SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small Cell Lung Cancer — A Multicentre Single-Arm Phase II Trial

Background: For patients with resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) neoadjuvant chemotherapy with three cycles of cisplatin and docetaxel followed by surgery has been shown to yield a 1-year event-free survival (EFS) rate of 48% and is an accepted standard of care. Neoadjuvant PD-(L)1 inhibitors can result in high response rates in resectable NSCLC. Methods: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m 2 and docetaxel 85 mg/m 2 q3w followed by two cycles of durvalumab 750 mg q2w. Adjuvant durvalumab was continued for 1 year after surgery. The primary endpoint was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. This trial is registered with ClinicialTrials.gov, NCT02572843. Findings: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43·3% (95%CI: 31·2-56·0) after neoadjuvant chemotherapy (complete remission (CR): 2·9%, partial remission (PR): 40·3%, stable disease (SD): 44·8%) and 58·1% (95%CI: 44·8-70·5) after additional neoadjuvant immunotherapy (CR: 6·5%, PR: 51·6%, SD: 25·8%). Fifty-five patients were resected, of which 34 (61·8%) achieved a major pathological response (MPR; ≤10% viable tumour cells), and 10 (18·2%) amongst them a complete pathological response. Postoperative nodal down-staging (ypN0-1) was observed in 37 patients (67·3%). Fifty-one (92·7%) patients had an R0 resection. There was no significant effect of pre-treatment PD-L1 expression on MPR or nodal down-staging. In the entire study population, the 1-year EFS rate was 73·4% (90%CI: 62·7-81·5). Median EFS and overall survival were not reached after 28 months of median follow-up. Fifty-nine (88·1%) patients had an adverse event (AE) grade ≥3 including two fatal AEs that were not assessed to be treatment-related. Interpretation: This is thus far the largest report on perioperative PD-(L)1 inhibition in patients with resectable stage IIIA(N2) NSCLC. The addition of perioperative durvalumab to neoadjuvant chemotherapy is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73·4%. Trial Registration: This trial is registered with ClinicialTrials.gov, NCT02572843. Funding Statement: The study was supported by research agreements with the following institutions: Swiss State Secretary for Education, Research and Innovation (SERI), Swiss Cancer Research Foundation (SCS) and Swiss Cancer League (SCL). Research funding for translational research projects was granted by Gateway for Cancer Research and Rising Tide Foundation. AstraZeneca provided drug and financial support. Declaration of Interests: SIR: Honoraria for advisory boards and consulting (all paid to the institution) from Astra-Zeneca, BMS, Boehringer-Ingelheim, Eisai, Eli Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche, Takeda. Research funding from AbbVie, Astra-Zeneca, BMS, Boehringer-Ingelheim, Merck. Support for travel and accommodations from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche, Takeda. Member of the Federal Drug Commission of the Federal Office of Public Health. AZ: Honoraria for advisory boards and consulting (all paid to the institution) from Bristol-Myers Squibb, Merck Sharp & Dohme, Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma and Hookipa. Non-commercial research agreements with Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma, Hookipa, and BeyondSpring. EIE: None SSP: Honoraria for advisory boards and consulting from Astra-Zeneca, BMS, Boehringer-Ingelheim, MSD, Novartis, Pfizer and Roche. DB: None AB: None MF: Research grants from Bristol-Myers-Squibb and Astra Zeneca (paid to the institution). Honoraria for advisory boards from Bristol-Myers Squibb, AstraZeneca, Takeda, Roche, Boehringer-Ingelheim and MSD. MJ: Research grants from Bristol-Myers Squibb, Roche and Merck. DL: None HG: None LAM: Honoraria for advisory boards from AstraZeneca, Bristol-Myers-Squibb, Takeda, Roche and MSD. Support for travel and accommodations from AstraZeneca and Roche. CB: Honoraria for advisory boards from AstraZeneca, Pfizer, Roche, Takeda, Janssen-Cilag and Boehringer-Ingelheim. Support for travel and accommodations from AstraZeneca and Takeda. WW: Honoraria for advisory boards and consulting from Astra Zeneca SP: Personal fees from Abbvie, grants and personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, grants and personal fees from F. Hoffman - La Roche, personal fees from Foundations Medicine, grants and personal fees from Illumina, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Pharma Mar, grants and personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics, personal fees from Takeda, grants and personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack. MM: Honoraria for advisory boards from AstraZeneca, Bristol-Myers-Squibb, MSD, Roche and Takeda. Research grant (to the institution) from AstraZeneca. RC: Honoraria for advisory boards (all paid to the institution) from AstraZeneca, Astellas, MSD, Bristol-Myers-Squibb, Janssen-Cilag, Roche, Pfizer, Merck Serono, Ipsen and Bayer. AFO: None WDJ: None CW: None NM: None PF: Honoraria for advisory from Pfizer, Roche, Takeda, Boehringer-Ingelheim and BristolMyers Squibb. MB: None PB: None GG: None CR: None MG: Honoraria for advisory boards and consulting (all paid to the institution) from Astra-Zeneca. MP: Honoraria for advisory boards from AbbVie, AstraZeneca, Boehringer-Ingelheim, BristolMyers-Squibb, Eisai, MSD, Novartis, Pfizer, Roche, Takeda and Merck. Speakers fee from Janssen-Cilag. Support for travel and accommodations from AstraZeneca, BoehringerIngelheim, Bristol-Myers-Squibb and Vifor. Ethics Approval Statement: The trial was done in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of each participating site. Written informed consent was obtained from all patients.