LBA6 - Neoadjvuant versus adjuvant pembrolizumab for resected stage III-IV melanoma (SWOG S1801)

Background

Adjuvant therapy (AT) is currently considered for resected stage IIB-III melanoma and selected patients with resected stage IV melanoma. AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. Neoadjuvant therapy (NAT) with anti-PD-1 therapy is hypothesized to generate a stronger immune response from the activation of resident tumor-infiltrating lymphocytes against in vivo tumor antigens, but this has not been demonstrated in a prospective randomized trial.

Methods

SWOG S1801 is a randomized phase II study of AT versus NAT with pembrolizumab (PEM, NCT03698019). Patients with histologically confirmed, measurable, clinically detectable and resectable Stage IIIB-IV cutaneous, acral and mucosal melanomas without brain metastasis were randomized 1:1 to AT (upfront surgery followed by 18 doses of PEM 200 mg IV q3w) or NAT (3 doses of preoperative PEM, surgery and 15 doses of adjuvant PEM q3w). Radiation therapy was allowed after surgery. The primary endpoint was event-free survival (EFS) measured from the date of randomization to the date of first protocol-defined event: documented progression that renders the patient unable to receive planned protocol surgery, failure to begin AT within 84 days of surgery, relapse after surgery, or death due to any cause.

Results

A total of 313 patients were randomized: 154 to NAT and 159 to AT. With a median follow-up of 14.7 months, EFS was significantly higher on NAT compared to AT (one-sided log-rank p=0.0015, Cox HR 0.59, 95% confidence interval (CI) 0.40-0.86). With 36 deaths observed (NAT=14, AT=22), overall survival HR was 0.63 (95% CI 0.32-1.24, one-sided p=0.091). Benefit of NAT over AT was consistent across age, sex, performance status, stage, LDH, ulceration and BRAF status. The same proportion of patients made it through surgery to adjuvant PEM in both arms. The rates of adverse events attributed to PEM or surgery were similar in both arms. In the NAT arm, 28 of 132 patients (21%) with submitted pathology reports were noted to have complete pathologic response (0% viable tumor) on local review.

Conclusions

Using single-agent PEM, NAT improves EFS compared to AT in high-risk resectable melanoma.

Clinical trial identification

NCT03698019.

Editorial acknowledgement

Legal entity responsible for the study

SWOG.

Funding

Merck & Co.

Disclosure

S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Novartis; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Advisory Board, Advisory Board and Corporate Day speaker (unbranded): Delcath; Financial Interests, Personal, Independent Data Monitoring Committee: Immunocore; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Institutional, Invited Speaker: Provectus, Lvgen, Bristol Myers Squibb, InxMed, Foghorn Therapeutics, Ideaya, Novartis, Seagen, Syntrix Bio, TriSalus Life Sciences; Non-Financial Interests, Member: ASCO, AACR, International Society of Ocular Oncology, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. M. Othus: Financial Interests, Personal, Consultant: Merck, Biosight; Financial Interests, Personal, Independent Data Safety Monitoring Committee Member: Celgene, Glycomimetics. V. Prieto: Financial Interests, Personal, Advisory Role: Castle Biosciences, Roche, Merck. M. Lowe: Financial Interests, Personal, Expert Testimony: Bristol Myers Squibb. E. Buchbinder: Financial Interests, Personal, Advisory Board: Instilbio, Nektar, Novartis, BMS; Financial Interests, Institutional, Invited Speaker: Genentech, Partners therapeutics; Spouse employment: AstraZeneca. Y. Chen: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myer Squibb, Mirati; Financial Interests, Personal, Speaker Faculty: AstraZeneca, Bristol Myer Squibb, Amgen, Pizer, Takeda, Jazz Pharmaceutical, Guardant Health; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Merck, Ipsen, Bristol Myer Squibb, Amgen, Helsinn, EMD/Sorono. J. Hyngstrom: Financial Interests, Personal, Advisory Board, Advisory Board participant 12/2020 BMS/Nektar; Financial Interests, Institutional, Invited Speaker, Local PI for trial sponsored by Merck: Merck; Financial Interests, Personal and Institutional, Invited Speaker, PI for a single institution, investigator initiated clinical trial receiving partial institutional/research funding: BMS; Financial Interests, Personal and Institutional, Invited Speaker, PI on investigator initiated clinical trial receiving institutional/research funding support: Takara; Financial Interests, Invited Speaker, Local PI for clinical trial: Oncosec; Financial Interests, Invited Speaker, Local PI for trial: Viralytics; Financial Interests, Invited Speaker, Local PI for trial: Philogen; Financial Interests, Invited Speaker, Local PI for trial: Morphogenesis; Financial Interests, Invited Speaker, Local PI for trial: Iovance. C.D. Lao: Financial Interests, Institutional, Invited Speaker, Research Funding: BMS, Novartis, Genentech, Oncosec. T. Truong: Financial Interests, Institutional, Institutional Trial Support, Subinvestigator: Merck; Non-Financial Interests, Member and Active Member and State Affiliate President (California): ASCO. S. Chandra: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pfizer, Sanofi Genzyme, Regeneron, EMD Serono, Exicure; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Novartis, EMD Serono, Regeneron, Pfizer, Exicure, Checkmate Pharmaceuticals, Merck; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb. A. Mangla: Financial Interests, Invited Speaker, Local PI for clinical study: BioAtla, Tracon Pharma; Financial Interests, Invited Speaker: Nektar Therapeutics, Trillium Therapeutics. A. Ribas: Financial Interests, Personal, Advisory Board, Honoraria for Consulting: Amgen, Apexigen, AstraZeneca, Merck, Novartis, Sanofi, Vedanta; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: 4C Biomed, Apricity, Appia, Arcus, Compugen, Highlight, Immpact, ImaginAb, Immunesensor, Inspirna, Lutris, MapKure, Merus, PACT Pharma, Pluto, Synthekine, Tango; Financial Interests, Personal, Invited Speaker, Member of the Board of Directors: Arcus, Lutris, PACT Pharma; Financial Interests, Personal, Stocks/Shares, Stock ownership: 4C Biomed, Apricity, Appia, Arcus, Compugen, Highlight, ImaginAb, Immpact, Immunesensor, Inspirna, Isoplexis, Lutris, MapKure, Merus, Pluto, Synthekine, PACT Pharma, Tango, Advaxis, CytomX, RAPT, Kite-Gilead; Financial Interests, Personal, Invited Speaker: Arsenal Bio; Financial Interests, Institutional, Funding: Agilent, Bristol Myers Squibb. All other authors have declared no conflicts of interest.