's judgment, cannot tolerate cisplatin). For non-squamous tissue, the choice is pemetrexed plus cisplatin or carboplatin.

[0156] 1) Squamous tumor histology: Carboplatin + Paclitaxel: Carboplatin serum drug concentration-time area under the curve (AUC) 6 (mg / mL / min) and paclitaxel 200 mg / mL 2 It is administered via IV infusion on day 1 of each 3-week cycle, for a total of 4 cycles.

[0157] 2) Histology of squamous cell carcinoma: Cisplatin + Gemcitabine: Cisplatin 75 mg / m² 2 The treatment lasted for four cycles, administered via IV infusion on day 1 of each three-week cycle, along with gemcitabine 1250 mg / m². 2 The medication was administered via IV infusion on days 1 and 8 of each 3-week cycle for 4 cycles. In the event of adverse tolerability, patients were switched from cisplatin to carboplatin at any point during the study period (assuming eligibility for switching therapy). In patients with comorbidities or those deemed intolerant of cisplatin by the investigator, carboplatin AUC 5 (mg / mL / min) was administered starting from cycle 1.

[0158] 3) Histology of non-squamous tumors: Pemetrexed + cisplatin: Pemetrexed 500mg / m² 2 And cisplatin 75mg / m 2 The medication was administered via IV infusion on day 1 of each 3-week cycle for 4 cycles. In the event of adverse tolerability, patients were switched from cisplatin to carboplatin at any point during the study period (assuming eligibility for switching therapy). In patients with comorbidities or those deemed intolerant to cisplatin by the investigator, carboplatin AUC 5 (mg / mL / min) was administered starting from cycle 1.

[0159] 4) Histology of non-squamous tumors: Pemetrexed + Carboplatin: Pemetrexed 500mg / m² 2 Carboplatin AUC 5 (mg / mL / min) was administered via IV infusion on day 1 of each 3-week cycle for 4 cycles.

[0160] Treatment duration: Unless unacceptable toxicity is present, consent is withdrawn or another interruption criterion is met, treatment is administered with 4 cycles of duvalumab or placebo plus platinum-based chemotherapy (Q3W) before surgery, and duvalumab or placebo is continued for 12 cycles (Q4W) (±1 cycle of platinum-based chemotherapy) after surgery.

[0161] Surgery is expected to be performed within 40 days of the last preoperative IP dose, and patients should begin duvalumab or placebo administration concurrently with clinical feasibility and within 10 weeks of surgery (except for patients receiving postoperative radiotherapy, who should begin within 8 weeks postoperatively; duvalumab / placebo should be administered within 3 weeks of the end of postoperative radiotherapy). For patients eligible for adjuvant duvalumab or placebo, surgery must be performed at an R0 or R1 resection margin, with no signs of disease on the first postoperative assessment using RECIST v1.1.

[0162] Progression during treatment: Discontinue treatment if local or distant recurrence or clinical progression (including progression excluding surgery or progression detected during an attempt to perform surgery) is identified by the investigator using RECIST 1.1.

[0163] Patient follow-up after interruption of investigational drug: Patients who interrupted investigational treatment due to toxicity or worsening of symptoms, clinical progression (excluding progression excluding surgery or progression discovered during attempted surgery), or who started subsequent anticancer therapy without local or distant recurrence (for resected patients) or radiological disease progression (PD) as defined in RECIST 1.1 (for patients who did not undergo surgery for reasons other than PD), were followed up with tumor assessment until local or distant recurrence (for resected patients) or radiological PD as defined in RECIST 1.1 (for patients who did not undergo surgery for reasons other than PD) was determined by the investigator, and survival was followed up. These patients were not eligible for retreatment at any time.

[0164] Endpoint and Assessment

[0165] The two primary efficacy endpoints in this study were event-free survival (EFS; according to blinded independent central review [BICR]) and pathological complete response (pCR; central assessment). Other secondary endpoints included assessment of primary and key secondary endpoints in patients with PD-L1 expression ≥1%; pharmacokinetics and immunogenicity; patient-reported outcomes; and safety. According to FDA guidance on clinical trial endpoints for approved cancer drugs and biologics (FDA 2018), EFS is defined as the time from randomization to any of the following events: disease progression (PD) excluding surgery, local or distant recurrence, or death from any cause. More specifically, EFS is defined as the time from randomization to the earliest of the following: (1) progressive disease that prevents surgery; (2) progressive disease discovered and reported by the investigator during surgery in an attempt to prevent the termination of surgery; (3) local or distant recurrence according to RECIST v1.1 using blinded independent central review; or (4) death from any cause. Failure to undergo / complete surgery due to reasons other than progressive disease is not considered an EFS event (i.e., the patient is still in follow-up for progression as defined by RECIST).

[0166] Using recommendations from the IASLC, the pathological response of the primary tumor and sampled lymph nodes to neoadjuvant therapy was assessed via central pathology review. To qualify for pathological evaluation, patients should undergo three cycles of neoadjuvant study therapy according to the protocol; patients ineligible for evaluation (including those with R2 resection margins assessed locally) or without surgical samples were classified as non-responders. pCR is defined as the absence of any viable tumor cells after complete evaluation of the resected lung cancer sample and all sampled regional lymph nodes, and MPR is defined as ≤10% viable tumor cells in a primary lung tumor (Travis et al., “IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy.” J Thorac Oncol. May 2020; 15(5):709-740. doi: 10.1016 / j.jtho.2020.01.005; Hellmann et al., “Pathological response after neoadjuvant chemotherapy inresectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.” Lancet Oncol 2014; 15(1):e42-50; Cottrell et al., “Pathologic features of response to neoadjuvant anti-PD-1 inresected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).” Ann Oncol 2018;29(8):1853-1860).

[0167] While time-onset endpoints and overall survival (OS) are generally considered preferred outcome measures for stage III cancer studies in early-stage disease, they often result in very long NSCLC studies. Therefore, time-onset endpoints and OS are difficult to achieve within a reasonable timeframe. Endpoints demonstrating early clinical benefit (such as mPR and pCR) can also be used to assess efficacy in early-stage NSCLC studies, provided the magnitude of the benefit is clinically meaningful.

[0168] Secondary efficacy endpoints in this study included disease-free survival (DFS) (modified resection set and PD-L1 TC≥1% resection set), pCR (PD-L1 TC≥1% analysis set), major pathological response (mPR) (mITT and PD-L1 TC≥1% analysis set), EFS (PD-L1 TC≥1% analysis set), and overall survival (OS) (mITT and PD-L1 TC≥1% analysis set).

[0169] Disease-free survival (DFS) is defined as the time from the date of surgery to the first date of disease recurrence (local or distant) or death from any cause, whichever comes first. Pathological confirmation of the biopsy lesion may also be considered, if applicable, based on investigator judgment and local practice. New primary malignancy confirmed by pathology is not considered a DFS event.

[0170] Table 6. Endpoints and Evaluation

[0171]

[0172]

[0173] Tumors were assessed according to RECIST v1.1 using images collected at the following time points: baseline (≤28 days before randomization); after completion of neoadjuvant therapy and before surgery; 5 weeks (±2 weeks) after surgery and before initiation of adjuvant therapy; every 12 weeks (±1 week) after surgery until week 48; every 24 weeks (±2 weeks) until week 192 (i.e., approximately 4 years after surgery); and thereafter every 48 weeks (±2 weeks) until local or distant recurrence, consent to withdrawal, or death.

[0174] Safety was monitored throughout the study, and AEs were graded using the National Cancer Institute Adverse Event (AE) General Toxicity Criteria version 5.0.

[0175] Efficacy assessments were performed and determined by pathological review or by using RECIST 1.1 to evaluate BICR (if applicable), including EFS (mITT and PD-L1 TC ≥ 1% analysis set), pCR (mITT and PD-L1 TC ≥ 1% analysis set), mPR (mITT and PD-L1 TC ≥ 1% analysis set), DFS (modified resection set and PD-L1 TC ≥ 1% resection set), and OS (mITT and PD-L1 TC ≥ 1% analysis set). PD excluding surgery or EFS events of PD detected during surgery that prevented surgical termination were determined by the investigator.

[0176] In the interim analysis of the first program, the EFS follow-up of the reviewed patients was 11.7 months (range: 0.0–46.1).

[0177] Statistical analysis

[0178] The two primary endpoints in this study were event-free survival (EFS) and pathological complete response (pCR) in the modified intention-to-treat (mITT) population. Key secondary endpoints were disease-free survival (DFS) in the modified resection population and major pathological response (mPR) and overall survival (OS) in the mITT population. The family error rate was strongly controlled at a 5% two-sided level through multiple testing procedures. The testing procedures were stratified as they began by testing the two primary endpoints, EFS and pCR. The overall 5% two-sided type I error was separated between the two primary endpoints, EFS and pCR. A 4.5% alpha level was allocated to the EFS analysis and a 0.5% alpha level was allocated to the pCR analysis.

[0179] The mITT consortium includes all randomized patients, excluding those whose tumors have epidermal growth factor receptor mutations (EGFRm) or anaplastic lymphoma kinase (ALK) translocations. Unless otherwise stated, mITT is used in all efficacy analyses, including PRO. Treatment groups are compared based on randomized study treatment, regardless of the actual treatment received.

[0180] An interim analysis (IA) of pCR was performed when approximately 400 mITT patients were available for surgery (actual N=402), and a final analysis was performed once all mITT patients (actual N=740) were available for surgery. Stratified CMH tests were used to compare pCR and MPR rates between study groups. The CI for differences between groups was estimated using the MN confidence limit. The first interim EFS analysis (presented here) was planned for approximately 30% of the due dates (actual EFS due dates: 31.9%).

[0181] Comparisons between study groups were analyzed using the stratified log-rank test. HR and 95% CI were estimated from the stratified Cox-Phase model. The median and threshold of the EFS were estimated using the KM method.

[0182] For pathological endpoints, stratified Cochran-Mantel-Haenszel tests were used to compare response rates between treatment groups; treatment efficacy was estimated by differences in response rates, with their corresponding 95% confidence intervals (CIs) calculated using stratified Miettinen and Nummien methods. Stratified log-rank tests were used to compare efficacy against deficiency for disease (EFS) between treatment groups; treatment efficacy was estimated by HR and 95% CI calculated using a stratified Cox proportional hazards model. The median and threshold of EFS were estimated using the Kaplan-Meier method. Stratification of primary and key secondary endpoints was based on disease stage and PD-L1 expression. Planned analyses of the primary endpoint were performed in pre-specified subgroups. For pCR, differences in response rates were calculated for each subgroup, with the corresponding 95% CI estimated using unstratified Miettinen and Nummien methods; for EFS, HR and 95% CI were calculated for each subgroup using a Cox proportional hazards model, with treatment as the sole covariate.

[0183] To strongly control type I error to 5% (two-sided), a stratified multiple testing procedure with a gating strategy was used between the primary endpoint and the secondary endpoint controlled by α. Initially, 0.5% α and 4.5% α were allocated to pCR and EFS, respectively. The Lan-DeMets consumption function was used to separate α between the interim and final analyses (IA and FA, respectively), which approximates the O'BrienFleming method to account for multiple time-point assessments (Lan and DeMets, "Discrete Sequential Boundaries for Clinical Trials", Biometrika Vol. 70, No. 3 (December 1983), pp. 659-663). A positive pCR result allowed α to be recycled to the critical secondary endpoint MPR, which in turn could be recycled to EFS (to provide a total of 5% α). Based on the total 0.5% α allocated to the pCR endpoint, the planned IA of pCR (assuming 400 patients in the modified intention-to-treat [mITT] group at IA and 740 patients in the mITT group at FA) had a 55% capability to detect statistically significant intergroup differences of 12%, with a two-sided significance level of 0.0078%; MPR (a secondary endpoint controlled by α) was also formally analyzed at IA. For EFS, a nonlinear (k=2) cumulative hazard was assumed over 33 months, with a 3-month hazard delay, resulting in a assumed hazard ratio of 1.0 for the previous 3 months and an assumed hazard ratio (HR) of 0.63 after 3 months, to give an approximate total HR of 0.67 at FA. Based on the total 4.5% alpha allocated to the EFS endpoint, for the first interim analysis of EFS, if the true total HR is 0.69 and there are 224 EFS events in the mITT population (each blinded independent center review) (N=740), the study would provide 50% capacity to demonstrate a statistically significant EFS effect, with a two-sided significance level of 0.6649%. Since pCR and MPR are statistically significant, EFS is tested using the allocated total 5% alpha. The actual significance level is calculated based on the number of patients or events observed at the time of the interim analysis, respectively, compared to the planned number of patients or events at the time of the final analysis for each endpoint.

[0184] Table 7. Interim Analysis Groups .

[0185]

[0186] result

[0187] Patients and treatment

[0188] 1,480 patients were recruited, of whom 802 were randomized to either the duvarubib group (n=400) or the placebo group (n=402), including the ITT population ( Figure 1B The characteristics of the ITT population (Table 4) generally represent a real-world population of patients with resectable NSCLC (Table 2). The mITT population (excluding patients with known EGFR / ALK abnormalities) comprised 740 patients, of whom 366 and 374 were randomized to the duvarubab and placebo groups, respectively. Baseline demographics and clinical characteristics, as well as the planned neoadjuvant chemotherapy dual regimen, were largely balanced between the treatment groups in the mITT population (Table 1). The median age was 65.0 years, and the majority of patients were male (71.6%), had a performance status of 0 (68.4%), and were current or former smokers (85.5%). Over 70% of patients had stage III disease, and half of all patients had N2 disease. Approximately equal proportions of patients had squamous and non-squamous histology. In both treatment groups, 33.4% of patients had <1% tumor PD-L1 expression, and carboplatin was the planned neoadjuvant platinum agent for over 70% of patients.

[0189] At the data cutoff point of this first-plan interim analysis of EFS, the median follow-up for EFS among the reviewed patients was 11.7 months (range, 0.0–46.1). In the mITT cohort, approximately 85% of patients completed four cycles of two chemotherapy agents in each treatment group, and over 60% of all patients initiated adjuvant durvalumab or placebo (Table 3; see Table 8 for details of neoadjuvant exposure). A small number of patients in either treatment group (5.8% in the mITT cohort) received postoperative radiation therapy (as permitted by protocol, and at the discretion of the treating physician if indicated). At the data cutoff point of this analysis, 24.0% and 21.1% of patients in the mITT cohort, respectively, completed 12 cycles of adjuvant durvalumab or placebo; 18.6% and 18.7% of patients in each group, respectively, had prematurely discontinued adjuvant study therapy. Approximately one-quarter of all patients in the mITT population are still receiving adjuvant study therapy (23.2% and 23.5% of patients in the duvarulimab and placebo groups, respectively).

[0190] Table 8. Neoadjuvant therapy exposures in the safety analysis set. .

[0191]

[0192] Surgical Overview

[0193] At the data cutoff, approximately 81% of patients in each treatment group (Table 3; mITT population) underwent surgery (note that thoracic surgery with curative intent was attempted regardless of completion). In total, 77.6% of patients in the duvalumab group and 76.7% of patients in the placebo group completed surgery (i.e., thoracic surgery with curative intent was completed according to investigator assessment), with a slightly higher proportion of R0 resections in the duvalumab group compared to the placebo group (94.7% vs. 91.3%). (For a summary of the most common reasons for not undergoing or completing surgery in the ITT population, details of surgical delays in the safety analysis set [Table 9], and surgical details and outcomes in the mITT population [Table 10], see Tables 9 and 10.)

[0194] Table 9. Details of Surgical Delays in the Safety Analysis Set .

[0195]

[0196] Table 10. Surgical details and outcomes in the revised treatment intention group .

[0197]

[0198]

[0199] effect

[0200] In the first-phase interim analysis with an EFS of 31.9% due date, the duvarubib group had a significantly prolonged EFS compared to the placebo group [stratified hazard ratio, 0.68; 95% CI, 0.53 to 0.88]; P = 0.003902], namely, the median time not reached (NR) (95% CI, 31.9 months to NR) and 25.9 months (95% CI, 18.9 months to NR) (…). Figure 2 In most pre-specified subgroups, the EFS benefit of duvarulimab compared to placebo was maintained. Figure 3 Consistent benefits were observed regardless of the planned new adjuvant platinum agent (Figure 4). This benefit was observed regardless of age or disease stage. Figure 4B ), PD-L1 tumor cell expression ( Figures 4C to 4E ) and tumor histology ( Figures 4F to 4G Benefits were observed in all cases. The magnitude of the benefit was greater for current smokers. Female patients appeared to have a smaller treatment effect, but the HR CI was wide in this subgroup, representing only 28.4% of the mITT population.

[0201] Table 11. Preoperative data in the modified treatment intention group based on blinded independent central review (RECIST v1.1) objective response .

[0202]

[0203] In the final analysis of pCR, a higher proportion of patients in the duvarulimab group achieved pCR (17.2%; 95% CI, 13.5 to 21.5) compared to the placebo group (4.3%; 95% CI, 2.5 to 6.9) (proportion difference, 13.0%; 95% CI, 8.7 to 17.6). Figure 5 A higher proportion of patients in the duvarubicin group also achieved MPR (33.3%; 95% CI, 28.5 to 38.4) compared to the placebo group (12.3%; 95% CI, 9.1 to 16.1) (proportion difference, 21.0; 95% CI, 15.1 to 26.9). Figure 5 The results of pCR and MPR were consistent in the interim analysis of pCR (N=402). Figures 7A to 7B In this early analysis, statistical significance for pCR (P=0.0036) and MPR (P=0.000002) was achieved. A trend toward pCR benefit from durvalumab was observed in all pre-specified subgroups, with results largely consistent with the overall mITT population. Figure 6 A similar trend was observed in the MPR subgroup. Figure 8 Overall, the pathological regression of primary tumors was greater in the durvalumab group than in the placebo group. Figure 9 Table 11 summarizes the objective preoperative response in the mITT population.

[0204] Security

[0205] Overall, adverse events (AEs) of any cause occurred in 96.5% of patients in the duvalumab group and 94.7% of patients in the placebo group (Table 5); AEs potentially related to any study treatment (i.e., duvalumab, placebo, or chemotherapy) occurred in 86.5% and 80.7%, respectively. The incidence of Grade 3 or 4 AEs of any cause was similar between the study groups (42.3% vs. 43.4%); similarly, the incidence of Grade 3 or 4 AEs potentially related to any study treatment was also similar (32.3% vs. 33.1%). AEs potentially related to any study treatment with a fatal outcome were uncommon, occurring in 1.8% and 0.5% of the duvalumab and placebo groups, respectively. The most common AEs of any cause largely reflected the safety profile of the chemotherapy agents used in the studies (Table 12); the rates of the most common AEs were largely similar in both treatment groups. Patients in the duvalumab group had a higher incidence of rash of any grade (14% vs. 8.5%) and pruritus (11.8% vs. 5.5%) than those in the placebo group; however, grade 3 or 4 events were uncommon and occurred at similar frequencies in both treatment groups. (See Table 13 for a summary of the most common AEs that may be associated with any study treatment.) In the duvalumab and placebo groups, immune-mediated AEs of any grade were reported in 23.7% and 9.8% of patients, respectively (Table 14); most were grade 1 or 2, with grade 3 or 4 events reported in 4.2% and 2.5% of patients, respectively. In the duvalumab and placebo groups, immune-mediated pneumonia of any grade was reported in 3.7% and 1.8% of patients, respectively.

[0206] Table 12. Most common adverse events of any cause in the safety analysis set .

[0207]

[0208] Table 13. Most common adverse events likely related to the study treatment in the safety analysis. .

[0209]

[0210] Table 14. Safety Analysis: Immune-mediated adverse events occurred in ≥1% of patients in any treatment group (groups). the term) .

[0211]

[0212] Summarize

[0213] Compared to neoadjuvant chemotherapy (CT) alone, perioperative durvalumab plus neoadjuvant CT significantly improved pCR and EFS in patients with resectable NSCLC. The pCR rate in the durvalumab group was significantly higher than in the placebo group (17.2% vs. 4.3% at the final analysis; difference: 13.0%; 95% CI, 8.7–17.6; P = 0.000036, assessed at the interim analysis [n = 402]). The improvement in pCR rate was 13.0% (95% CI: 8.7–17.6). The improvement in EFS was also significant (EFS stratification HR = 0.68 (95% CI: 0.53–0.88; P = 0.003902; median follow-up of 11.7 months and 31.9% due date). Benefit was observed regardless of disease stage and PD-L1 expression.

[0214] Improvements in pCR and EFS were largely consistent across predefined subgroups, and EFS benefits were observed regardless of the planned new auxiliary platinum reagent (HR 0.59 (95% CI: 0.35–1.00) for cisplatin and 0.73 (95% CI: 0.54–0.98) for carboplatin).

[0215] Perioperative durvalumab plus neoadjuvant CT was also associated with a manageable safety profile consistent with the known safety profiles of durvalumab and CT. Grade 3 or 4 adverse events of any cause occurred in 42.3% and 43.4% of cases, respectively. The addition of durvalumab did not affect the completion of neoadjuvant CT (4 cycles) or the surgery.

[0216] In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy significantly improved pCR and EFS compared to neoadjuvant chemotherapy alone, with a manageable safety profile. This study is the first phase 3 study to characterize the benefits of perioperative immunotherapy plus neoadjuvant CT and to demonstrate that perioperative durvalumab plus neoadjuvant CT is a potential new treatment for patients with resectable NSCLC.

[0217] In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy significantly improved the primary endpoints of EFS (HR, 0.68; P = 0.003902) and pCR (proportional difference, 13.0%; P = 0.000036) compared with neoadjuvant chemotherapy alone, with a manageable safety profile and no impact on completion of neoadjuvant chemotherapy or surgery. Notably, a significant EFS benefit was achieved at the first planned interim analysis, based on a median follow-up of less than 1 year (at the expiry date) and approximately one-quarter of patients were still receiving adjuvant study therapy (as over half of all patients were randomized in the final year of enrollment). These findings support an enhanced treatment strategy where immunotherapy is used perioperatively, rather than solely as a neoadjuvant or adjuvant regimen.

[0218] The EFS and pCR benefits of duvarulimab were widely observed in all predefined subgroups and were consistent with the improvements observed in the entire mITT population. For example, the EFS benefit was observed regardless of age, disease stage (including patients with N2 disease), histology, and PD-L1 expression, notably including patients with PD-L1 expression <1% (although the magnitude of the benefit was numerically better in patients with PD-L1 expression ≥50%). A larger magnitude of benefit was observed in current smokers relative to non-smokers; however, this is consistent with findings from other immunotherapy studies (Zhao et al., “Impact of Smoking History on Response to Immunotherapy in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.” Front Oncol. 2021 Aug 23; 11:703143. PMID: 34497760; PMCID: PMC8419340). Female patients appeared to receive a smaller relative benefit; although the EFS HR confidence interval was wider and overlapped with the male subgroup, this may be at least partly due to the higher proportion of female patients who were never smokers (28.9% vs. 7.1%) and the lower proportion with PD-L1 expression ≥50% (24.6% vs. 32.1%). While EFS and pCR benefits of duvalumab were observed regardless of disease stage, the magnitudes differed slightly, with a larger pCR benefit in stage II patients and a relatively larger EFS benefit in stage IIIA patients (the largest subgroup). However, it is noteworthy that fewer EFS events occurred in the stage II subgroup in this first interim analysis because these patients had better prognoses, and many continued to receive duvalumab or placebo at the data cutoff. Therefore, it is possible that the full benefits from adjuvant duvalumab, particularly for the stage II subgroup, have not been fully realized in the current analysis, and additional expiration dates and follow-ups are warranted to clearly assess the EFS benefit, as well as overall survival and other longer-term secondary endpoints. Finally, a clear and consistent EFS benefit was observed with duvarulimab regardless of whether the planned neoadjuvant chemotherapy regimen was based on cisplatin or carboplatin; this underscores the efficacy of the widely used platinum-based regimens in neoadjuvant settings in real-world practice.

[0219] In this study, the use of perioperative durvalumab plus neoadjuvant chemotherapy was associated with a manageable safety profile consistent with the known safety profiles of durvalumab and chemotherapy alone. The incidence of Grade 3 or 4 adverse events (AEs) of any cause was similar between the study groups, occurring in 42.3% of patients in the durvalumab group and 43.4% in the placebo group. AEs with fatal outcomes that may be related to study Tx were rare in both groups. Immune-mediated AEs were more common in the durvalumab group compared to the placebo group (23.5% vs. 9.8%); however, most of these were Grade 1 or 2. Furthermore, while differences in the cohorts and study design between AEGEAN and PACIFIC confounded the study comparisons (particularly in the latter's use of chemoradiotherapy), it is noteworthy that the rates of any grade and grade 3 or 4 immune AEs were similar across these studies (Antonia et al., N Engl J Med 2017; 377:1919–29; Antonia et al., N Engl J Med 2018;379:2342–50). Finally, despite AEGEAN recruiting patients during the height of the global Covid-19 pandemic, only 6 out of 80 patients with any grade of Covid-19 (7.5%) had grade 5 Covid-19 events; in contrast, based on publicly available reports prior to the widespread use of vaccines, patients with lung cancer were associated with 18%–47% Covid-19 mortality (Passaro et al., J Immunother Cancer 2021; 9:e002266).

[0220] While comparisons of findings from this study (AEGEAN) with those from other studies of immunotherapy as neoadjuvant or adjuvant therapy can be considered informative, differences in patient populations and study designs have obscured crossover trial comparisons. Several differences between AEGEAN and other immunotherapy trials in resectable NSCLC settings are noteworthy (Forde et al. N Engl J Med 2022; 386:1973-85; Felip et al. Lancet 2021; 398:1344-57; O'Brien et al. Lancet Oncol 2022; 12:1274-86). Key advantages include: a large patient enrollment; the use of a double-blind, placebo-controlled design throughout neoadjuvant and adjuvant therapy; exclusion of patients with documented EGFR / ALK abnormalities from a pre-specified cohort for efficacy analysis; use of the AJCC Staging Manual, 8th edition; use of IASLC recommendations for assessing pathological response; and flexibility in neoadjuvant chemotherapy regimens. That said, AEGEAN is not designed to evaluate the contribution of either neoadjuvant or adjuvant therapy components alone. Nevertheless, the results reported in this article demonstrate the effectiveness of the perioperative treatment strategy and confirm the compatibility of this approach with other studies of immunotherapy in melanoma and NSCLC settings (Patel et al., N Engl J Med 2023; 388:813-823; Lu et al., Journal of Clinical Oncology 41, Vol. 36, Supplement (April 20, 2023) 425126-425126). Furthermore, the full benefit of perioperative durvalumab treatment can only be realized if all patients have the opportunity to complete adjuvant study therapy.

[0221] All patents and publications mentioned in this specification are incorporated herein by reference to the extent that each individual patent and publication is specifically and individually cited. No reference or designation in any part of this application should be construed as an admission that such reference is available as prior art to this disclosure.

Claims

1. A method of treating a subject identified as having resectable non-small cell lung cancer (R-NSCLC), the method comprising administering to the subject a combination therapy comprising duvalumab and platinum-based chemotherapy.

2. The method of claim 1, wherein the combination therapy is administered approximately every 14 to 28 days for approximately 3 to 6 cycles.

3. The method according to claim 1 or claim 2, wherein the combination therapy is administered approximately every 21 days (Q3W) for approximately 4 cycles.

4. The method of claim 2, further comprising resecting the R-NSCLC after about 3 to 6 cycles of the combination therapy.

5. The method of claim 3, further comprising resecting the R-NSCLC after approximately four cycles of the combination therapy.

6. The method of claim 4 or claim 5, further comprising administering durvalumab to the patient approximately every 14 to 28 days after resection of the R-NSCLC for up to approximately twelve cycles.

7. The method of claim 4 or claim 5, further comprising administering durvalumab to the patient approximately every 28 days (Q4W) after resection of the R-NSCLC for up to approximately twelve cycles.

8. The method according to any one of claims 1 to 7, wherein the combination therapy comprises about 1000 mg to 2000 mg of durvalumab.

9. The method according to any one of claims 1 to 8, wherein the combination therapy comprises about 1500 mg of duvalumab.

10. A method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), the method comprising: (i) The patients were given approximately 1500 mg of duvarubicin and platinum-based chemotherapy approximately every 3 weeks (Q3W) for approximately 4 cycles; (ii) surgical removal of the R-NSCLC; and then (iii) Administer approximately 1500 mg of durvalumab to the patient approximately every four weeks (Q4W) for at least approximately 12 weeks.

11. The method according to any one of claims 1 to 10, wherein the platinum-based chemotherapy is one or more of the following: carboplatin, cisplatin, nedaplatin, and oxaliplatin.

12. The method of claim 11, wherein the platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of about 5 mg / mL / min to about 6 mg / mL / min, or about 75 mg / mL / min. 2 The cisplatin dosage.

13. The method according to any one of claims 1 to 12, wherein the platinum-based chemotherapy further comprises one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib.

14. The method of claim 13, wherein the platinum-based chemotherapy comprises about 200 mg / m². 2 The dosage of paclitaxel is approximately 500 mg / m². 2 The dosage of pemetrexed is approximately 1250 mg / m². 2 Gemcitabine dosage.

15. The method according to any one of claims 1 to 14, wherein the R-NSCLC is squamous cell carcinoma.

16. The method of claim 15, wherein the platinum-based chemotherapy comprises: (i) Carboplatin and paclitaxel; (ii) cisplatin and gemcitabine; and / or (iii) Carboplatin and gemcitabine.

17. The method according to any one of claims 1 to 14, wherein the R-NSCLC is a non-squamous cell carcinoma.

18. The method of claim 17, wherein the platinum-based chemotherapy comprises: (i) Carboplatin and pemetrexed; and / or (ii) Cisplatin and Pemetrexed.

19. The method according to any one of claims 1 to 18, wherein the patient does not have an EGFR mutation and / or an ALK translocation.

20. The method according to any one of claims 5 to 18, wherein the resection of the R-NSCLC occurs within about 10 weeks after about 3 to 6 cycles of the combination therapy.

21. The method according to any one of claims 5 to 18, wherein the method further comprises postoperative radiotherapy.

22. The method of claim 21, wherein the postoperative radiotherapy is initiated approximately 8 weeks after resection of the R-NSCLC.

23. The method of claim 22, wherein duvalumab is initiated approximately 3 weeks after the end of the postoperative radiotherapy.

24. The method according to any one of claims 1 to 23, wherein the method causes one or more of the following to occur: (i) Event-free survival (EFS) improved by at least approximately 13 months; (ii) Improvement of at least approximately 13% in pathological complete response (pCR); as well as (iii) Improvement in major pathological response (mPR) by at least approximately 21%.

25. The method according to any one of claims 1 to 24, wherein the method improves one or more of EFS, pCR, mPR, DFS and OS compared to the standard of care.

26. The method according to any one of claims 1 to 24, wherein the method improves one or more of EFS, pCR, mPR, DFS and OS compared to platinum-based chemotherapy.

27. A combination therapy comprising duvalumab and platinum-based chemotherapy, said combination therapy for use in the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients in need.

28. The combination therapy according to claim 27, wherein the combination therapy is administered approximately every 14 to 28 days for approximately 3 to 6 cycles.

29. The combination therapy according to claim 27, wherein the combination therapy is administered approximately every 21 days (Q3W) for approximately 4 cycles.

30. The combination therapy for use according to claim 28 or claim 29, wherein the combination therapy further comprises resection of the R-NSCLC after about 3 to 6 cycles of the combination therapy.

31. The combination therapy for use according to claim 28 or claim 29, wherein the combination therapy further comprises resection of the R-NSCLC after about 4 cycles of the combination therapy.

32. The combination therapy for use according to claim 30 or claim 31, the combination therapy further comprising administering durvalumab to the patient approximately every 14 to 28 days after resection of the R-NSCLC for up to approximately twelve cycles.

33. The combination therapy for use according to claim 30 or claim 31, wherein the combination therapy further comprises administering durvalumab to the patient approximately every 28 days (Q4W) after resection of the R-NSCLC for up to approximately twelve cycles.

34. The combination therapy according to any one of claims 27 to 33, wherein the combination therapy comprises about 1000 mg to 2000 mg of durvalumab.

35. The combination therapy according to any one of claims 27 to 34, wherein the combination therapy comprises about 1500 mg of duvalumab.

36. A combination therapy for use in treating a patient diagnosed with resectable non-small cell lung cancer (R-NSCLC), wherein the combination therapy comprises: (i) The patients were administered approximately 1500 mg of duvarubicin and platinum-based chemotherapy approximately every 3 weeks (Q3W) for approximately 4 cycles; and then (ii) After surgical removal of the R-NSCLC, the patient was given approximately 1500 mg of duvarubicin every four weeks (Q4W) for at least approximately 12 weeks.

37. The combination therapy according to any one of claims 27 to 36, wherein the platinum-based chemotherapy is one or more of the following: carboplatin, cisplatin, nedaplatin, and oxaliplatin.

38. The combination therapy according to claim 37, wherein the platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of about 5 mg / mL / min to about 6 mg / mL / min, or about 75 mg / mL. 2 The cisplatin dosage.

39. The combination therapy according to any one of claims 27 to 38, wherein the platinum-based chemotherapy further comprises one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib.

40. The combination therapy according to claim 39, wherein the platinum-based chemotherapy comprises about 200 mg / m². 2 The dosage of paclitaxel is approximately 500 mg / m². 2 The dosage of pemetrexed is approximately 1250 mg / m². 2 Gemcitabine dosage.

41. The combination therapy according to any one of claims 27 to 40, wherein the R-NSCLC is squamous cell carcinoma.

42. The combination therapy according to claim 41, wherein the platinum-based chemotherapy comprises: (i) Carboplatin and paclitaxel; (ii) Cisplatin and gemcitabine; and / or (iii) Carboplatin and gemcitabine.

43. The combination therapy according to any one of claims 27 to 40, wherein the R-NSCLC is non-squamous cell carcinoma.

44. The combination therapy according to claim 43, wherein the platinum-based chemotherapy comprises: (i) Carboplatin and pemetrexed; and / or (ii) Cisplatin and Pemetrexed.

45. The combination therapy according to any one of claims 27 to 44, wherein the patient does not have an EGFR mutation and / or an ALK translocation.

46. ​​The combination therapy according to any one of claims 31 to 45, wherein resection of the R-NSCLC occurs within approximately 10 weeks after approximately 3 to 6 cycles of the combination therapy.

47. The combination therapy for use according to any one of claims 31 to 46, wherein the combination therapy further comprises postoperative radiotherapy.

48. The combination therapy according to claim 47, wherein the postoperative radiotherapy is initiated approximately 8 weeks after resection of the R-NSCLC.

49. The combination therapy according to claim 48, wherein duvalumab is initiated approximately 3 weeks after the end of the postoperative radiotherapy.

50. The combination therapy according to any one of claims 27 to 49, wherein the use of said combination therapy causes one or more of the following to occur: (i) Event-free survival (EFS) improved by at least approximately 13 months; (ii) Improvement of at least approximately 13% in pathological complete response (pCR); as well as (iii) Improvement in major pathological response (mPR) by at least approximately 21%.

51. The combination therapy according to any one of claims 27 to 50, wherein the use of the combination therapy improves one or more of EFS, pCR, mPR, DFS, and OS compared to the standard of care.

52. The combination therapy according to any one of claims 27 to 50, wherein the use of the combination therapy improves one or more of EFS, pCR, mPR, DFS and OS compared to platinum-based chemotherapy.

53. Use of a combination therapy comprising duvalumab and platinum-based chemotherapy to manufacture a medicine for the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients of need.

54. The use according to claim 53, wherein the drug is administered approximately every 14 to 28 days for approximately 3 to 6 cycles.

55. The use according to claim 53, wherein the drug is administered approximately every 21 days (Q3W) for approximately 4 cycles.

56. The use according to claim 54 or claim 55, further comprising resection of the R-NSCLC after about 3 to 6 cycles of the combination therapy.

57. The use according to claim 54 or claim 55, further comprising resection of the R-NSCLC after about 4 cycles of the combination therapy.

58. The use according to claim 56 or claim 57, further comprising administering durvalumab to the patient approximately every 14 to 28 days after resection of the R-NSCLC for up to approximately twelve cycles.

59. The use according to claim 56 or claim 57, further comprising administering durvalumab to the patient approximately every 28 days (Q4W) after resection of R-NSCLC for up to twelve cycles.

60. The use according to any one of claims 53 to 59, wherein the drug comprises about 1000 mg to 2000 mg of duvalumab.

61. The use according to any one of claims 53 to 60, wherein the drug comprises about 1500 mg of duvalumab.

62. Use of duvalumab and platinum-based chemotherapy in the manufacture of a medicament for the treatment of resectable non-small cell lung cancer (R-NSCLC) in combination therapy, wherein said combination therapy comprises: (i) The patients were given approximately 1500 mg of duvarubicin and platinum-based chemotherapy approximately every 3 weeks (Q3W) for approximately 4 cycles; (ii) surgical removal of the R-NSCLC; and then (iii) Administer approximately 1500 mg of durvalumab to the patient approximately every four weeks (Q4W) for at least approximately 12 weeks.

63. The use according to any one of claims 53 to 62, wherein the platinum-based chemotherapy is one or more of the following: carboplatin, cisplatin, nedaplatin, and oxaliplatin.

64. The use according to claim 63, wherein the platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area under the curve (AUC) dose of about 5 mg / mL / min to about 6 mg / mL / min, or about 75 mg / mL / min. 2 The cisplatin dosage.

65. The use according to any one of claims 53 to 64, wherein the platinum-based chemotherapy further comprises one or more of the following: afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib.

66. The use according to claim 65, wherein the platinum-based chemotherapy comprises about 200 mg / m². 2 The dosage of paclitaxel is approximately 500 mg / m². 2 The dosage of pemetrexed is approximately 1250 mg / m². 2 Gemcitabine dosage.

67. The use according to any one of claims 53 to 66, wherein the R-NSCLC is squamous cell carcinoma.

68. The use according to claim 67, wherein the platinum-based chemotherapy comprises: (i) Carboplatin and paclitaxel; (ii) cisplatin and gemcitabine; and / or (iii) Carboplatin and gemcitabine.

69. The use according to any one of claims 53 to 66, wherein the R-NSCLC is a non-squamous cell carcinoma.

70. The use according to claim 69, wherein the platinum-based chemotherapy comprises: (i) Carboplatin and pemetrexed; and / or (ii) Cisplatin and Pemetrexed.

71. The use according to any one of claims 53 to 70, wherein the patient does not have an EGFR mutation and / or an ALK translocation.

72. The use according to any one of claims 53 to 71, wherein the resection of the R-NSCLC occurs within about 10 weeks after about 3 to 6 cycles of the combination therapy.

73. The use according to any one of claims 53 to 72, wherein the use further comprises postoperative radiotherapy.

74. The use according to claim 73, wherein the postoperative radiotherapy is initiated approximately 8 weeks after resection of the R-NSCLC.

75. The use according to claim 74, wherein duvalumab is initiated approximately 3 weeks after the end of the postoperative radiotherapy.

76. The use according to any one of claims 53 to 75, wherein the use of said combination therapy results in one or more of the following: (i) Event-free survival (EFS) improved by at least approximately 13 months; (ii) Improvement of at least approximately 13% in pathological complete response (pCR); as well as (iii) Improvement in major pathological response (mPR) by at least approximately 21%.

77. The use according to any one of claims 53 to 76, wherein the use of the combination therapy improves one or more of EFS, pCR, mPR, DFS, and OS compared to the standard of care.

78. The use according to any one of claims 53 to 76, wherein the use of the combination therapy improves one or more of EFS, pCR, mPR, DFS and OS compared to platinum-based chemotherapy.

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