Background

In the randomized, 2-part, multicenter, open-label, phase 3 COLUMBUS study, encorafenib (enco) + binimetinib (bini)—approved in the US, EU, and other countries—and enco alone improved 5-year PFS and OS vs vemurafenib (vemu) in patients (pts) with BRAF V600E/K–mutant metastatic melanoma. We retrospectively investigated genetic and transcriptional correlates of response and intrinsic resistance to enco + bini in an exploratory biomarker (BM) analysis of COLUMBUS Part 1.

Methods

Baseline (BL) tumor samples were analyzed using the ACE ImmunoID NeXT whole exome and whole transcriptome sequencing assays (Personalis). PFS and OS were analyzed (data cutoff: 15 Sep 2020) based on treatment (tx) type and presence of specific genetic or transcriptomic alterations at BL. High tumor mutation burden (TMB) was defined as above median TMB [8.6 mutations (muts)/megabase].

Results

366 tissue samples were successfully analyzed. We present results from the comparison of enco + bini (116 pts) vs vemu arms (130 pts). Median (m) PFS in the enco + bini and vemu arms was 14.9 and 5.7 mo, respectively (HR [95% CI], 0.55 [0.40–0.76]), and mOS was 34.8 and 18.6 mo, respectively (HR, 0.67 [0.50–0.90], similar to that observed in the safety cohort. PFS and OS by tx arm and BM status are shown in the table. High TMB, PD-L1 expression (exp), and IFNg signature were associated with longer PFS and OS in the enco + bini arm vs vemu arm. High ErbB2 exp and PI3KCA pathway muts were associated with shorter survival outcomes in the enco + bini arm vs the vemu arm.

Conclusions

Pts with high immune-related signatures derived greater clinical benefit from enco + bini vs vemu. High ErbB2 exp and PI3KCA pathway muts are potential resistance mechanisms to enco + bini. Addition of checkpoint inhibitors or PI3KCA pathway–targeted therapies to enco + bini in selected pts may further improve clinical benefit for pts with BRAF V600E/K–mutant metastatic melanoma. Table: 786O

Clinical trial identification

NCT01909453.

Editorial acknowledgement

Medical writing support was provided by Qing Yun Chong, PhD, at MediTech Media, Nucleus Global, and Asu Erden, PhD, of Health Interactions, Nucleus Global, and was funded by Pfizer.

Legal entity responsible for the study

The COLUMBUS study was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Funding

Pfizer.

Disclosure

R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. N. Pathan: Financial Interests, Personal, Full or part-time Employment: Pfizer. S. Deng: Financial Interests, Personal, Full or part-time Employment: Pfizer. C. Robert: Financial Interests, Personal, Advisory Board: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, AstraZeneca, Pfizer. A.M. Arance Fernandez: Financial Interests, Personal, Advisory Board, Consultant /Advisory/ Speaker / Travel, Accomodations, Expenses/: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi; Financial Interests, Institutional, Other, Research Funding: Pierre Fabre, Novartis, MSD, BMS, Merck, Roche, Sanofi, Amgem. J.W.B. de Groot: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Servier. C. Garbe: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, CeCaVa, MSD, NeraCare, Novartis, Philogen, Sanofi. H.J. Gogas: Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: MSD, BMS, Novartis, Pierre Fabre, Sanofi; Financial Interests, Invited Speaker: Amgen, Replimune; Financial Interests, Institutional, Invited Speaker: Amgen, MSD, BMS, Replimune, Iovance; Financial Interests, Institutional, Research Grant: BMS, Pfizer. R. Gutzmer: Financial Interests, Personal, Other, Receiving honoraria for a speaker, consultancy, or advisory role: 4SC, Almirall, Amgen, Bristol Myers Squibb, Immunocore, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma. G. Liszkay: Financial Interests, Personal, Other, Invited speaker, serving as a Principal Investigator: Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Principal Investigator: Incyte. C. Loquai: Financial Interests, Personal, Advisory Board: Almirall, BioNTech, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma; Financial Interests, Personal, Other, Receiving travel reimbursement: Almirall, BioNTech, Bristol Myers Squibb, Kyowa Kirin, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma. M. Mandala: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi, Merck, Novartis, BMS, MSD, 4SC, Nektar; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Roche, Merck Serono, Immunocore, 4SC, Pierre Fabre, Sanofi/Regeneron, Array Biopharma, Pfizer, Philogen, NEKTAR, Sandoz, Neracare; Financial Interests, Institutional, Research Grant: Novartis, BMS, MSD, Array/Pfizer; Financial Interests, Institutional, Invited Speaker: Novartis, BMS, MSD, Pierre Fabre, Sanofi, Roche, Philogen, 4SC, Nektar; Non-Financial Interests, Invited Speaker: EORTC-MG. N. Yamazaki: Financial Interests, Personal, Invited Speaker, +Advisory Board: Ono Pharmaceutical, MSD; Financial Interests, Personal, Advisory Board: Chugai pharna; Financial Interests, Personal, Invited Speaker: Novartis, Bristol Myers Squibb Japan; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical, Bristol Myers Squibb Japan, Novartis, Astellas Amgen Biopharma, Merck Serono, Takara Bio. A. di Pietro: Financial Interests, Personal, Full or part-time Employment: Pfizer. T. Xie: Financial Interests, Personal, Full or part-time Employment: Pfizer. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Pfizer/Array, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna, Bio-AI Health; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: Dohme, iTeos; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Invited Speaker, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR; Other, Travel Support: MSD. K. Flaherty: Financial Interests, Personal, Member of the Board of Directors: Checkmate Pharmaceuticals, Clovis Oncology, Strata Oncology, Vivid Biosciences; Financial Interests, Personal, Advisory Board: Adaptimmune, Aeglea, Amgen, Apricity, Asana, Fog Pharma, Fount, Monopteros, Neon, Oncoceutics, PIC Therapeutics, Sanofi, Shattuck Labs, Tolero, Tvardi, Vibliome, X4 Pharmaceuticals, xCures, Boston Biomedical; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb, Debiopharm, Genentech, Lilly, Merck, Novartis, Takeda, Verastem; Financial Interests, Personal, Other, ConsultantConsultant: Pierre Fabre; Financial Interests, Personal, Other, Research funding: Novartis, Sanofi. All other authors have declared no conflicts of interest.

Background

In patients (pts) with resectable melanoma, circulating tumor DNA (ctDNA) detection post-resection may be useful to inform disease state and recurrence risk.

Methods

Post-resection pre-treatment plasma from 1127 pts with stage IIIB-D/IV resected melanoma treated with nivolumab + ipilimumab vs nivolumab in the phase 3 CheckMate 915 study (NCT03068455) was retrospectively evaluated for ctDNA status and level, using a tumor-guided, pt-specific panel of up to 200 variants (Invitae Personalized Cancer MonitoringÔ). Kaplan-Meier and Cox regression models were used to evaluate the association between ctDNA status and recurrence-free survival (RFS), alone and combined with baseline clinical factors and biomarkers, including interferon-γ, TMB, tumor PD-L1, CD8+ T cells, tumor thickness, ulceration, and lymph node involvement.

Results

Overall pre-treatment ctDNA prevalence was ∼16% (95% CI: 14%–18%) and similar across most baseline demographics. A trend of greater ctDNA+ prevalence in higher stage III substages of melanoma was observed (IIIB = 11% [35/333], IIIC = 18% [110/596], IIID = 41% [13/32]). Pre-treatment ctDNA was associated with an increased risk of recurrence (HR 1.87, 95% CI: 1.48–2.36; Table). No significant interaction between ctDNA status and treatment arm was seen (ratio of hazard ratios: 0.99, 95% CI: 0.63–1.57). Patients with ctDNA present exhibited a greater rate of recurrence, seen as early as week 13 of therapy (Table). Distant metastasis-free survival results were similar. In composite analyses, improved RFS prediction was observed after combining ctDNA with clinical factors and biomarkers. Table: 788O

RFS probability by pre-treatment ctDNA status in CheckMate 915 treated patients

Conclusions

Pre-treatment ctDNA was associated with increased risk of early recurrence across treatment arms. ctDNA is a useful biomarker for combined analyses predicting outcome for adjuvant melanoma.

Clinical trial identification

NCT03068455.

Editorial acknowledgement

Professional medical writing and editorial assistance was provided by Emily Motola, PharmD, and Matthew Weddig, BA, of Spark Medica Inc, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

G.V. Long: Financial Interests, Personal, Advisory Board: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Merch Sharpe & Dohme (Australia) Pty Limited, Novartis Pharma AG, OncoSec Medical Austr, Pierre Fabre, Provectus, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc. K. Desai: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. T. Tang: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. J.S. Weber: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Principal Investigator: Bristol Myers Squibb; Financial Interests, Personal, Sponsor/Funding: Bristol Myers Squibb. S. Dolfi: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. C. Ritchings: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. S. Huang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M. Bolisetty: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. M. Sausen: Financial Interests, Institutional, Full or part-time Employment: Personal Genome Diagnostics; Financial Interests, Institutional, Stocks/Shares: Personal Genome Diagnostics. M. Del Vecchio: Non-Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Novartis, Merck Sharpe & Dohme; Non-Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Merck Sharpe & Dohme; Non-Financial Interests, Personal, Principal Investigator: Bristol Myers Squibb, Novartis; Non-Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Novartis, Merck Sharpe & Dohme; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Role: Pierre Fabre. J. Larkin: Financial Interests, Personal, Research Grant: Achilles, Bristol Myers Squibb, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo ; Financial Interests, Personal, Other, Honorariums, consultancy, speaker fee: Eisai, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honorariums, speaker fee: Novartis, Pfizer; Financial Interests, Personal, Other, Honorariums, Consultancy: Incyte; Financial Interests, Personal, Other, Honorariums: touchIME, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, RGCP, VJOncology, Agence Unik; Financial Interests, Personal, Other, Consultancy: iOnctura, Apple Tree, Debipharm; Financial Interests, Personal, Other, Speaker fee: Pierre Fabre, Ipsen, Roche, EUSA Pharma, Aptitude, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, eCancer, Inselgruppe, Goldman Sachs, MSD. J. Baden: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb, Johnson & Johnson. D. Balli: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. H. Chang: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. J. Loffredo: Financial Interests, Institutional, Full or part-time Employment: Janssen; Financial Interests, Institutional, Stocks/Shares: Janssen. N. Zhang: Financial Interests, Institutional, Full or part-time Employment: Janssen; Financial Interests, Institutional, Stocks/Shares: Janssen. M. Wind-Rotolo: Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Agios Pharmaceuticals; Financial Interests, Institutional, Full or part-time Employment: Agios Pharmaceuticals. D. Tenney: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb.

Background

MCC is a rare, immunogenic but aggressive skin cancer. Even after complete resection and radiation relapse rates are high. PD-1/PD-L1 immune checkpoint inhibitors (ICI) showed clinical benefit in locally advanced MCC. ADMEC-O is the first trial to investigate the efficacy/safety of adjuvant PD-1 blockade by ICI in completely resected MCC, i.e. in a situation with no systemic Standard of Care.

Methods

This multicenter phase 2 trial enrolled MCC patients (pts) (any stage, ECOG PS 0-1) with tumor lesions completely resected within 12 weeks prior to a 2:1 randomization to either NIVO 480 mg Q4W for up to 1 year, or observation, stratified by stage of disease (AJCC I/II vs. III/IV), age (<65 vs. ≥65 years) and gender. DFS was the primary endpoint, overall survival (OS) and adverse events (AE) secondary endpoints. This planned interim analysis was triggered when the Last Patient In was followed for at least 1 year.

Results

From 03/2017 until 08/2020 179 pts (NIVO, n=118; observation, n=61) were enrolled from 20 centers (ITT population; 62% male, 68% ≥65 years, 67% stage III/IV), with baseline characteristics well balanced across both arms. At this interim analysis with a median follow-up of 24.3 months (IQR 19.2-33.4), all pts had ended treatment. DFS rates at 12 and 24 months favored NIVO with 87.9% vs 78.5%, and 86.9% vs 74.3%, respectively. OS results are not yet mature. Treatment was well tolerated, with 41% of NIVO pts and 31% of pts in the observation group experiencing grade 3/4 AEs; only 5% of pts discontinued due to adverse events. No treatment-related deaths were reported. Table: 787O

Conclusions

In this first randomized trial for MCC, a hazard ratio for DFS of 0.56 (95% CI 0.28-1.15) in favor of NIVO was observed at a median follow-up of 2 years, suggesting clinical benefit in this unmet medical need. Remarkably, the spontaneous course of MCC was considerably better than historical data would have suggested.

Clinical trial identification

NCT02196961; EudraCT-No. 2013-000043-78.

Editorial acknowledgement

Writing assistance by Dr Markus Hartmann, Ecc-Oncology, Trier, Germany.

Legal entity responsible for the study

University Hospital Essen, represented by Prof. Dr. Dirk Schadendorf Hufelandstr. 55, D-45147 Essen, Germany.

Funding

Bristol Myers Squibb.

Disclosure

J.C. Becker: Financial Interests, Personal, Advisory Board, Consultancy: Almirall Hermal, Boehringer Ingelheim, InProTher, 4SC; Financial Interests, Personal, Advisory Board, Speaker's Bureau, Consultancy: Merck Serono; Financial Interests, Personal, Advisory Board, Consultancy, Speaker's Bureau: Sanofi, Recordati, Pfizer; Financial Interests, Personal, Other, DSMB Member: ICON; Financial Interests, Personal, Funding: HTG; Financial Interests, Institutional, Research Grant: Merck Serono, Bristol Myers Squibb, Sanofi; Financial Interests, Institutional, Funding: Alcedis, IQVIA. S. Ugurel: Financial Interests, Personal, Advisory Board, Speaker's Bureau: Merck Serono, Bristol Myers Squibb, MSD; Financial Interests, Personal, Other, Travel Support: Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, Merck Serono. U. Leiter-Stoppke: Financial Interests, Personal, Advisory Board, Speaker's Bureau: Novartis, Roche, MSD, Sanofi, Almirall Hermal, Sun Pharma. F. Meier: Financial Interests, Personal, Invited Speaker, Advisory Board: Novartis, Roche, BMS, MSD, Pierre Fabre, Sanofi. R. Gutzmer: Financial Interests, Personal, Invited Speaker: Roche, 4SC, Immunocore; Financial Interests, Personal and Institutional, Invited Speaker: BMS; Financial Interests, Personal and Institutional, Invited Speaker, Funding: MSD, Novartis, Pierre Fabre, Sanofi, Merck Serono, Sun Pharma; Financial Interests, Personal, Invited Speaker, Funding: Amgen, Almirall Hermal; Financial Interests, Personal, Funding: Johnson & Johnson, Kyowa Kirin; Financial Interests, Institutional, Funding: IO Biotech; Financial Interests, Institutional, Research Grant: Pfizer; Other, Personal and Institutional, Leadership Role: ADO & DeCOG. S. Haferkamp: Financial Interests, Personal, Invited Speaker, Advisory Board: BMS, MSD, Pierre Fabre, Novartis. L. Zimmer: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, MSD, Sunpharma, Pierre Fabre, Sanofi; Financial Interests, Personal, Other, Travel Support: Bristol Myers Squibb, MSD, Sunpharma, Pierre Fabre, Sanofi, Novartis, Amgen; Financial Interests, Personal, Invited Speaker: Novartis, MSD, Pierre Fabre, Roche; Financial Interests, Personal and Institutional, Research Grant: Novartis; Non-Financial Interests, Member: German Cancer Society, Dermatologic Cooperative Oncology Group. E. Livingstone: Financial Interests, Personal, Advisory Board: Novartis, BMS, Sanofi, Sun Pharma, Recordati; Financial Interests, Personal, Invited Speaker: Novartis, BMS, Medac; Financial Interests, Personal, Other, Innvator´s Circle: Pierre Fabre; Financial Interests, Personal, Expert Testimony: MSD; Non-Financial Interests, Principal Investigator: BMS, Novartis, Regeneron, MSD, Philogen, 4SC, Biontech; Non-Financial Interests, Member: DeCOG, DKG. T. Eigentler: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pierre Fabre, Sanofi, Immunogenics. A. Hauschild: Financial Interests, Personal, Advisory Board: BMS, MSD, Philogen, Pierre Fabre, Regereron, Roche, Sanofi, Novartis, Eisai, Immunocore, Replimune, Seagen; Financial Interests, Personal, Invited Speaker: MerckPfizer; Financial Interests, Institutional, Invited Speaker: BMS, MSD, Pierre Fabre, Amgen, Regeneron, Roche, Novartis. J.C. Hassel: Financial Interests, Personal, Invited Speaker: BMS, Novartis, sanofi, MSD, Sunpharma, Almirall, Roche, Amgen, GSK, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, Pierre Fabre, Sunpharma, GSK; Financial Interests, Institutional, Advisory Board: Novartis, BMS, Immunocore, Nektar, Philogen; Financial Interests, Institutional, Research Grant: BMS, Sunpharma; Financial Interests, Institutional, Invited Speaker: Philogen, BMS, Genentech, Immunocore, Immunocore, 4SC, Novartis, BioNTech, Idera, Iovance, Nektar, Pierre Fabre, Regeneraon, Sanofi; Non-Financial Interests, Leadership Role: DeCOG; Non-Financial Interests, Member: ASCO. P. Mohr: Financial Interests, Personal and Institutional, Invited Speaker, Advisory Board: BMS, Novartis, MSD; Financial Interests, Personal, Invited Speaker, Advisory Board: Roche, Almirall Hermal, Amgen, Merck Serono, Bayer, Pierre Fabre, Sanofi; Financial Interests, Personal, Advisory Board: Sun Pharma, Beyersdorf; Non-Financial Interests, Personal and Institutional, Advisory Role: Onkowissen; Other, Personal, Member: DKG & DeCOG. M. Fluck: Financial Interests, Personal, Invited Speaker, Advisory Board: BMS, Novartis, Roche, MSD, Pierre Fabre, Sanofi; Non-Financial Interests, Personal, Member: DKG & DeCOG. I. Thomas: Financial Interests, Personal, Advisory Board, Investigator Role (Clinical trials): BMS; Financial Interests, Personal, Funding, Investigator Role (Clinical trials): Pfizer, MSD; Financial Interests, Personal and Institutional, Funding, Investigator Role (Clinical trials): Amgen, Novartis, Sanofi, 4SC, AstraZeneca, Biontech, Roche (Genentech), Curevac, HUYA, Incyte, Idera, Iovance, Infla-Rx, Cerpass, Kartos, Nektar, Philogen, Pierre Fabre, Regeneron; Financial Interests, Institutional, Funding, Investigator Role (Clinical trials): Leo, UCB, Replimune; Non-Financial Interests, Personal, Member: EADO & DKG & ADO. I. Grimmelmann: Financial Interests, Personal and Institutional, Invited Speaker, Advisory Board: BMS, Novartis; Financial Interests, Personal, Advisory Board: Almirall Hermal, Pierre Fabre, Sanofi Genzyme; Financial Interests, Personal and Institutional, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker, Advisory Board: Sun Pharma; Financial Interests, Personal, Invited Speaker: Kyowa Kirin; Financial Interests, Institutional, Funding: Pfizer. S. Eckhardt: Financial Interests, Personal, Full or part-time Employment: Alcedis . D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi, Merck, Novartis, BMS, MSD, 4SC, Nektar; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Roche, Merck Serono, Immunocore, 4SC, Pierre Fabre, Sanofi/Regeneron, Array Biopharma, Pfizer, Philogen, Nektar, Sandoz, Neracare; Financial Interests, Institutional, Research Grant: Novartis, BMS, MSD, Array/Pfizer; Financial Interests, Institutional, Invited Speaker: Novartis, BMS, MSD, Pierre Fabre, Sanofi, Roche, Philogen, 4SC, Nektar; Non-Financial Interests, Invited Speaker: EORTC-MG. All other authors have declared no conflicts of interest.

Background

CSCC is highly immune-responsive; a prior pilot study demonstrated a high rate of pathologic complete response (pCR) or major pathologic response (MPR, ≤10% viable tumor), using cemiplimab anti-programmed death 1 (PD-1) therapy in the neoadjuvant setting. Here, we present the primary analysis of a confirmatory, open-label, multicenter, Phase 2, single-arm trial of neoadjuvant cemiplimab in pts with resectable Stage II–IV (M0) CSCC.

Methods

Pts received cemiplimab 350 mg IV q3W for up to 4 doses before surgery. The primary endpoint was pCR rate per independent central pathologic review (ICPR). Key secondary endpoints included MPR rate per ICPR, objective response rate (ORR; complete response [CR] + partial response [PR]) per RECIST v1.1, investigator-assessed pCR and MPR, safety and tolerability.

Results

At data cutoff date of 01 Dec 2021, 79 pts were enrolled (67 male; median age 73.0 yrs [range, 66.0–81.0]; ECOG performance status 0 (n=60) and 1 (n=19) with stage II (n=5), III (n=38), or IV(M0) (n =36) disease; 62 pts received all 4 doses (median number of doses given (Q1:Q3), 4 (4:4); 70 pts underwent surgery. The study met its primary endpoint: pCR was observed in 40 (50.6%) pts (95% confidence interval [CI], 39.1–62.1%). MPR was observed in an additional 10 (12.7%) pts (95% CI, 6.2–22.0%). ORR was 68.4% (95% CI, 56.9–78.4) (5 CR, 49 PR, 16 stable disease, 8 progressive disease (PD), 1 non evaluable. Reasons 9 pts did not have surgery: 3 responders declined surgery, 2 lost to follow-up or noncompliance, 2 had inoperable PD, 2 due to AE. Fourteen (17.7%) pts experienced Grade ≥3 AE. Four pts died due to AEs: 1 exacerbation of cardiac failure, 2 myocardial infarctions, and 1 COVID-19 pneumonia. The most common AEs regardless of attribution (all grades) were fatigue (30.4%), rash maculo-papular (13.9%), diarrhea (13.9%) and nausea (13.9%).

Conclusions

The pCR + MPR of 63.3% by ICPR in pts with Stage II–IV (M0) CSCC is the highest observed in a multicenter anti-PD-1 neoadjuvant monotherapy study for any solid tumor type. The safety profile of neoadjuvant cemiplimab is consistent with previous anti-PD-1 monotherapy experience. Ongoing follow-up will describe disease-free survival.

Clinical trial identification

NCT04154943.

Editorial acknowledgement

Medical writing support was provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc., and Sanofi.

Funding

Regeneron Pharmaceuticals, Inc., and Sanofi.

Disclosure

N. Gross: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Board: PDS Biotechnology, Shattuck Labs and Genzyme; Financial Interests, Personal, Advisory Role: PDS Biotechnology, Shattuck Labs and Genzyme. D.M. Miller: Financial Interests, Personal, Advisory Role: Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron, Sanofi Genzyme; Financial Interests, Personal, Ownership Interest: Checkpoint Therapeutics; Financial Interests, Personal, Research Grant: Kartos Therapeutics, NeoImmune Tech, Inc., Regeneron Pharmaceuticals, Inc. N. Khushanlani: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, HUYA Bioscience International, Merck, Novartis, GlaxoSmithKline, Celgene, Amgen; Financial Interests, Personal, Advisory Board: EMD Serono, Regeneron Pharmaceuticals, Inc., Genentech, AstraZeneca (data safety monitoring committee), Merck, Array Biopharma, Jounce Therapeutics, Immunocore, Bristol Myers Squibb, HUYA Bioscience International; Financial Interests, Personal, Other, honoraria: Sanofi; Financial Interests, Personal, Stocks/Shares: Bellicum Pharmaceuticals, Mazor Robotics, Amarin, Transenetrix. V. Divi: Financial Interests, Institutional, Research Grant: Genentech. E.S. Ruiz: Financial Interests, Personal, Advisory Board: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Advisory Role, consulting fees: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Member of the Board of Directors: Checkpoint Therapeutics. E.J. Lipson: Financial Interests, Personal, Other, Advisory board and consulting fees: Bristol Myers-Squibb, Eisai, Genentech, Immunocore, Instil Bio, MacroGenics, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, OncoSec, Pfizer, Rain Therapeutics, Regeneron, Sanofi; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck, Regeneron. F. Meier: Financial Interests, Personal, Other, Travel support, speaker’s fees or advisor’s honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi; Financial Interests, Personal, Research Grant: Novartis and Roche. P.L. Swiecicki: Financial Interests, Institutional, Research Grant: Ascentage Pharma, Pfizer; Financial Interests, Personal, Advisory Board: Prelude Therapeutics, Elevar Therapeutics, Regeneron Pharmaceuticals. J.L. Atlas: Financial Interests, Personal, Advisory Role: Regeneron Pharmaceuticals, Inc., Sanofi, and Bristol Myers Squibb. J.L. Geiger: Financial Interests, Institutional, Research Grant: Alkermes, Debio, Merck, Regeneron Pharmaceuticals, Inc., and Roche/Genentech; Financial Interests, Personal, Advisory Role: Exelixis, Merck and Regeneron Pharmaceuticals, Inc. A. Hauschild: Financial Interests, Personal and Institutional, Other, Institutional grants, speaker’s honoraria and consultancy fees: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche; Financial Interests, Institutional, Other, Institutional grants and consultancy fees: EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Role: OncoSec Medical. J.H. Choe: Financial Interests, Personal, Advisory Role: Exelixis, Coherus Biosciences, Regeneron Pharmaceuticals, Inc. B.G.M. Hughes: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche; Financial Interests, Institutional, Research Grant: Amgen. S. Yoo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. K. Fenech: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.D. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. H. Han: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.G. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. D. Rischin: Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals, Inc., Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Merck KGaA, Bristol Myers Squibb, GlaxoSmithKline, ALX Oncology; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb. All other authors have declared no conflicts of interest.