Treatment of non-small cell lung cancer

Abstract

This disclosure relates, in general terms, to methods and compositions for treating patients with resectable non-small cell lung cancer.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 496,200, filed on 14 April 2023, and U.S. Provisional Application No. 63 / 509,408, filed on 21 June 2023, each of which is incorporated herein by reference in whole for all purposes.

[0002] This disclosure relates, in general terms, to methods and compositions for treating patients with non-small cell lung cancer using durvalumab and platinum-based chemotherapy.

[0003] Sequence List This application includes a sequence listing, which is incorporated herein by reference in its entirety. The sequence listing submitted herein is contained in an XML file titled “23-0535-US-PRO2_SequenceListing.xml”, created on 26 May 2023, and has a size of 8,192 bytes. [Background technology]

[0004] Lung cancer is a leading cause of cancer-related death 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 percentage is expected to increase with the increased use of lung cancer screening programs. Surgery remains the primary curative treatment for eligible patients with early-stage NSCLC. Nevertheless, many patients experience tumor recurrence within five years of surgery (approximately 30–55%, depending on the stage at diagnosis), which reduces health-related quality of life and increases the likelihood of disease-related death. Chemotherapy, in neoadjuvant or adjuvant settings, is a well-established treatment strategy, but it only provides a slight improvement of about 5% in the five-year survival rate compared to surgery alone.

[0005] Lung cancer has been the most common cancer in the world for decades, with an estimated 1.8 million new cases in 2012 (12.9% of all new cancers), and was also the most common cause of cancer death in 2012, killing 1.6 million people (19.4% of all cancer deaths; GLOBOCAN 2012). Non-small cell lung cancer (NSCLC) accounts for 80%–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) for patients in Europe and the United States remains low (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 Suppl 5: v116-9; Howlade et al. "SEER Cancer Statistics Review, 1975–2014," National Cancer Institute. Bethesda, MD. April 2017).

[0006] In early-stage NSCLC, the primary treatment is curative surgery. Only about 30% of patients have stage I-IIIA lung cancer. However, this percentage is expected to increase as a result of the implementation of lung cancer screening. Unfortunately, the 5-year survival rate for patients treated with surgery alone is low, ranging from 67% (stage IA) to 23% (stage IIIA) (Mountain, "Revision in the international system for staging lung cancer." Chest 1997;111:1710-7).

[0007] Studies of adjuvant chemotherapy in NSCLC patients have demonstrated a moderate but clinically significant improvement in overall survival. Intraoperative platinum-based chemotherapy showed a 5.4 percentage point higher survival rate than surgery alone, and grade 3 or higher toxicity was observed in over 60% of patients (Pignon et al. "Lung adjuvant cisplatin evaluation: a pooled 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, randomized, phase 3 trial." Lancet Oncol 2017;18:1610-23).

[0008] Numerous studies have demonstrated the clinical benefits of neoadjuvant chemotherapy in early-stage NSCLC. However, despite these advances, new therapies are needed to further improve the long-term prognosis of NSCLC patients who have undergone surgical resection. [Overview of the project]

[0009] This disclosure relates, in general, to a method for treating patients with resectable non-small cell lung cancer (NSCLC). This disclosure demonstrates that intraoperative durvalumab plus neoadjuvant chemotherapy results in significant improvements in both pathological complete response (PCR) and event-free survival (EFS) in patients with resectable NSCLC.

[0010] In one embodiment, the present disclosure provides a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), comprising administering to the patient a combination therapy comprising durvalumab and platinum-based chemotherapy.

[0011] In some embodiments, the drug is administered approximately every 14–28 days or every 21 days. In some embodiments, the combination therapy is administered approximately every 14–28 days for approximately 3–6 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 excision of the R-NSCLC after approximately 3–6 cycles of combination therapy. In some embodiments, the method further includes excision 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 14–28 days for up to approximately 12 cycles after excision of the R-NSCLC. In some embodiments, the method further includes administering durvalumab to the patient approximately every 28 days (Q4W) for up to approximately 12 cycles after excision of the R-NSCLC.

[0012] In some embodiments, the combination therapy includes approximately 1000–2000 mg of durvalumab. In some embodiments, the combination therapy includes approximately 1500 mg of durvalumab.

[0013] In another aspect, the present disclosure relates to a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), (i) The patient is to be administered approximately 1500 mg of durvalumab and platinum-based chemotherapy every three weeks (Q3W) for approximately four cycles, (ii) Removal of R-NSCLC by surgery, and then, (iii) Administer approximately 1500 mg of durvalumab to the patient every 4 weeks (Q4W) for at least approximately 12 weeks, This provides a method that includes [something].

[0014] In some embodiments of the methods disclosed herein, the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, the platinum-based chemotherapy is administered at a carboplatin serum drug concentration-time curve area under the curve (AUC) of about 5 to about 6 mg / mL / min, or cisplatin administration of about 75 mg / m 2 ². In some embodiments, the platinum-based chemotherapy further comprises one or more of afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and bemrafenib. In some embodiments, the platinum-based chemotherapy comprises paclitaxel administration of about 200 mg / m 2 ², pemetrexed administration of about 500 mg / m 2 ², or gemcitabine administration of about 1250 mg / m 2 ².

[0015] In some embodiments of the methods disclosed herein, the R-NSCLC is squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and paclitaxel, (ii) cisplatin and gemcitabine, and / or (iii) carboplatin and gemcitabine.

[0016] In some embodiments of the methods disclosed herein, the R-NSCLC is non-squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and pemetrexed, and / or (ii) cisplatin and pemetrexed.

[0017] In some embodiments of the methods disclosed herein, the patient does not have an EGFR mutation and / or an ALK translocation.

[0018] In some embodiments of the methods disclosed herein, the resection of R-NSCLC is performed within about 10 weeks after about 3 to 6 cycles of combination therapy.

[0019] In some embodiments of the methods disclosed herein, the methods further comprise postoperative radiation therapy. In some embodiments, the postoperative radiation therapy is initiated within about 8 weeks after resection of R-NSCLC. In some embodiments, durvalumab is initiated within about 3 weeks after the end of the postoperative radiation therapy.

[0020] In some embodiments of the methods disclosed herein, the methods result in one or more of (i) an improvement in event-free survival (EFS) of at least about 13 months, (ii) an improvement in pathologic complete response (pCR) of at least about 13%, and (iii) an improvement in major pathologic response (mPR) of at least about 21%. In some embodiments, the methods result in an improvement in one or more of EFS, pCR, mPR, DFS, and OS as compared to standard therapy. In some embodiments, the methods result in an improvement in one or more of EFS, pCR, mPR, DFS, and OS as compared to platinum-based chemotherapy, or postoperative or preoperative platinum-based chemotherapy.

[0021] In one aspect, the present disclosure provides a combination therapy comprising durvalumab and platinum-based chemotherapy for use in the treatment of resectable non-small cell lung cancer (R-NSCLC) in a patient who needs it.

[0022] In some embodiments, the combination therapy is administered approximately every 14–28 days or every 21 days. In some embodiments, the combination therapy is administered approximately every 14–28 days for approximately 3–6 cycles. In some embodiments, the combination therapy is administered approximately every 21 days (Q3W) for approximately 4 cycles. In some embodiments, the combination therapy further includes excision of R-NSCLC after approximately 3–6 cycles of combination therapy. In some embodiments, the combination therapy further includes excision of R-NSCLC after approximately 4 cycles of combination therapy. In some embodiments, the combination therapy further includes administration of durvalumab to the patient approximately every 14–28 days for up to approximately 12 cycles after excision of R-NSCLC. In some embodiments, the combination therapy further includes administration of durvalumab to the patient approximately every 28 days (Q4W) for up to approximately 12 cycles after excision of R-NSCLC.

[0023] In some embodiments, the combination therapy includes approximately 1000–2000 mg of durvalumab. In some embodiments, the combination therapy includes approximately 1500 mg of durvalumab.

[0024] In another aspect, the present disclosure provides a combination therapy for use in the treatment of a patient identified with resectable non-small cell lung cancer (R-NSCLC), comprising 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) for at least approximately 12 weeks after surgical removal of the R-NSCLC.

[0025] In some embodiments of the combination therapy, the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, the platinum-based chemotherapy is administered at a carboplatin serum drug concentration-time area (AUC) of approximately 5–6 mg / mL / min, or approximately 75 mg / m². 2This includes cisplatin administration. In some embodiments, the platinum-based chemotherapy further comprises one or more of afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments of the combination therapy, the platinum-based chemotherapy is approximately 200 mg / m² 2 Paclitaxel administration, approximately 500 mg / m² 2 Administration of pemetrexed, or approximately 1250 mg / m² 2 This includes gemcitabine administration.

[0026] In some embodiments of the combination therapy, R-NSCLC is squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and paclitaxel, (ii) cisplatin and gemcitabine, and / or (iii) carboplatin and gemcitabine.

[0027] In some embodiments of the combination therapy, R-NSCLC is non-squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and pemetrexed, and / or (ii) cisplatin and pemetrexed.

[0028] In some embodiments of the combination therapy, the patient does not have an EGFR mutation and / or ALK translocation.

[0029] In some embodiments of combination therapy, excision of R-NSCLC is performed within approximately 10 weeks after about 3 to 6 cycles of combination therapy.

[0030] In some embodiments, the combination therapy further includes postoperative radiotherapy. In some embodiments, postoperative radiotherapy is initiated within approximately 8 weeks after resection of R-NSCLC. In some embodiments, durvalumab is initiated within approximately 3 weeks after the completion of postoperative radiotherapy.

[0031] In some embodiments of combination therapy, the use of combination therapy results in one or more of the following: (i) an improvement of at least about 13 months in event-free survival (EFS), (ii) an improvement of at least about 13% in pathological complete response (pCR), and (iii) an improvement of at least about 21% in pathological marked response (mPR). In some embodiments, the use of combination therapy results in one or more improvements in EFS, pCR, mPR, DFS, and OS compared to standard treatment. In some embodiments, the use of combination therapy results in one or more improvements in EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy, or postoperative or preoperative platinum-based chemotherapy.

[0032] In one embodiment, the present disclosure provides the use of a combination therapy comprising durvalumab and platinum-based chemotherapy for the manufacture of a medicament for treating resectable non-small cell lung cancer (R-NSCLC) in patients in need thereof.

[0033] In some embodiments, the drug is administered approximately every 14–28 days or every 21 days. In some embodiments, the drug is administered approximately every 14–28 days over approximately 3–6 cycles. In some embodiments, the drug is administered approximately every 21 days (Q3W) over approximately 4 cycles. In some embodiments, the use of the drug further includes excision of R-NSCLC after approximately 3–6 cycles of combination therapy. In some embodiments, the use of the drug further includes excision of R-NSCLC after approximately 4 cycles of combination therapy. In some embodiments, the use of the drug further includes administering durvalumab to the patient approximately every 14–28 days over up to approximately 12 cycles after excision of R-NSCLC. In some embodiments, the use of the drug further includes administering durvalumab to the patient approximately every 28 days (Q4W) over up to 12 cycles after excision of R-NSCLC.

[0034] In some embodiments of the use of the pharmacopoeia, the pharmacopoeia contains about 1000 to 2000 mg of durvalumab. In some embodiments, the pharmacopoeia contains about 1500 mg of durvalumab.

[0035] In another aspect, the present disclosure provides the use of durvalumab and platinum-based chemotherapy in the manufacture of a medicament for treating resectable non-small cell lung cancer (R-NSCLC) in combination therapy, the combination therapy comprising administering to a patient approximately 1500 mg of durvalumab and platinum-based chemotherapy every approximately 3 weeks (Q3W) over approximately 4 cycles, removing the R-NSCLC by surgery, and then administering to the patient approximately 1500 mg of durvalumab every approximately 4 weeks (Q4W) over at least approximately 12 weeks.

[0036] In some embodiments of the use of the medicament, the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, the platinum-based chemotherapy comprises administration of carboplatin at a serum drug concentration-time curve area under the curve (AUC) of approximately 5 to approximately 6 mg / mL / min, or administration of cisplatin at approximately 75 mg / m 2 In some embodiments of the use of the medicament, the platinum-based chemotherapy further comprises one or more of afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments of the use of the medicament, the platinum-based chemotherapy comprises administration of paclitaxel at approximately 200 mg / m 2 In some embodiments of the use of the medicament, the platinum-based chemotherapy comprises administration of pemetrexed at approximately 500 mg / m 2 In some embodiments of the use of the medicament, the platinum-based chemotherapy comprises administration of gemcitabine at approximately 1250 mg / m 2 In some embodiments of the use of the medicament, the R-NSCLC is squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and paclitaxel, (ii) cisplatin and gemcitabine, and / or (iii) carboplatin and gemcitabine.

[0037] In some embodiments of the use of the medicament, the R-NSCLC is non-squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and pemetrexed, and / or (ii) cisplatin and pemetrexed.

[0038] In some embodiments of the use of the medicament, the R-NSCLC is non-squamous cell carcinoma. In some embodiments, the platinum-based chemotherapy comprises (i) carboplatin and pemetrexed, and / or (ii) cisplatin and pemetrexed.

[0039] In some embodiments of the use of the pharmacopoeia, the patient does not have an EGFR mutation and / or ALK translocation.

[0040] In some embodiments of the use of the pharmacopoeia, excision of R-NSCLC is performed within approximately 10 weeks after about 3 to 6 cycles of combination therapy.

[0041] In some embodiments of the use of the drug, the use further includes postoperative radiotherapy. In some embodiments, postoperative radiotherapy is initiated within approximately 8 weeks after resection of R-NSCLC. In some embodiments, durvalumab is initiated within approximately 3 weeks after the completion of postoperative radiotherapy.

[0042] In some embodiments of the use of the pharmacotherapy, the use of combination therapy results in one or more of the following: (i) an improvement of at least about 13 months in event-free survival (EFS), (ii) an improvement of at least about 13% in pathological complete response (pCR), and (iii) an improvement of at least about 21% in pathological marked response (mPR). In some embodiments, the use of combination therapy results in one or more improvements among EFS, pCR, mPR, DFS, and OS compared to standard treatment. In some embodiments, the use of combination therapy results in one or more improvements among EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy, or postoperative or preoperative platinum-based chemotherapy.

[0043] These and other features and advantages of this disclosure will be better understood from the following detailed description, along with the attached claims. Note that the claims are defined by their enumeration rather than by a specific consideration of the features and advantages described herein. [Brief explanation of the drawing]

[0044] 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 the description, help to illustrate the principles and operation of this disclosure. [Figure 1A] This disclosure outlines the study design for the Phase III international randomized, double-blind, placebo-controlled study. *The protocol was modified during enrollment to exclude patients with (1) tumors classified as T4 for any reason other than size, (2) patients scheduled for lung resection, and (3) patients with demonstrated EGFR / ALK abnormalities. †Ventana SP263 immunohistochemical assay. ‡Selection of CT regimen as determined by histological findings and at the discretion of the investigator. For non-squamous tumors: cisplatin + pemetrexed, or carboplatin + pemetrexed. For squamous tumors: carboplatin + paclitaxel or cisplatin + gemcitabine (or carboplatin + gemcitabine for patients with comorbidities or, at the discretion of the investigator, patients who cannot tolerate cisplatin). §Postoperative radiotherapy (PORT) was permitted as directed in accordance with national guidance. All efficacy analyses reported herein were performed in the mITT population, including all randomized patients with demonstrated EGFR / ALK abnormalities. AJCC, Joint American Cancer Committee; BICR, blinded independent central review; DFS, disease-free survival; EFS, event-free survival; mITT, modified treatment intent; MPR, pathological response; pCR, pathological complete response. [Figure 1B] The CONSORT flow chart is shown. *Signed informed consent was received. †Efficacy endpoints were analyzed based on a modified population excluding patients with demonstrated EGFR / ALK abnormalities. ‡The safety analysis set 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, disease progression; Tx, treatment. [Figure 2]This graph shows event-free survival (EFS) by blinded independent central review (BICR) in the modified intention-to-treat (mITT) population. Data cutoff was November 10, 2022 (N=740). The graph shows the EFS of patients in the modified intention-to-treat population (i.e., all randomized patients without demonstrated EGFR / ALK abnormalities). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded independent central review with respect to Response Evaluation Criteria in Solid Tumors version 1.1; or (iv) death from any cause. The median EFS follow-up in censored patients was 11.7 months (range: 0.0~46.1); EFS maturity: 31.9%. P-values ​​were calculated using a stratified log-rank test with a significance threshold of 0.009899 (based on a total of 5% α) calculated using the Lan-DeMets α consumption function with the O'Brien-Fleming boundary. CI: Confidence interval; D: Durvalumab; eCRF (electronic case report form): Electronic case report form; EFS: Event-free survival; HR: Hazard ratio; NR: Not reached; PBO: Placebo. [Figure 3]This shows event-free survival (EFS) by blinded independent central review (BICR) in the modified intention-to-treat (mITT) population. Data cutoff date: November 10, 2022 (N=740). Forest plot of EFS in pre-specified patient subgroups (circle size is proportional to the number of events in each subgroup, horizontal bars represent 95% CI). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded independent central review with response criteria version 1.1 in solid tumors; or (iv) death from any cause. *Race was self-reported according to the eCRF. †Determined using Ventana SP263 immunohistochemical assay. AJCC, Joint American Cancer Committee; CI, Confidence Interval; D, Durvalumab; ECOG PS, General Status of the US East Coast Cancer Clinical Trials Group; eCRF (Electronic Case Report Form), Electronic Case Report Form; EFS, Event-Free Survival; HR, Hazard Ratio; NR, Not Reached; PBO, Placebo; PD-L1, Programmed Death Ligand 1; TC Tumor Cells. [Figure 4A]This shows event-free survival (EFS) by blinded, independent central review (pre-specified subgroup analysis) with planned neoadjuvant platinum agents in the modified intention-to-treatment population. There was flexibility in the selection of neoadjuvant chemotherapy combinations* - clear and consistent EFS benefits were observed regardless of the planned platinum agent. Median and landmark estimates were calculated using the Kaplan-Meier method. HR was calculated using an unstratified Cox proportional hazards model. *Selection of CT regimen determined by histological findings and at the discretion of the investigator. For non-squamous epithelium: cisplatin + pemetrexed, or carboplatin + pemetrexed. For squamous epithelium: carboplatin + paclitaxel or cisplatin + gemcitabine (or carboplatin + gemcitabine for patients with comorbidities or patients to whom cisplatin is unacceptable, as determined by the investigator). †HR < 1 favors the D arm compared to the PBO arm. The results show a clear and consistent EFS benefit observed regardless of the planned platinum agent. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo. [Figure 4B] The panel shows event-free survival by stage in the modified treatment intention population, based on blinded, independent central review (pre-specified subgroup analysis). Data cutoff date: November 10, 2022 (N=740). The upper panel shows EFS for a subgroup of patients with stage II disease, and the lower panel shows EFS for a 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) advanced disease that prevents surgery; (ii) advanced disease that prevents completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded, independent central review with response criteria version 1.1 for solid tumors; or (iv) death from any cause. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo. [Figure 4C]Figure 4C shows event-free survival (EFS) based on PD-L1 tumor cell expression in the modified treatment intention population, as determined by blinded, independent central review (pre-specified subgroup analysis). Data cutoff date: November 10, 2022 (N=740). Figure 4C shows EFS for a subgroup of patients with PD-L1 tumor cell expression <1%, Figure 4D shows EFS for a subgroup of patients with PD-L1 tumor cell expression 1–49%, and Figure 4E shows EFS for patients with PD-L1 tumor cell expression ≥50% (at study baseline). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded, independent central review with response criteria version 1.1 for solid tumors; or (iv) death from any cause. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo; PD-L1, programmed death ligand-1; TC, tumor cells. [Figure 4D] Figure 4C shows event-free survival (EFS) based on PD-L1 tumor cell expression in the modified treatment intention population, as determined by blinded, independent central review (pre-specified subgroup analysis). Data cutoff date: November 10, 2022 (N=740). Figure 4C shows EFS for a subgroup of patients with PD-L1 tumor cell expression <1%, Figure 4D shows EFS for a subgroup of patients with PD-L1 tumor cell expression 1–49%, and Figure 4E shows EFS for patients with PD-L1 tumor cell expression ≥50% (at study baseline). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded, independent central review with response criteria version 1.1 for solid tumors; or (iv) death from any cause. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo; PD-L1, programmed death ligand-1; TC, tumor cells. [Figure 4E]Figure 4C shows event-free survival (EFS) based on PD-L1 tumor cell expression in the modified treatment intention population, as determined by blinded, independent central review (pre-specified subgroup analysis). Data cutoff date: November 10, 2022 (N=740). Figure 4C shows EFS for a subgroup of patients with PD-L1 tumor cell expression <1%, Figure 4D shows EFS for a subgroup of patients with PD-L1 tumor cell expression 1–49%, and Figure 4E shows EFS for patients with PD-L1 tumor cell expression ≥50% (at study baseline). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded, independent central review with response criteria version 1.1 for solid tumors; or (iv) death from any cause. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo; PD-L1, programmed death ligand-1; TC, tumor cells. [Figure 4F] Figure 4F shows event-free survival (EFS) based on histological findings of tumors in the modified treatment intention population, as determined by blinded, independent central review (pre-specified subgroup analysis). Data cutoff date: November 10, 2022 (N=740). Figure 4F shows EFS for a subgroup of patients with histological findings of squamous cell tumors, and Figure 4G shows EFS for a subgroup of patients with histological findings of non-squamous cell tumors (at study baseline). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded, independent central review with response criteria version 1.1 for solid tumors; or (iv) death from any cause. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo. [Figure 4G]Figure 4F shows event-free survival (EFS) based on histological findings of tumors in the modified treatment intention population, as determined by blinded, independent central review (pre-specified subgroup analysis). Data cutoff date: November 10, 2022 (N=740). Figure 4F shows EFS for a subgroup of patients with histological findings of squamous cell tumors, and Figure 4G shows EFS for a subgroup of patients with histological findings of non-squamous cell tumors (at study baseline). EFS was defined as the time from randomization to the earliest of the following: (i) advanced disease that interferes with surgery; (ii) advanced disease that interferes with the completion of surgery, as discovered and reported by the investigator at the time of attempting surgery; (iii) local or distant recurrence using blinded, independent central review with response criteria version 1.1 for solid tumors; or (iv) death from any cause. CI, confidence interval; D, durvalumab; EFS, event-free survival; HR, hazard ratio; PBO, placebo. [Figure 5] The final analysis of centrally determined pathological responses in the modified treatment intention population is shown. Data cutoff date: November 10, 2022 (N=740). The left panel shows pCR. The right panel shows MPR. pCR was defined as the absence of viable tumor cells after complete evaluation of the resected lung cancer specimen and all sampled local lymph nodes. MPR was defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer specimen. To be eligible for pathological evaluation, patients had to have received three cycles of neoadjuvant research treatment according to the protocol and undergone the research surgery; patients who were not evaluable were classified as non-responders. In the final analysis of pathological complete response, formal statistical testing was not performed (data cutoff, November 10, 2022; n=740 [show data]); statistical significance was achieved in the interim analysis (data cutoff, January 14, 2022; n=402), and the p-value was calculated using a stratified Cochrane-Mantel-Henzel test with a significance threshold of 0.000082, calculated using the Lan-DeMets α consumption function with an O'Brien-Fleming boundary. [Figure 6]The final analysis of pathological responses by central review in the modified treatment intention population is shown. Data cutoff date: November 10, 2022 (N=740). Forest plots are plots of pCR in pre-specified patient subgroups (circle size is proportional to the number of patients in each subgroup, and horizontal bars represent 95% CI). Statistical significance was achieved in the interim analysis (data cutoff date: January 14, 2022; n=402), and p-values ​​were calculated using the stratified Cochrane-Mantel-Henzel test with a significance threshold of 0.000082, calculated using the Lan-DeMets α consumption function with an O'Brien-Fleming boundary. *Race was self-reported according to eCRF. †Determined using Ventana SP263 immunohistochemical assay. AJCC stands for the Joint American Cancer Committee, ECOG PS stands for General Status of the East Coast Cancer Clinical Trials Group, eCRF stands for Electronic Case Report Form, PD-L1 stands for Programmed Cell Death Ligand 1, and TC stands for Tumor Cell. [Figure 7A] This report presents an interim analysis of centrally assessed pathological responses in the modified intention-to-treatment (mITT) population. Data cutoff date: January 14, 2022 (N=402). Figure 7A shows pCR, and Figure 7B shows MPR in the pCR interim analysis cohort (the first approximately 400 patients in the mITT population who underwent surgery and had the opportunity to complete central pathological evaluation of pCR [including patients not eligible for surgery]). pCR was defined as the absence of viable tumor cells after complete evaluation of the resected lung cancer specimen and all sampled local lymph nodes. MPR was defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer specimen. To be eligible for pathological evaluation, patients should have received three cycles of neoadjuvant research treatment according to the protocol; patients who were not evaluable were classified as non-responders. Statistical significance was achieved in this interim analysis (N=402). P-values ​​were calculated using a stratified Cochrane-Mantel-Henzel test with a significance threshold of 0.000082, calculated using the Lan-DeMets α consumption function with the O'Brien-Fleming boundary. CI: confidence interval; D: durvalumab; MPR: pathological response; PBO: placebo; pCR: pathological complete response. [Figure 7B] This report presents an interim analysis of centrally assessed pathological responses in the modified intention-to-treatment (mITT) population. Data cutoff date: January 14, 2022 (N=402). Figure 7A shows pCR, and Figure 7B shows MPR in the pCR interim analysis cohort (the first approximately 400 patients in the mITT population who underwent surgery and had the opportunity to complete central pathological evaluation of pCR [including patients not eligible for surgery]). pCR was defined as the absence of viable tumor cells after complete evaluation of the resected lung cancer specimen and all sampled local lymph nodes. MPR was defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer specimen. To be eligible for pathological evaluation, patients should have received three cycles of neoadjuvant research treatment according to the protocol; patients who were not evaluable were classified as non-responders. Statistical significance was achieved in this interim analysis (N=402). P-values ​​were calculated using a stratified Cochrane-Mantel-Henzel test with a significance threshold of 0.000082, calculated using the Lan-DeMets α consumption function with the O'Brien-Fleming boundary. CI: confidence interval; D: durvalumab; MPR: pathological response; PBO: placebo; pCR: pathological complete response. [Figure 8]This figure shows subgroup analyses of pathological response by central review in the modified treatment intention population. Data cutoff date: November 10, 2022 (N=740). This figure shows a forest plot of MPR in pre-specified patient subgroups (circle size is proportional to the number of patients in each subgroup, and horizontal bars represent 95% confidence intervals). MPR was defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer specimen. To be eligible for pathological evaluation, patients had to have received 3 cycles of neoadjuvant research treatment according to the protocol; patients who were not evaluable were classified as non-responders. *Race was self-reported according to eCRF. †Determined using Ventana SP263 immunohistochemical assay. AJCC, Joint American Cancer Committee; D, durvalumab; ECOG PS, General status of the US East Coast Cancer Clinical Trials Group; eCRF (electronic case report form), electronic case report form; MPR, pathological response; PBO, placebo; PD-L1, programmed death ligand 1; TC, tumor cells. [Figure 9] This shows pathological regression in the modified treatment intention population. Data cutoff date: November 10, 2022 (N=740). Pathological regression is summarized based on patients with evaluable %RVT. The waterfall plot shows pathological regression of primary tumors in the D arm (left panel) and PBO arm (right panel). Black stars indicate patients with evidence of carcinoma in examined lymph nodes or patients whose lymph nodes were not evaluable. pCR was defined as the absence of viable tumor cells after complete evaluation of the resected lung cancer specimen and all sampled local lymph nodes. MPR was defined as ≤10% viable tumor cells in the primary lung tumor after complete evaluation of the resected lung cancer specimen. D, durvalumab; MPR, pathological response; PBO, placebo; pCR, pathological complete response; RVT, residual surviving tumor. [Figure 10]This shows the most frequently reported adverse events (AEs)* in the Phase III study (safety analysis set). DCO = November 10, 2022. *AEs reported with a frequency of 10% or more in the D arm during the entire study period are shown; the entire study period spans from the first dose of study Tx (D / PBO / CT) to the last dose of study Tx or surgery + 90 days (date of last dose / surgery of D / PBO / CT + 90 days); DCO day; or the earliest of the dates of the first dose of subsequent anticancer Tx. †Two patients (n=1 / arm) experienced decreased appetite with a fatal outcome (grade 5); fatal events in the D arm were assessed by the principal investigator as potentially related to study Tx. ‡Six patients had Grade 5 COVID-19 events (D arm, n=5; PBO arm, n=1); all COVID-19 deaths were assessed by the principal investigator as unrelated to study Tx (Note: COVID-19 is summarized as a grouped term including the basic terms “COVID-19” and “COVID-19 pneumonia”).

[0045] Those skilled in the art will understand that the elements in the figures are shown for simplification and clarity and are not necessarily drawn to scale. For example, the dimensions of some elements in the figures may be exaggerated relative to others to help improve the understanding of embodiments of the present disclosure. [Modes for carrying out the invention]

[0046] Unless otherwise defined, all technical and scientific terms used herein have the meanings generally understood by those skilled in the art to the extent of this disclosure. The following references provide general definitions of many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). Where used herein, the following terms have the meanings set forth below unless otherwise specified.

[0047] As used herein, the terms “comprise” and “include,” and their variations (e.g., “comprises,” “comprising,” “includes,” and “including”) are understood to include the described component, feature, element, or process, or group of components, features, elements, or processes, but not to exclude any other component, feature, element, or process, or group of components, features, elements, or processes. The terms “comprising,” “consisting essentially of,” and “consisting of” may be substituted for any of the other two terms while retaining their usual meanings.

[0048] As used herein, the singular forms "a," "an," and "the" refer to multiple objects unless the context clearly indicates otherwise.

[0049] As used herein, "one or more" may refer to a selection from a group.

[0050] The percentages disclosed herein may vary by ±10, 20, or 30% from the disclosed values ​​and may fall within the intended scope of disclosure.

[0051] Unless otherwise indicated, or unless it is obvious from the context and the understanding of those skilled in the art, values ​​expressed herein as ranges may, unless the context clearly indicates otherwise, be assumed to be any specific value or subrange within the ranges described in the different embodiments of this disclosure, up to one-tenth of the lower limit of the range.

[0052] Where used herein, ranges and quantities may be expressed as “approximately” a specific value or range. The term “approximately” also includes the exact quantity. For example, “approximately 5%” means “approximately 5%” and also “5%”. The term “approximately” may also refer to ±10% of a given value or range of values. Thus, approximately 5% also means, for example, 4.5% to 5.5%. Furthermore, “approximately” or “essentially including” may mean a range of up to ±10%. Moreover, particularly with respect to biological systems or processes, these terms may mean up to one decimal place or up to five times the value. Where a specific value or composition is provided in this application and claims, unless otherwise stated, the meaning of “approximately” or “essentially including” should be assumed to be within an acceptable margin of error for that specific value or composition. Unless otherwise evident from the context, all numerical values ​​provided herein are modified by the term “approximately”.

[0053] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood, unless otherwise indicated, to include any integer values ​​within the listed ranges, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer).

[0054] Units, prefixes, and symbols are given in the format recognized by the International System of Units (SI). Numerical ranges include the number defining the range. Unless otherwise indicated, nucleotide sequences are written from left to right in a 5' to 3' orientation. Amino acid sequences are written from left to right in an amino to carboxyl orientation. The headings provided herein are not intended to limit the various aspects of this disclosure and can be obtained by referring to this specification as a whole. Thus, the terms defined immediately below are more fully defined by referring to this specification as a whole.

[0055] As used herein, the terms “or” and “and / or” may be used in combination with each other or exclusively to describe multiple components. For example, “x, y, and / or z” may 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.”

[0056] This disclosure relates, in general, to a method for treating patients with resectable non-small cell lung cancer (R-NSCLC). This disclosure demonstrates that intraoperative durvalumab plus neoadjuvant chemotherapy results in significant improvements in both pathological complete response and event-free survival in patients with resectable NSCLC.

[0057] When used in accordance with this disclosure, unless otherwise indicated, all technical and scientific terms shall be understood to have the same meaning as that generally understood by those skilled in the art. Unless specifically required by context, singular terms shall include plural forms and plural terms shall include singular forms.

[0058] In one embodiment, the present disclosure provides a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), comprising administering to the patient a combination therapy comprising durvalumab and platinum-based chemotherapy.

[0059] In one embodiment, the present disclosure provides a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), comprising administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every three weeks (Q3W) for approximately four cycles, surgically removing the R-NSCLC, and then administering approximately 1500 mg of durvalumab to the patient approximately every four weeks (Q4W) for at least approximately 12 weeks.

[0060] In one embodiment, the disclosure provides a combination therapy comprising durvalumab and platinum-based chemotherapy for use in the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients in need.

[0061] In one embodiment, the present disclosure provides a combination therapy for use in treating a patient identified with resectable non-small cell lung cancer (R-NSCLC), comprising 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) for at least approximately 12 weeks after surgical removal of the R-NSCLC.

[0062] In one embodiment, the present disclosure provides a combination therapy formulated for use in treating a patient identified with resectable non-small cell lung cancer (R-NSCLC), comprising administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every three weeks (Q3W) for approximately four cycles, and then administering approximately 1500 mg of durvalumab to the patient approximately every four weeks (Q4W) for at least approximately 12 weeks after surgical removal of the R-NSCLC.

[0063] In one embodiment, the present disclosure provides the use of a combination therapy comprising durvalumab and platinum-based chemotherapy for the manufacture of a medicament for treating resectable non-small cell lung cancer (R-NSCLC) in patients in need thereof.

[0064] In one embodiment, the present disclosure provides a use of durvalumab and platinum-based chemotherapy in the manufacture of a pharmaceutical product for the treatment of resectable non-small cell lung cancer (R-NSCLC) in combination therapy, the combination therapy comprising administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient approximately every three weeks for approximately four cycles (Q3W), surgical removal of the R-NSCLC, and then administering approximately 1500 mg of durvalumab to the patient approximately every four weeks for at least approximately 12 weeks (Q4W).

[0065] As used herein, in the context of treating cancer, the terms “to treat,” “to cure,” or “to treat” mean to alleviate the pathology of a disease, reduce or eliminate the symptoms of a disease, promote an increase in survival rates, and / or reduce discomfort. For example, to treat can mean the ability of a treatment to alleviate the symptoms, signs, or causes of a disease when administered to a subject. To treat can also mean the reduction or decrease of at least one clinical symptom and / or the inhibition or delay of the progression of a condition and / or the prevention or delay of the onset of a disease or illness.

[0066] As used herein, the terms “subject,” “individual,” or “patient” refer to any subject, particularly mammalian subjects, for which diagnosis, prognosis, or treatment is desired. Mammalian subjects include, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, and so on. The term “patient” may refer to a human being.

[0067] In one embodiment, the present 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 has not been previously treated. In some embodiments, the patient with R-NSCLC has been histologically or cytologically demonstrated to have stage II or stage III cancer (according to the Joint Committee on Cancer [AJCC] Manual of Tumor Staging, 8th Edition). In some embodiments, the patient with R-NSCLC has been histologically or cytologically demonstrated to have stage IIA to select [N2] stage IIIB cancer (according to the Joint Committee on Cancer [AJCC] Manual of Tumor Staging, 8th Edition). In some embodiments, the patient with R-NSCLC is newly diagnosed, previously untreated, and has histologically or cytologically demonstrated resectable NSCLC (stage IIA to select [N2] stage IIIB according to the Joint Committee on Cancer [AJCC] Manual of Tumor Staging, 8th Edition). In some embodiments, patients with R-NSCLC have disease that is resectable (stage II to selective [i.e., N2] stage IIIB) according to version 8 of the IASLC Staging Manual in Thoracic Oncology 2016. In some embodiments, patients with R-NSCLC are candidates for lobectomy, sleevectomy, or bilobectomy as the planned surgery at enrollment.

[0068] In some embodiments, the PD-L1 status of the patient's R-NSCLC is determined before treatment. In some embodiments, the patient's R-NSCLC has less than 1% PD-L1 tumor cell expression (i.e., less than 1% of tumor cells express PD-L1). In some embodiments, the patient's R-NSCLC has 1–49% PD-L1 tumor cell expression. In some embodiments, the patient's R-NSCLC has 50% or more PD-L1 tumor cell expression. In some embodiments, the patient's tumor PD-L1 expression status is determined using a Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay applied to formalin-fixed paraffin-embedded tissue samples.

[0069] In some embodiments, R-NSCLC is squamous cell carcinoma. In some embodiments, R-NSCLC is non-squamous cell carcinoma. In some embodiments, the tumor EGFR and ALK status of the patient's R-NSCLC is determined before treatment. In some embodiments, the patient does not have an EGFR mutation and / or ALK translocation. In some embodiments, patients with a Kirsten rat sarcoma (KRAS) mutation in the tumor did not need to be tested for EGFR / ALK, and patients with squamous cell carcinoma did not need to be tested for ALK.

[0070] As used herein, the term “durvalumab” refers to an antibody that selectively binds to PD-L1 and blocks the binding of PD-L1 to the PD-1 receptor and the CD80 receptor. The durvalumab 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 durvalumab has a triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to complement component C1q and the Fcγ receptor, which is involved in mediating antibody-dependent cell-mediated cytotoxicity (“ADCC”). In some embodiments, the triple mutation refers to the IgG1 Fc region containing the L234F / L235E / P331S triple mutation (EU numbering; see also U.S. Patent No. 9,493,565). Durvalumab can mitigate PD-L1-mediated suppression of human T cell activation in vitro and inhibit tumor growth in xenograft models via a T cell-dependent mechanism. The amino acid sequence of durvalumab is as follows:

[0071] [Table 1]

[0072] As used herein, the term “platinum-based chemotherapy” refers to chemotherapeutic agents containing the element platinum. Platinum-based chemotherapy has been used to treat many different types of cancer. In some embodiments, platinum-based chemotherapy refers to a chemotherapeutic 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 a chemotherapeutic treatment comprising at least one of triplatin tetranitrate, phenantriplatin, picoplatin, and satraplatin. In some embodiments, platinum-based chemotherapy further comprises one or more of afatinib, cetuximab, bevacizumab, erlotinib, gemcitabine, paclitaxel, pemetrexed, and vemurafenib. In some embodiments, platinum-based chemotherapy comprises carboplatin and paclitaxel. In some embodiments, platinum-based chemotherapy comprises cisplatin and gemcitabine. In some embodiments, the platinum-based chemotherapy comprises carboplatin and gemcitabine. In some embodiments, the platinum-based chemotherapy comprises carboplatin and pemetrexed. In some embodiments, the platinum-based chemotherapy comprises cisplatin and pemetrexed. In some embodiments, the platinum-based chemotherapy comprises a carboplatin serum drug concentration-time area (AUC) administration of approximately 5-6 mg / mL / min. In some embodiments, the platinum-based chemotherapy comprises approximately 75 mg / m² 2 This includes cisplatin administration. In some embodiments, platinum-based chemotherapy is administered at approximately 200 mg / m². 2 This includes the administration of paclitaxel. In some embodiments, platinum-based chemotherapy is administered at approximately 500 mg / m². 2 This includes administration of pemetrexed. In some embodiments, platinum-based chemotherapy is administered at approximately 1250 mg / m². 2 This includes gemcitabine administration.

[0073] In some embodiments, the combination therapy may be neoadjuvant durvalumab and neoadjuvant chemotherapy. In some embodiments, the combination therapy may be intraoperative durvalumab and neoadjuvant chemotherapy. In some embodiments, the combination therapy may include neoadjuvant durvalumab, neoadjuvant chemotherapy, and adjuvant durvalumab.

[0074] In some embodiments, the combination therapy includes administering approximately 1000 mg to approximately 2000 mg of durvalumab once every approximately 14 to 28 days for up to approximately 3 to 6 cycles prior to surgery to remove resectable NSCLC, and then administering approximately 1000 mg to approximately 2000 mg of durvalumab once every approximately 14 to 28 days for up to approximately 12 cycles postoperatively. In some embodiments, the combination therapy includes administering approximately 1500 mg of durvalumab once every approximately 3 weeks (Q3W) for up to approximately 4 cycles prior to surgery to remove resectable NSCLC, and then administering approximately 1500 mg of durvalumab once every approximately 4 weeks (Q4W) for up to approximately 12 cycles postoperatively. In some embodiments, the combination therapy includes administering an amount of durvalumab determined from the patient's body weight. For example, if a patient's weight drops to 30 kg or less [≤30 kg], the patient should receive approximately 20 mg / kg of durvalumab [or placebo] for approximately Q3 or Q4 weeks based on their weight until their weight improves to over 30 kg. At that point, the patient should begin receiving a fixed dose of approximately 1500 mg of durvalumab [or placebo] for approximately Q3 or Q4 weeks.

[0075] In some embodiments, durvalumab may be provided as a 500 mg vial solution for infusion after dilution. In some embodiments, the solution contains 50 mg / mL durvalumab, 26 mM histidine / histidine hydrochloride, 275 mM trehalose dihydrate, and 0.02% w / v polysorbate 80, with a pH of 6.0 and a density of 1.054 g / mL. In some embodiments, an administration of approximately 1500 mg (for patients weighing more than 30 kg) may be performed using an IV bag containing 0.9% (w / v) saline or 5% (w / v) dextrose, with a final durvalumab concentration in the range of 1–15 mg / mL, delivered through an IV dosing set equipped with a 0.2 or 0.22 μm filter. In some embodiments, the amount of durvalumab is determined from the patient's body weight. For example, if a patient's weight falls below 30 kg, a weight-based administration of 20 mg / kg may be performed using an IV bag selected to result in a final concentration between 1 and 15 mg / mL. In some embodiments, the standard infusion time is 1 hour (±10 minutes). However, in case of interruptions, the total acceptable time at room temperature should not exceed 8 hours.

[0076] In one embodiment, the present disclosure provides a method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), comprising: (i) administering to the patient approximately 1000-2000 mg of durvalumab and platinum-based chemotherapy every 14-28 days for approximately 3-6 cycles; (ii) surgically removing the R-NSCLC; and then (iii) administering to the patient approximately 1000-2000 mg of durvalumab every 14-28 days for at least approximately 12 weeks.

[0077] In some embodiments, after surgery to remove resectable NSCLC, patients should begin durvalumab administration as soon as they are clinically ready and within approximately 10 weeks of surgery to remove resectable NSCLC. A minimum of approximately 3 weeks is recommended between surgery to remove resectable NSCLC and the initiation of durvalumab treatment (if necessary, the first postoperative scan should be performed before initiating adjuvant therapy and postoperative radiotherapy). Complete postoperative wound healing must have occurred after surgery.

[0078] In some embodiments, surgery to remove resectable NSCLC should be performed within approximately 40 days of the last dose of durvalumab.

[0079] In some embodiments, surgery to remove resectable NSCLC includes lung resection, lobectomy, segmentectomy or wedge resection, sleeve resection, or bilobectomy. Lung resection is surgery to remove the entire lung and may be necessary when the tumor is close to the center of the chest. Lobectomy is the removal of one or more of the five affected lobes of the lung (three in the right lung and two in the left lung), removing the entire lobe containing the tumor. Segmentectomy or wedge resection removes only a portion of the lobe (i.e., a segment or wedge portion) and may be used when the patient does not have sufficient normal lung function to withstand the removal of the entire lobe. Sleeve resection involves removing a portion of the bronchus in addition to the surrounding lobe, and then anastomosing the healthy end of the bronchus. In some embodiments, surgery to remove resectable NSCLC includes anatomical lung resection of the NSCLC. In some embodiments, either thoracotomy or video-assisted thoracoscopic surgical access may be performed as appropriate, depending on the surgeon's expertise. In some embodiments, lung-sparing anatomical resection (sleeve lobectomy) is preferred over lung resection when anatomically appropriate and negative margins can be achieved. In some embodiments, T3 (infiltrative) and T4 locally extending tumors may require en bloc resection of the involved structures to achieve negative margins.

[0080] In some embodiments, patients may receive postoperative radiotherapy (PORT) after surgery to remove resectable NSCLC. PORT can be administered within approximately 8 weeks post-surgery. In some embodiments, adjuvant durvalumab is initiated within approximately 3 weeks after completion of PORT. In some embodiments, adjuvant durvalumab is initiated within approximately 10 weeks post-surgery. In some embodiments, PORT is permitted for patients as directed in accordance with national guidance. In some embodiments, PORT may include, but is not limited to, doses ranging from 50–60 Gy, 1.8–2 Gy per fraction, and 5 fractions per week for patients with positive margins of disease (R1). In some embodiments, PORT may include, but is not limited to, doses ranging from 60–66 Gy, 1.8–2 Gy per fraction, and 5 fractions per week. In some embodiments, intensity-modulated radiation therapy (IMRT) or three-dimensional conformal radiation therapy (3D-CRT) is possible.

[0081] In some embodiments, the success of the treatment method is determined by an improvement in pathological complete response (pCR) compared to standard treatment.

[0082] In some embodiments, the success of the treatment method is determined by an improvement in pathological response (mPR) compared to standard treatment.

[0083] In some embodiments, the success of the treatment method is determined by the improvement in event-free survival (EFS) compared to standard treatment, such as neoadjuvant chemotherapy including neoadjuvant platinum-based chemotherapy.

[0084] 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) intraoperative 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.

[0085] In some embodiments, the success of the treatment method is determined by an improvement of at least approximately 13% in pathological complete response (pCR) compared to standard treatment. In some embodiments, the success of the treatment method is determined by an improvement of at least approximately 21% in pathological marked response (mPR) compared to standard treatment. In some embodiments, the success of the treatment method is determined by an improvement of at least approximately 13 months in event-free survival (EFS) compared to standard treatment.

[0086] In some embodiments, the use of combination therapy results in an improvement of one or more of EFS, pCR, mPR, DFS, and OS compared to standard treatment. In some embodiments, the use of combination therapy results in an improvement of one or more of EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy or postoperative or preoperative platinum-based chemotherapy.

[0087] As used herein, the term “Standard Treatment” (SoC) may refer to one or more of the following: 1) Carboplatin + Paclitaxel: For 4 cycles, on day 1 of each 3-week cycle, carboplatin AUC 6 (mg / mL / min) and paclitaxel 200 mg / m² were administered. 2 Administer via IV infusion (in cases of histological findings of squamous cell tumor). 2) Cisplatin + Gemzar: For 4 cycles, 75 mg / m² of cisplatin was administered on day 1 of each 3-week cycle. 2The drug was administered via IV infusion, and gemcitabine 1250 mg / m² was administered on day 1 and day 8 of each 3-week cycle for 4 cycles. 2 Administer via IV infusion (in the case of histological findings of squamous cell tumor). If tolerability is unfavorable, the patient may switch from cisplatin therapy to carboplatin therapy at any point during the study (assuming eligibility for the replacement therapy is met). In patients with comorbidities or who, in the judgment of the principal investigator, are intolerant to cisplatin, carboplatin AUC 5 (mg / mL / min) may be administered from cycle 1. 3) Pemetrexed + Cisplatin: Pemetrexed 500 mg / m² on day 1 of each 3-week cycle for 4 cycles. 2 and cisplatin 75 mg / m² 2 Administer via IV infusion (in the case of histological findings of non-squamous cell tumors). If tolerability is unfavorable, the patient may switch from cisplatin therapy to carboplatin therapy at any point during the study (assuming eligibility for the replacement therapy is met). In patients with comorbidities or who, in the judgment of the principal investigator, are intolerant to cisplatin, carboplatin AUC 5 (mg / mL / min) may be administered from cycle 1. 4) Pemetrexed + Carboplatin: Pemetrexed 500 mg / m² on day 1 of each 3-week cycle for 4 cycles. 2 In addition, carboplatin (AUC 5 mg / mL / min) is administered by IV infusion (in the case of histological findings of non-squamous cell tumors).

[0088] As used herein, the terms “event-free survival” or “EFS” refer to the time from randomization to the first of the following: a) local or distant recurrence as determined by BICR using RECIST 1.1 assessment; b) death from any cause (event date is the date of death); c) PD that interferes with surgery (event date is the date of this assessment) or PD that interferes with the completion of surgery as discovered and reported by the principal investigator at the time of the surgery attempt (event date is the date of the first surgery attempt). Event-free survival can be analyzed using a log-rank test based on blinded independent central review (BICR) assessment using RECIST v1.1, as well as pathological assessments stratified by disease stage (stage II vs stage III) and PD-L1 expression status on mITT (<1% vs ≥1%). The p-value can be obtained from a stratified log-rank test using the Efron approach (Hertz-Picciotto and Rockhill, "Validity and efficiency of approximation methods for tied survival times in Cox regression." Biometrics 1997;53(3):1151-6.) for handling ties.

[0089] As used herein, the terms “pathological complete response,” “pathological CR,” or “pCR” refer to the percentage of patients who have 0% residual surviving tumor cells in all resected tissue (including primary lung lesions and lymph nodes) after neoadjuvant therapy, as assessed by the central pathology laboratory. Patients who are not evaluable by central pathological assessment (including patients with R2 margins) or who do not have surgical specimens may be considered non-pCR (e.g., pathological assessments that are, as necessary, “unevaluable” or “missing”). Central pathological assessment of pCR is performed in accordance with 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. May 2020;15(5):709-740.doi:10.1016 / j.jtho.2020.01.005). The analysis can be performed using the Cochrane-Mantel-Henzel (CMH) test, stratified by disease stage (stage II vs. stage III) and PD-L1 expression status (<1% vs. ≥1%). The effect of treatment is estimated by the difference in proportions between treatment groups and their corresponding CI and p-values.

[0090] As used herein, the terms “disease-free survival” and “DFS” refer to the time from the date of surgery to the date of the first disease recurrence as determined by BICR using RECIST 1.1 assessment (local or distant), or the date of death from any cause, whichever occurs first. Pathological confirmation from biopsy lesions may also be considered (as necessary). A newly identified primary malignant tumor, pathologically confirmed, 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, as well as pathological assessments stratified by disease stage (stage II vs. stage III) and PD-L1 expression status on a modified set of resection analyses (<1% vs. ≥1%). The p-value can be obtained from the stratified log-rank test using the Efron (Hertz-Picciotto and Rockhill 1997) approach for handling ties.

[0091] As used herein, the terms “pathological response” and “mPR” refer to the proportion of patients in whom residual surviving tumor tissue in primary lung tumors after neoadjuvant therapy at the time of resection is 10% or less, as assessed by the central pathology laboratory. Patients who are not evaluable by central pathological assessment (including patients with R2 margins) or who do not have surgical specimens may be considered to have non-mPR (e.g., responses that are captured as “unevaluable” or “missing” as necessary). Analysis may be performed using a CMH test stratified by disease stage (stage II vs. stage III) and PDL1 expression status (<1% vs. ≥1%). The effect of treatment can be estimated by the difference in proportions between treatment groups and their corresponding CI and p-values.

[0092] As used herein, the terms “overall survival” and “OS” refer to the time from the date of randomization to death from any cause, regardless of whether the subject discontinued randomized therapy or received another anticancer therapy. Any patient whose death was not known at the time of analysis is censored based on the last recorded date on which the patient was known to be alive. Overall survival can be analyzed in the mITT population using the same method as described for EFS. The effect of treatment can be estimated by the HR and its corresponding CI. Kaplan-Meier plots may be presented for each treatment arm. To estimate the number of OS patients at 12, 24, 36, 48, and 60 months, analyses can be performed using Kaplan-Meier estimates of OS.

[0093] Intention-to-Treat (ITT) population set: The ITT analysis set includes all randomized patients. Treatment groups are compared based on the randomized study treatment, regardless of the treatment actually received. Patients who were randomized but did not subsequently receive the study treatment are included in the analysis of the randomized treatment group.

[0094] Modified Intention-to-Treat (mITT) population set: The mITT includes all patients in the ITT, except those whose tumors have an EGFRm / ALK translocation. Unless otherwise specified, the mITT will be used for all efficacy analyses, including PROs. Treatment arms will be compared based on randomized study treatments, regardless of the treatment actually received.

[0095] Resection population set: The resection set may consist of all ITT patients who underwent surgical resection after the neoadjuvant period, did not have an R2 margin, and whose first postoperative scan did not show evaluable disease (defined as no postoperative R2 margin and no RECIST evidence for disease).

[0096] Modified resection population set: The modified resection set may consist of all patients in the resection set, excluding those whose tumors have an EGFRm / ALK translocation. Unless otherwise specified, this analysis set is used only for DFS. Treatment arms are compared based on randomized study treatment, regardless of the treatment actually received.

[0097] As used herein, the terms “administer” or “to administer” mean providing, contacting, and / or delivering one or more compounds by any suitable route to achieve a desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, intrathecal, intrafocal, or intracranial injection), percutaneous, topical, buccal, rectal, vaginal, nasal, ocular, inhalation, and implantation.

[0098] It should be understood that certain aspects of this specification are not limited to the specific embodiments presented and may vary. It should also be understood that the terms used herein are for the purpose of describing only specific embodiments and are not intended to be limiting unless specifically defined herein. Furthermore, certain embodiments disclosed herein can be combined with other embodiments disclosed herein without limitation, as will be recognized by those skilled in the art.

[0099] Without limiting the scope of this disclosure, several embodiments of this disclosure are described below for illustrative purposes. [Examples]

[0100] The following embodiments illustrate specific embodiments of the present disclosure and various uses thereof. They are provided for illustrative purposes only and should not be construed as limiting the scope of the invention.

[0101] Example 1: Neoadjuvant / adjuvant durvalumab for the treatment of patients with resectable non-small cell lung cancer (R-NSCLC). The AEGEAN (NCT03800134) study described herein was a phase III, double-blind, placebo-controlled, multicenter international study evaluating intraoperative (i.e., neoadjuvant and adjuvant) durvalumab plus neoadjuvant chemotherapy for the treatment of patients with resectable stage II and stage III non-small cell lung cancer (R-NSCLC).

[0102] While radical surgery is the primary treatment for early-stage non-small cell lung cancer (NSCLC [stages I-IIIA]), the 5-year survival rate for patients treated with surgery alone is low, ranging from 67% (stage IA) to 23% (stage IIIA) (Mountain 1997).

[0103] Early studies of immunotherapy in a neoadjuvant setting in patients with resectable NSCLC have shown promising clinical activity and an acceptable safety profile (Forde et al. "Neoadjuvant PD-1 blockade in resectable lung cancer." N Engl J Med2018;378:1976-86; Shu et al. "Neoadjuvant atezolizumab + chemotherapy in patients with resectable non-small cell lung cancer (NSCLC)." Poster presentation: ASCO Annual Meeting 2018). Combining chemotherapy with durvalumab before surgery may offer clinical benefits compared to chemotherapy + placebo. Therefore, this Phase III study investigated the administration of durvalumab + platinum-based chemotherapy before surgery, followed by further administration of durvalumab after surgery, to determine whether this treatment regimen can improve disease activity and, consequently, long-term clinical outcomes in patients with resectable NSCLC.

[0104] patient Approximately 1,300 patients were enrolled in this study, and approximately 800 eligible patients were randomized. Eligible patients had newly diagnosed, previously untreated, histologically or cytologically evidenced resectable NSCLC (stage II to selective [N2] stage IIIB according to the Joint American Cancer Committee [AJCC] Manual of Tumor Staging, 8th Edition). Patients were randomized in a 1:1 ratio to receive either durvalumab plus platinum-based chemotherapy preoperatively followed by durvalumab postoperatively (Arm 1: intravenous administration of platinum-based chemotherapy plus durvalumab every 3 weeks preoperatively (4 cycles), followed by intravenous administration of durvalumab every 4 weeks (12 cycles)), or placebo plus platinum-based chemotherapy preoperatively followed by placebo postoperatively (Arm 2: intravenous administration of platinum-based chemotherapy plus placebo every 3 weeks preoperatively (4 cycles), followed by intravenous administration of placebo every 4 weeks (12 cycles)). Patients were also stratified by disease stage (stage II vs. stage III) and PD-L1 expression status (<1% vs. ≥1%).

[0105] Patients had resectable disease (stage IIA to selective [i.e., N2] stage IIIB) (according to version 8 of the IASLC Staging Manual in Thoracic Oncology 2016) and were candidates for lobectomy, sleeve resection, or bilobectomy as the planned surgery at enrollment. In screening, complete surgical resection of primary NSCLC was considered achievable by a multidisciplinary assessment including thoracic surgeons who perform lung cancer surgery as a major part of their practice. Additional inclusion criteria included being 18 years of age or older; having a general status of 0 or 1 in the US East Coast Cancer Clinical Trials Group; having an estimated mean life expectancy of 12 weeks or more; demonstrating tumor PD-L1 status (assessed in the central laboratory using VENTANA SP263 immunohistochemical assay); and having one or more previously irradiated lesions that were eligible as target lesions under the Response Evaluation Criteria Version 1.1 (RECIST v1.1) for solid tumors.

[0106] T4 tumors were only considered eligible if they were defined as T4 based solely on their size (greater than 7 cm). Other reasons for T4 status (e.g., attachment to any of the following structures: diaphragm, mediastinum, heart, great blood vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or keel) were considered ineligible.

[0107] The nodule status was investigated using whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contrast-enhanced computed tomography (CT). If the PET / CT scan was positive in the mediastinum, or if the scan was negative but a T, central tumor, or clinical N1 (cN1) exceeding 3 cm was present, it was recommended to confirm the nodule status by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. Essential magnetic resonance imaging (preferably MRI) was performed with IV contrast, or brain CT with IV contrast was performed during staging.

[0108] The patients had not been previously exposed to any immuno-mediated therapies, including but not limited to other anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies, with the exception of therapeutic anti-cancer vaccines.

[0109] The tumor PD-L1 status of patients was confirmed prior to randomization using a Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay applied to formalin-fixed paraffin-embedded tissue samples, and the tests were completed by the central laboratory.

[0110] EGFR and ALK status were also checked during screening. Patients with Kirsten rat sarcoma (KRAS) mutations in their tumors did not need to be tested for EGFR / ALK, and patients with squamous cell carcinoma did not need to be tested for ALK. Patients with demonstrated EGFR / ALK abnormalities were excluded from the efficacy analysis in the modified treatment intention population (N=740).

[0111] Patients were considered suitable for enrollment if the planned surgery was a lobectomy, sleeve resection, or bilobectomy, as determined by the attending physician based on baseline findings. Patients were considered to have adequate cardiac and pulmonary function according to multidisciplinary assessment. FEV1 before or after bronchodilator administration was 1.0 L, with a postoperative prediction of >40%. The use of these cutoff values ​​to assess resection candidate status was guided by the results of cardiopulmonary exercise tests, as outlined in the European Society for Medical Oncology (ESMO) guidelines for pre-treatment risk assessment. Both FEV1 and DLCO tests were required to assess pre-resection pulmonary function.

[0112] [Table 2]

[0113] [Table 3]

[0114] [Table 4]

[0115] [Table 5]

[0116] [Table 6]

[0117] Research design and treatment Approximately 800 patients with resectable NSCLC (stages IIA to selective stage IIIB; either squamous or non-squamous) were randomized in a 1:1 ratio to receive either durvalumab plus platinum-based chemotherapy preoperatively followed by durvalumab postoperatively (arm 1), or placebo plus platinum-based chemotherapy preoperatively followed by placebo postoperatively (arm 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%).

[0118] Patients received four cycles of durvalumab or placebo plus platinum-based chemotherapy (every three 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 not eligible for this study. All patients were staged and managed according to the National Comprehensive Cancer Network 2020 Guidelines (version 1.2021). Surgery was scheduled within 40 days of administration.

[0119] Patients initiated durvalumab or placebo postoperatively as soon as clinically possible and within 10 weeks of surgery (excluding patients receiving postoperative radiotherapy initiated within 8 weeks postoperatively). Durvalumab / placebo was administered within 3 weeks of completion of postoperative radiotherapy. Patients randomized to receive durvalumab plus platinum-based chemotherapy preoperatively received an additional 12 cycles of durvalumab 1500 mg every 4 weeks (Q4W), while patients randomized to receive placebo plus platinum-based chemotherapy preoperatively received an additional 12 cycles of placebo Q4W.

[0120] Treatment and duration: Patients received 1500 mg of durvalumab or placebo via intravenous (IV) infusion for up to 4 cycles Q3W before surgery and 12 cycles Q4W after surgery, unless unacceptable toxicity, withdrawal of consent, or other discontinuation criteria were met. If a patient's weight (WT) decreased to ≤30 kg, the patient received WT-based doses equivalent to 20 mg / kg of durvalumab [or placebo] at Q3W or Q4W, after consultation between the principal investigator and the research physician / medical scientist, until their WT improved to over 30 kg. At that point, the patient began a fixed dose of 1500 mg of durvalumab [or placebo] at Q3W or Q4W.

[0121] Standard of Care (SoC): Patients received one of the following four SoC regimens as part of their preoperative treatment regimen, based on the histological findings of the tumor and the discretion of the investigator. For patients with squamous epithelial histological findings, the options were carboplatin + paclitaxel or cisplatin + gemcitabine (or carboplatin + gemcitabine for patients with comorbidities or, at the discretion of the investigator, patients who could not tolerate cisplatin). For patients with non-squamous epithelial histological findings, the options were either pemetrexed + cisplatin or carboplatin.

[0122] 1) Histological findings of squamous cell tumor: Carboplatin + paclitaxel: Over 4 cycles, on day 1 of each 3-week cycle, the area under the serum drug concentration-time curve (AUC) of carboplatin was 6 (mg / mL / min) and paclitaxel was 200 mg / m². 2 It is administered via IV infusion. 2) Histological findings of squamous cell tumor: Cisplatin + Gemzar: Cisplatin 75 mg / m² on day 1 of each 3-week cycle for 4 cycles. 2 The drug was administered via IV infusion, and gemcitabine 1250 mg / m² was administered on day 1 and day 8 of each 3-week cycle for 4 cycles. 2The drugs were administered via IV infusion. If tolerability was unfavorable, patients were switched from cisplatin therapy to carboplatin therapy at any point during the study (assuming eligibility for switching therapy was met). Patients with comorbidities or those who were intolerant to cisplatin as determined by the investigator were given carboplatin AUC 5 (mg / mL / min) starting from cycle 1. 3) Histological findings of non-squamous cell tumors: Pemetrexed + cisplatin: Pemetrexed 500 mg / m² on day 1 of each 3-week cycle for 4 cycles. 2 and cisplatin 75 mg / m² 2 The drugs were administered via IV infusion. If tolerability was unfavorable, patients were switched from cisplatin therapy to carboplatin therapy at any point during the study (assuming eligibility for switching therapy was met). Patients with comorbidities or those who were intolerant to cisplatin as determined by the investigator were given carboplatin AUC 5 (mg / mL / min) starting from cycle 1. 4) Histological findings of non-squamous cell tumors: Pemetrexed + carboplatin: Pemetrexed 500 mg / m² on day 1 of each 3-week cycle for 4 cycles. 2 Carboplatin AUC 5 (mg / mL / min) was administered via IV infusion.

[0123] Treatment duration: Unless unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met, four cycles of durvalumab or placebo plus platinum-based chemotherapy (Q3W) were administered preoperatively, followed by 12 cycles of durvalumab or placebo (Q4W) postoperatively (±1 cycle of platinum-based chemotherapy).

[0124] The scheduled surgery was within 40 days of the last IP dose preoperatively, and patients initiated durvalumab or placebo postoperatively as soon as clinically possible and within 10 weeks of surgery (excluding patients receiving postoperative radiotherapy initiated within 8 weeks postoperatively). Durvalumab / placebo was administered within 3 weeks of completion of postoperative radiotherapy. For patients to be eligible for adjuvant durvalumab or placebo, surgery must have been completed with R0 or R1 resection margins showing no evidence of disease at the first postoperative evaluation using RECIST v1.1.

[0125] Progression during treatment: Treatment was discontinued at the point of clinical progression, including local or distant recurrence as determined by the principal investigator using RECIST 1.1, or progression that interfered with surgery or was discovered during an attempt at surgery.

[0126] Patient follow-up after discontinuation of the study drug: Patients who discontinued the study treatment due to toxicity or worsening of symptoms, clinical progression (excluding progression that would interfere with surgery or progression discovered during an attempted surgery), or patients who initiated subsequent anticancer therapy in the absence of local or distant recurrence (in the case of resected patients) or radiological disease progression (PD) as defined in RECIST 1.1 (in the case of patients who did not undergo surgery for reasons other than PD), were followed up by tumor evaluation until local or distant recurrence (in the case of resected patients) or radiological PD as defined in RECIST 1.1 (in the case of patients who did not undergo surgery for reasons other than PD), as determined by the principal investigator, and were followed up for survival. These patients were not eligible for retreatment at any point in time.

[0127] Endpoints and evaluation The two primary efficacy endpoints in this study were event-free survival (EFS; by blinded independent central review [BICR]) and pathological complete response (pCR; by central review). Other secondary endpoints included the primary and key secondary endpoints in patients with PD-L1 expression of ≥1%, pharmacokinetics and immunogenicity, patient-reported outcomes, and safety assessments. In accordance with the FDA Guidance on Clinical Trial Endpoints for Approval of Anticancer and Biologics (FDA 2018), EFS was defined as the time from randomization to any of the following events: disease progression (PD) that interferes with surgery, local or distant recurrence, or death from any cause. More specifically, EFS was defined as the time from randomization to the earliest of the following: (1) disease progression that interferes with surgery; (2) disease progression that interferes with the completion of surgery, as discovered and reported by the principal investigator at the time of attempting surgery; (3) local or distant recurrence using blinded independent central review according to RECIST v1.1; or (4) death from any cause. If surgery was not performed or completed for reasons other than disease progression, it was not considered an EFS event (i.e., the patient remained under follow-up for progression according to the RECIST definition).

[0128] Primary tumors and sampled lymph nodes were evaluated for pathological response to neoadjuvant therapy by central pathological review using recommendations from the IASLC. To be eligible for pathological evaluation, patients should have received three cycles of neoadjuvant research therapy according to the protocol. Patients who were ineligible for evaluation (including those with R2 resection margins as determined by local evaluation) or who did not have surgical specimens were classified as non-responders. pCR was defined as the absence of any viable tumor cells after a complete evaluation of the resected lung cancer specimen and all sampled local lymph nodes, and MPR was defined as having 10% or less viable tumor cells in the primary lung tumor (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); Hellmann et al. "Pathological response after neoadjuvant chemotherapy in resectable 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 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).” Ann Oncol2018;29(8):1853-1860).

[0129] While time-to-event endpoints and OS are generally considered preferred outcome measures for Phase III cancer studies in early-stage disease, they often result in very long NSCLC studies. Therefore, time-to-event 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.

[0130] Secondary efficacy endpoints in this study included disease-free survival (DFS) (modified resection set and PD-L1 TC ≥ 1% resection set), pathological complete response (pCR) (PD-L1 TC ≥ 1% analysis set), pathological complete response (mPR) (mITT and PD-L1 TC ≥ 1% analysis set), end-effective survival (EFS) (PD-L1 TC ≥ 1% analysis set), and overall survival (OS) (mITT and PD-L1 TC ≥ 1% analysis set).

[0131] Disease-free survival (DFS) was defined as the time from the date of surgery to the date of the first disease recurrence (local or distant), or the date of death from any cause, whichever occurred earlier. Pathological confirmation from biopsy lesions was also considered (as needed) when performed at the discretion of the principal investigator and in accordance with local practice. Newly confirmed primary malignancies were not considered DFS events.

[0132] [Table 7]

[0133] Tumors were evaluated according to RECIST v1.1 using images collected at the following time points: baseline (within 28 days prior to randomization); after completion of neoadjuvant therapy and prior to surgery; 5 weeks (±2 weeks) after surgery and prior to the initiation of adjuvant therapy; every 12 weeks (±1 week) until 48 weeks post-surgery; every 24 weeks (±2 weeks) until 192 weeks (i.e., approximately 4 years post-surgery); and thereafter every 48 weeks (±2 weeks) until local or distant recurrence, withdrawal of consent, or death.

[0134] Safety was monitored throughout the study, and adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria for AE version 5.0.

[0135] Efficacy was evaluated and determined by pathological review or BICR using RECIST 1.1 assessments, 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), as needed. Efficacy was evaluated and determined by pathological review or BICR. EFS events that interfered with surgery or interfered with surgical completion discovered during surgery were determined by the principal investigator.

[0136] In the first planned interim analysis, the EFS follow-up for censored patients was 11.7 months (range: 0.0–46.1).

[0137] statistical analysis The two primary endpoints in this study were event-free survival (EFS) and pathological complete response (pCR) in the modified intention-to-treatment (mITT) population. Key secondary endpoints included disease-free survival (DFS) in the modified resection population, as well as pathological marked response (mPR) and overall survival (OS) in the mITT population. Family-wise error rates were strongly controlled at a 5% two-sided level across multiple trial procedures. The trial procedures were hierarchical, starting with testing the two primary endpoints, EFS and pCR. The overall two-sided 5% type I error was split between the two primary endpoints, EFS and pCR. 4.5% alpha levels were allocated to the EFS analysis, and 0.5% alpha levels were allocated to the pCR analysis.

[0138] The mITT population included all randomized patients except those whose tumors had epidermal growth factor receptor mutations (EGFRm) or anaplastic lymphoma kinase (ALK) translocations. Unless otherwise specified, mITT was used for all efficacy analyses, including PROs. Treatment groups were compared based on the randomized study intervention, regardless of the treatment actually received.

[0139] An interim pCR analysis (IA) was conducted when approximately 400 mITT patients had the opportunity to undergo surgery (actual N=402), and the final analysis was conducted when all mITT patients (actual N=740) had the opportunity to undergo surgery. Stratified CMH trials were used to compare pCR and MPR rates across study arms. The CI of the differences between arms was estimated using MN confidence limits. The first interim EFS analysis (presented here) was planned at approximately 30% maturity (actual EFS maturity: 31.9%).

[0140] Comparisons between study arms were analyzed using stratified log-rank tests. HR and 95% CI were estimated from a stratified Cox PH model. EFS median and landmarks were estimated using the KM method.

[0141] For pathological endpoints, response rates were compared between treatment arms using the stratified Cochrane-Mantel-Henzel test. Treatment efficacy was estimated by the difference in response rates, and the corresponding 95% confidence intervals (CIs) were calculated using the stratified Miettinen and Nurminen method. EFS was compared between treatment arms using the stratified log-rank test. Treatment efficacy was estimated by the HR and 95% CI calculated using a stratified Cox proportional hazards model. The median EFS and landmark rates were estimated using the Kaplan-Meier method. Stratification of the primary and important secondary endpoints was by disease stage and PD-L1 expression. Planned analyses of the primary endpoint were performed in pre-specified subgroups. For pCR, the difference in response rates was calculated for each subgroup, and the corresponding 95% CIs were estimated using the unstratified Miettinen and Nurminen method. For EFS, the HR and 95% CI were calculated for each subgroup using a Cox proportional hazards model with treatment as the sole covariate.

[0142] To strongly control for Type I errors at 5% (two-sided), a hierarchical multiple testing procedure with a gatekeeping strategy was used across the primary endpoint and the alpha-controlled secondary endpoint. Initially, 0.5% and 4.5% of alpha were allocated to pCR and EFS, respectively. Alpha was split between the interim and final analyses (IA and FA, respectively) using a Lan-DeMets consumption function approximating the O'Brien-Fleming approach 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). Positive pCR allowed for alpha recycling to the critical secondary endpoint MPR, which could be recycled to EFS (to provide a total of 5% alpha). Based on a total of 0.5% α allocated to the pCR endpoint, the planned IA for pCR (assuming 400 patients in the modified intention-to-treatment [mITT] population in the IA and 740 patients in the mITT population in the FA) had 55% power to detect a statistically significant 12% inter-arm difference at a two-sided significance level of 0.0078%. The MPR (α-controlled secondary endpoint) was also formally analyzed in the IA. For EFS, assuming a 3-month delay in the hazard due to a 33-month non-linear (k=2) occurrence, the assumed hazard ratio for the first 3 months was 1.0, and assuming a hazard ratio (HR) of 0.63 after 3 months, we obtained an approximate overall HR of 0.67 at the time of the FA. Based on a total 4.5% alpha allocated to the EFS endpoint, for the first interim analysis of EFS, with a true overall HR of 0.69 and 224 EFS events (per blinded independent central review) in the mITT population (N=740), this study provides 50% power to demonstrate a statistically significant EFS effect at a two-sided significance level of 0.6649%. Since pCR and MPR were statistically significant, EFS was tested with a total 5% alpha allocated. The actual significance level was calculated for each endpoint based on the number of patients or events observed in the interim analysis compared to the planned number of patients or events in the final analysis.

[0143] [Table 8]

[0144] result Patients and treatment 1,480 patients were enrolled, of which 802 were randomized to either the durvalumab arm (n=400) or the placebo arm (n=402), including the ITT population (Figure 1B). The characteristics of the ITT population (Table 4) were generally representative of the real-world population of patients with resectable NSCLC (Table 2). The mITT population (excluding patients with known EGFR / ALK abnormalities) included 740 patients, of which 366 and 374 were randomized to the durvalumab arm and placebo arm, respectively. Baseline demographics and clinical characteristics, as well as the planned neoadjuvant chemotherapy doublet regimens, were roughly balanced between the treatment arms in the mITT population (Table 1). The median age was 65.0 years, most patients were male (71.6%), general status was 0 (68.4%), and current or former smokers (85.5%). Over 70% of patients had stage III disease, and half of all patients had N2 disease. Nearly equal proportions of patients had squamous and non-squamous histological findings. Across both treatment arms, 33.4% of patients had tumor PD-L1 expression of less than 1%, and carboplatin was the planned neoadjuvant platinum agent for over 70% of patients.

[0145] At the data cutoff for this first planned interim analysis of EFS, the median follow-up for EFS in censored patients was 11.7 months (range, 0.0–46.1). In the mITT population, approximately 85% of patients completed 4 cycles of both chemotherapy agents in each treatment arm, and over 60% of all patients initiated either adjuvant durvalumab or placebo (Table 3; see Table 8 for details on neoadjuvant treatment exposure). In each treatment arm, a small number of patients (5.8% of the mITT population) received postoperative radiotherapy (as permitted by protocol, if directed at the discretion of the treating physician). At the data cutoff for this analysis, 24.0% and 21.1% of patients in the mITT population completed 12 cycles of adjuvant durvalumab or placebo, respectively. 18.6% and 18.7% of patients in each arm discontinued adjuvant study treatment early, respectively. Approximately one-quarter of all patients in the mITT population were still receiving adjuvant research treatment (23.2% in the durvalumab arm and 23.5% in the placebo arm).

[0146] [Table 9]

[0147] Surgical Overview At the data cutoff, approximately 81% of patients in each treatment arm (Table 3; mITT population) had undergone surgery (note that curative thoracic surgery was attempted, regardless of whether it was completed). In total, 77.6% of patients in the durvalumab arm and 76.7% of patients in the placebo arm completed surgery (i.e., curative thoracic surgery was considered completed as assessed by the investigator), with a slightly higher rate of R0 resection in the durvalumab arm compared to the placebo arm (94.7% vs. 91.3%). (See Tables 9 and 10 for a summary of the most common reasons for not undergoing or completing surgery in the ITT population, details of surgery delays in the safety analysis set [Table 9], and details of surgery and surgical outcomes in the mITT population [Table 10]).

[0148] [Table 10]

[0149] [Table 11]

[0150] Effectiveness In this initial interim analysis of EFS at maturity 31.9%, EFS was significantly extended in the durvalumab arm compared to the placebo arm (stratified hazard ratio, 0.68; 95% CI, 0.53–0.88; P=0.003902), with median time not reached (NR) (95% CI, 31.9 months to NR) versus 25.9 months (95% CI, 18.9 months to NR), respectively (Figure 2). The benefit of EFS with durvalumab compared to placebo was maintained across most pre-specified subgroups (Figure 3). Consistent benefits were observed regardless of the planned neoadjuvant platinum agent (Figure 4). Benefits were also observed regardless of age, disease stage (Figure 4B), PD-L1 tumor cell expression (Figures 4C–4E), and tumor histological findings (Figures 4F–4G). The magnitude of the benefit was greater in current smokers. Female patients appeared to have a smaller therapeutic effect at first glance, but the HR CI was broad for this subgroup, constituting only 28.4% of the mITT population.

[0151] [Table 12]

[0152] In the final analysis of pCR, a higher proportion of patients achieved pCR in the durvalumab arm (17.2%; 95% CI, 13.5–21.5) versus the placebo arm (4.3%; 95% CI, 2.5–6.9) (difference in proportion, 13.0%; 95% CI, 8.7–17.6) (Figure 5). Furthermore, a higher proportion of patients achieved MPR in the durvalumab arm (33.3%; 95% CI, 28.5–38.4) versus the placebo arm (12.3%; 95% CI, 9.1–16.1) (difference in proportion, 21.0%; 95% CI, 15.1–26.9) (Figure 5). The results for pCR and MPR were consistent across the interim analysis of pCR (N=402) (Figures 7A–7B). Statistical significance for pCR (P=0.0036) and MPR (P=0.000002) was achieved in this initial analysis. The trend toward pCR benefit with durvalumab was observed across all pre-specified subgroups, and the results were in close agreement with the overall mITT population (Figure 6). A similar trend was observed for MPR across subgroups (Figure 8). Pathological regression of the primary tumor was greater overall in the durvalumab arm compared to the placebo arm (Figure 9). See Table 11 for a summary of preoperative objective responses in the mITT population.

[0153] safety Overall, adverse events (AEs) of any cause occurred in 96.5% of patients in the durvalumab arm and 94.7% of patients in the placebo arm (Table 5). AEs potentially related to any study treatment (i.e., durvalumab, 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 arms (42.3% vs. 43.4%). Similarly, the incidence of grade 3 or 4 AEs potentially related to any study treatment was similar (32.3% vs. 33.1%). AEs potentially related to any study treatment with a fatal outcome were rare, occurring in 1.8% and 0.5% of the durvalumab and placebo arms, respectively. The most common AEs of any cause largely reflected the safety profiles of the chemotherapy agents used in the study (Table 12). The proportion of the most common AEs was nearly similar across both treatment arms. The rates of rash (14% vs. 8.5%) and pruritus (11.8% vs. 5.5%) of any grade were higher in patients in the durvalumab arm compared to the placebo arm. However, grade 3 or 4 events were rare and occurred with similar frequency in both treatment arms. (See Table 13 for a summary of the most common AEs that may be associated with any study treatment.) Immune-mediated AEs of any grade were reported in 23.7% and 9.8% of patients in the durvalumab arm and placebo arm, 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. Immune-mediated pneumonia of any grade was reported in 3.7% and 1.8% of patients in the durvalumab arm and placebo arm, respectively.

[0154] [Table 13]

[0155] [Table 14]

[0156] [Table 15]

[0157] overview Compared to neoadjuvant CT alone, intraoperative durvalumab combined with neoadjuvant chemotherapy (CT) significantly improved both pCR and EFS in patients with resectable NSCLC. The pCR rate was significantly higher in the durvalumab arm compared to the placebo arm (17.2% vs. 4.3% at final analysis; difference, 13.0%; 95% CI, 8.7–17.6; P=0.000036 [n=402], assessed at interim analysis). The improvement in pCR rate was 13.0% (95% CI: 8.7–17.6). The improvement in EFS was also significant (EFS-stratified HR=0.68 (95% CI: 0.53–0.88; P=0.003902; median follow-up of 11.7 months and maturity of 31.9%). Benefits were observed regardless of disease stage and PD-L1 expression.

[0158] Improvements in both pCR and EFS were largely consistent across predefined subgroups, and an EFS benefit was observed regardless of the planned neoadjuvant platinum agent (HRs were 0.59 (95% CI: 0.35–1.00) for cisplatin and 0.73 (95% CI: 0.54–0.98) for carboplatin).

[0159] Intraoperative durvalumab plus neoadjuvant CT 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 patients, respectively. The addition of durvalumab did not affect the completion of neoadjuvant CT (4 cycles) or surgery.

[0160] Compared to neoadjuvant chemotherapy alone, intraoperative durvalumab plus neoadjuvant chemotherapy significantly improved pCR and EFS in patients with R-NSCLC with a manageable safety profile. This study is the first Phase III study to explain the benefits of intraoperative immunotherapy plus neoadjuvant CT and demonstrate that intraoperative durvalumab plus neoadjuvant CT is a potentially novel treatment for patients with resectable NSCLC.

[0161] In patients with resectable NSCLC, intraoperative durvalumab plus neoadjuvant chemotherapy significantly improved both primary endpoints, EFS (HR, 0.68; P=0.003902) and pCR (difference in ratios, 13.0%; P=0.000036), compared to neoadjuvant chemotherapy alone, with a manageable safety profile and without impact on neoadjuvant chemotherapy or surgical completion. Notably, in the first planned interim analysis, a significant EFS benefit was achieved based on maturity of 31.9% and median follow-up of less than one year (censored patients), at which point approximately one-quarter of patients were still receiving adjuvant study treatment (more than half of all patients were randomized in the final year of enrollment). These findings support an enhanced treatment strategy using immunotherapy as an intraoperative regimen, rather than merely as a neoadjuvant or adjuvant regimen.

[0162] The benefits of durvalumab in EFS and pCR were widely observed across all predefined subgroups and were consistent with the improvements observed across the entire mITT population. For example, the benefit in EFS was observed regardless of age, disease stage (including patients with N2 disease), histological findings, and PD-L1 expression, particularly in patients with PD-L1 expression <1% (however, the magnitude of the benefit was numerically better in patients with PD-L1 expression ≥50%). Greater benefits were observed in current smokers compared to non-smokers. However, this is consistent with findings across other studies of immunotherapy (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. 23 Aug. 2021; 11:703143. PMID:34497760; PMCID:PMC8419340). Female patients did not appear to have gained a relative benefit at first glance. The EFS HR confidence interval was wide and overlapped with that of the male subgroup, which may be at least in part due to the higher proportion of non-smoking female patients (28.9% vs. 7.1%) and the lower proportion of PD-L1 expression ≥50% (24.6% vs. 32.1%) compared to male patients. Benefits of durvalumab in EFS and pCR were observed regardless of disease stage, but their magnitude varied somewhat, with stage II patients having a greater pCR benefit and stage IIIA patients (the largest subgroup) having a relatively large EFS benefit. However, it should be noted that in this initial interim analysis, the stage II subgroup had fewer EFS events, which may be because these patients had a better prognosis and many continued to receive durvalumab or placebo at the data cutoff point.Therefore, the full benefit from adjuvant durvalumab has not been fully realized in the current analysis, particularly for the stage II subgroup, and further maturation and follow-up are likely needed to clearly evaluate the EFS benefit, as well as overall survival and other longer-term secondary endpoints. Finally, a clear and consistent EFS benefit with durvalumab was observed regardless of whether the planned neoadjuvant chemotherapy regimen was cisplatin-based or carboplatin-based. This highlights the efficacy of a wide range of platinum-based regimens used in neoadjuvant settings in clinical practice.

[0163] The use of intraoperative durvalumab plus neoadjuvant chemotherapy in this study was associated with a manageable safety profile consistent with the known safety profiles of durvalumab and chemotherapy. The incidence of grade 3 or 4 adverse events (AEs) of any cause was similar between the study arms, occurring in 42.3% and 43.4% of patients in the durvalumab and placebo arms, respectively. AEs potentially related to study Tx with fatal outcomes were rare in both arms. Immune-mediated AEs were more common in the durvalumab arm compared to the placebo arm (23.5% vs. 9.8%). However, most were grade 1 or 2. Furthermore, while differences in population and study design between AEGEAN and PACIFIC were confusing between the study comparisons (particularly the use of chemoradiotherapy in the latter), it is noteworthy that the proportion of any grade and grade 3 or 4 immune AEs was similar across these studies (Antonia et al. N Engl J Med2017;377:1919-29; Antonia et al. N Engl J Med2018;379:2342-50). Finally, although AEGEAN enrolled patients during the peak of the global Covid-19 pandemic, only 6 out of 80 Covid-19 patients of any grade (7.5%) had a grade 5 Covid-19 event. In comparison, based on reports published before widespread vaccine use, the Covid-19 mortality rate for lung cancer patients was 18-47% (Passaro et al. J Immunother Cancer 2021;9:e002266).

[0164] While a comparison of findings from this study (AEGEAN) with those from other studies investigating immunotherapy as either neoadjuvant or adjuvant therapy may be beneficial, differences in patient population and study design complicated cross-research comparisons. AEGEAN stands out for several differences compared to other trials of immunotherapy in the context of resectable NSCLC (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 strengths include a large number of enrolled patients; the use of a double-blind, placebo-controlled design throughout both the neoadjuvant and adjuvant treatment periods; the exclusion of patients with demonstrated EGFR / ALK abnormalities from a pre-specified population for efficacy analysis; the use of the AJCC Staging Manual, 8th Edition; the use of IASLC recommendations for evaluating pathological responses; and the flexibility of the neoadjuvant chemotherapy regimen. However, AEGEAN was not designed to evaluate the individual contributions of the neoadjuvant and adjuvant components of treatment. Nevertheless, the results reported herein justify the intraoperative treatment strategy and demonstrate other studies using this approach in conjunction with immunotherapy in the context of melanoma and NSCLC (Patel et al., N Engl J Med 2023; 388: 813-823; Lu et al., Journal of Clinical Oncology 41, no. 36_suppl (April 20, 2023) 425126-425126). Furthermore, the benefits of the entire intraoperative durvalumab course can only be fully realized by the time all patients have had the opportunity to complete adjuvant study treatment.

[0165] All patents and publications referenced herein are incorporated herein by reference to the same extent as each independent patent and publication is specifically and individually indicated as being incorporated by reference. No citation or specification of any reference in any section of this application should be construed as an acknowledgment that such reference is available as prior art to this disclosure.

Claims

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

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

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

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

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

6. The method according to claim 4 or 5, further comprising administering durvalumab to the patient every 14 to 28 days for up to approximately 12 cycles after excision of the R-NSCLC.

7. The method according to claim 4 or 5, further comprising administering durvalumab to the patient every 28 days (Q4W) for up to approximately 12 cycles after excision of the R-NSCLC.

8. The combination therapy according to any one of claims 1 to 7, comprising approximately 1,000 to 2,000 mg of durvalumab.

9. The combination therapy according to any one of claims 1 to 8, wherein the combination therapy comprises approximately 1500 mg of durvalumab.

10. A method for treating a patient identified as having resectable non-small cell lung cancer (R-NSCLC), (i) administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient for approximately 4 cycles, approximately every 3 weeks (Q3W), (ii) Removing the R-NSCLC by surgery, and then, (iii) Administer approximately 1500 mg of durvalumab to the patient every four weeks (Q4W) for at least approximately 12 weeks, Methods that include...

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

12. The aforementioned platinum-based chemotherapy involves administering carboplatin at a serum drug concentration-time area (AUC) of approximately 5 to 6 mg / mL / min, or approximately 75 mg / m². ２ The method according to claim 11, comprising the administration of cisplatin.

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

14. The aforementioned platinum-based chemotherapy was administered at approximately 200 mg / m². ２ Paclitaxel administration, approximately 500 mg / m² ２ Administration of pemetrexed, or approximately 1250 mg / m² ２ The method according to claim 13, comprising the administration of gemcitabine.

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

16. The aforementioned platinum-based chemotherapy is (i) Carboplatin and paclitaxel, (ii) cisplatin and gemcitabine, and / or (iii) Carboplatin and gemcitabine The method according to claim 15, including the method described in claim 15.

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

18. The aforementioned platinum-based chemotherapy is (i) Carboplatin and pemetrexed, and / or (ii) Cisplatin and pemetrexed The method according to claim 17, including the method described in claim 17.

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

20. The method according to any one of claims 5 to 18, wherein the excision of the R-NSCLC is performed within approximately 10 weeks after approximately 3 to 6 cycles of combination therapy.

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

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

23. The method according to claim 22, wherein durvalumab is initiated within approximately three weeks after the completion of the postoperative radiotherapy.

24. The aforementioned method, (i) Improvement of at least approximately 13 months in event-free survival (EFS), (ii) Improvement of at least approximately 13% in pathological complete response (pCR), and (iii) Improvement of at least approximately 21% in pathological efficacy (mPR) The method according to any one of claims 1 to 23, comprising one or more of the above.

25. The method according to any one of claims 1 to 24, which results in an improvement in one or more of EFS, pCR, mPR, DFS, and OS compared to standard treatment.

26. The method according to any one of claims 1 to 24, which results in an improvement of one or more of EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy.

27. A combination therapy comprising durvalumab and platinum-based chemotherapy for use in the treatment of resectable non-small cell lung cancer (R-NSCLC) in patients who require it.

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

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

30. The combination therapy for use according to claim 28 or 29, further comprising excising the R-NSCLC after approximately 3 to 6 cycles of the combination therapy.

31. The combination therapy for use according to claim 28 or 29, further comprising excising the R-NSCLC after approximately four cycles of the combination therapy.

32. The combination therapy for use according to claim 30 or 31, further comprising administering durvalumab to the patient every 14 to 28 days for up to approximately 12 cycles after resection of the R-NSCLC.

33. The combination therapy for use according to claim 30 or 31, further comprising administering durvalumab to the patient every 28 days (Q4W) for up to approximately 12 cycles after resection of the R-NSCLC.

34. The combination therapy for use according to any one of claims 27 to 33, comprising approximately 1,000 to 2,000 mg of durvalumab.

35. The combination therapy for use according to any one of claims 27 to 34, comprising approximately 1500 mg of durvalumab.

36. A combination therapy for use in the treatment of patients identified with resectable non-small cell lung cancer (R-NSCLC), (i) administer approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient for approximately 4 cycles, approximately every 3 weeks (Q3W), and then, (ii) Administer approximately 1500 mg of durvalumab to the patient approximately every 4 weeks (Q4W) for at least approximately 12 weeks after surgical removal of the R-NSCLC, Methods that include...

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

38. The aforementioned platinum-based chemotherapy involves administering carboplatin at a serum drug concentration-time area (AUC) of approximately 5 to 6 mg / mL / min, or approximately 75 mg / m². ２ A combination therapy for use according to claim 37, comprising the administration of cisplatin.

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

40. The aforementioned platinum-based chemotherapy was administered at approximately 200 mg / m². ２ Paclitaxel administration, approximately 500 mg / m² ２ Administration of pemetrexed, or approximately 1250 mg / m² ２ A combination therapy for use according to claim 39, comprising gemcitabine administration.

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

42. The aforementioned platinum-based chemotherapy is (i) Carboplatin and paclitaxel, (ii) cisplatin and gemcitabine, and / or (iii) Carboplatin and gemcitabine A combination therapy for use according to claim 41, including the combination therapy described in claim 41.

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

44. The aforementioned platinum-based chemotherapy is (i) Carboplatin and pemetrexed, and / or (ii) Cisplatin and pemetrexed A combination therapy for use according to claim 43, including the combination therapy described in claim 43.

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

46. The combination therapy for use according to any one of claims 31 to 45, wherein the excision of the R-NSCLC is performed within approximately 10 weeks after approximately 3 to 6 cycles of combination therapy.

47. A combination therapy for use according to any one of claims 31 to 46, further comprising postoperative radiotherapy.

48. The adjunctive therapy for use according to claim 47, wherein the adjunctive radiotherapy is initiated within approximately eight weeks after the resection of the R-NSCLC.

49. The combination therapy for use according to claim 48, wherein durvalumab is initiated within approximately three weeks of the completion of the postoperative radiotherapy.

50. The use of the aforementioned combination therapy is (i) Improvement of at least approximately 13 months in event-free survival (EFS), (ii) Improvement of at least approximately 13% in pathological complete response (pCR), and (iii) Improvement of at least approximately 21% in pathological efficacy (mPR) A combination therapy for use according to any one of claims 27 to 49, which results in one or more of the following:

51. The combination therapy for use according to any one of claims 27 to 50, wherein the use of the combination therapy results in an improvement of one or more of EFS, pCR, mPR, DFS, and OS compared to standard treatment.

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

53. The use of a combination therapy comprising durvalumab and platinum-based chemotherapy for the manufacture of a pharmaceutical product for treating resectable non-small cell lung cancer (R-NSCLC) in patients who require it.

54. The use of the pharmaceutical product according to claim 53, wherein the pharmaceutical product is administered approximately every 14 to 28 days over approximately 3 to 6 cycles.

55. The use of the pharmaceutical product according to claim 53, wherein the pharmaceutical product is administered approximately every 21 days (Q3W) over approximately 4 cycles.

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

57. The use according to claim 54 or 55, further comprising excising the R-NSCLC after approximately four cycles of the combination therapy.

58. The use according to claim 56 or 57, further comprising administering durvalumab to the patient every 14 to 28 days for up to approximately 12 cycles after excision of the R-NSCLC.

59. The use according to claim 56 or 57, further comprising administering durvalumab to the patient every 28 days (Q4W) for up to approximately 12 cycles after excision of the R-NSCLC.

60. The use of the pharmaceutical product according to any one of claims 53 to 59, comprising approximately 1,000 to 2,000 mg of durvalumab.

61. The use of the pharmaceutical product according to any one of claims 53 to 60, comprising approximately 1500 mg of durvalumab.

62. The use of durvalumab and platinum-based chemotherapy in the manufacture of a pharmaceutical product for the treatment of resectable non-small cell lung cancer (R-NSCLC) in combination therapy, wherein the combination therapy is (i) administering approximately 1500 mg of durvalumab and platinum-based chemotherapy to the patient for approximately 4 cycles, approximately every 3 weeks (Q3W), (ii) Removing the R-NSCLC by surgery, and then, (iii) Administer approximately 1500 mg of durvalumab to the patient every four weeks (Q4W) for at least approximately 12 weeks, Includes, use.

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

64. The platinum-based chemotherapy is administered at a carboplatin serum drug concentration-time curve area under the curve (AUC) of about 5 to about 6 mg / mL / min, or cisplatin administration of about 75 mg / m ２ The method according to claim 63, comprising

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

66. The aforementioned platinum-based chemotherapy was administered at approximately 200 mg / m². ２ Paclitaxel administration, approximately 500 mg / m² ２ Administration of pemetrexed, or approximately 1250 mg / m² ２ The use according to claim 65, comprising the administration of gemcitabine.

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

68. The aforementioned platinum-based chemotherapy is (i) Carboplatin and paclitaxel, (ii) cisplatin and gemcitabine, and / or (iii) Carboplatin and gemcitabine The use according to claim 67, including the use described in claim 67.

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

70. The aforementioned platinum-based chemotherapy is (i) Carboplatin and pemetrexed, and / or (ii) Cisplatin and pemetrexed The method according to claim 69, including the method described in claim 69.

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

72. The use according to any one of claims 53 to 71, wherein the excision of the R-NSCLC is performed within approximately 10 weeks after approximately 3 to 6 cycles of combination therapy.

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

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

75. The use of durvalumab according to claim 74, wherein durvalumab is initiated within approximately three weeks of the completion of the postoperative radiotherapy.

76. The use of the aforementioned combination therapy is (i) Improvement of at least approximately 13 months in event-free survival (EFS), (ii) Improvement of at least approximately 13% in pathological complete response (pCR), and (iii) Improvement of at least approximately 21% in pathological efficacy (mPR) A use according to any one of claims 53 to 75 that results in one or more of the following:

77. The use of the combination therapy described above results in an improvement in one or more of EFS, pCR, mPR, DFS, and OS compared to standard treatment, as described in any one of claims 53 to 76.

78. The use of the combination therapy described above results in an improvement in one or more of EFS, pCR, mPR, DFS, and OS compared to platinum-based chemotherapy, as described in any one of claims 53 to 76.

Images