Background

Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develop brain metastases. In the SECOMBIT study patients received the combination of encorafenib/binimetinib (E+B) as targeted therapy (T-T) or the combination of ipilimumab/nivolumab (I+N) as immunotherapy (I-O). In the present analysis, we updated survival outcomes and investigated if the incidence of and timing to brain metastasis onset were significantly different in patients receiving T-T (Arm A) or I-O (Arm B) as first line with switch at progression, as well as the “sandwich” strategy with T-T first preplanned switched to combo I-O after 8 weeks, returning back to T-T after progression (Arm C). In our previous reports, 4-year survival outcomes confirmed long-term benefit in ARM B and C pts. We also described preliminary biomarkers analyses where the loss-of-function affecting JAK or low baseline levels of serum interferon gamma (IFNy) are correlated to PFS and OS.

Methods

From Nov 2016 to May 2019, of 251 pts enrolled, 69 were randomized in ARM A, 71 pts in ARM B and 69 pts in ARM C. BMFS (Brain Metastasis Free Survival) was defined as time from start of first systemic therapy until new brain metastasis detection or last pts contact (censored BMFS). The Kaplan-Meier method was used to estimate OS and PFS. The median follow up was 43 months (IQR: 37-51).

Results

Pts treated in arm B and C had a lower risk to develop brain metastasis compared to pts in arm A. Brain metastasis occurred during first line treatment, in 17, 6, and 8 patients, respectively, treated in ARM A, B and C. During the study, an intracranial progression was detected in a total of 23, 11 and 9 patients in ARM A, B and C. The exploratory HR for BMFS was of 0.51 (0.25-1.04) for ARM B vs ARM A, and 0.37 (0.17-0.81) for ARM C vs ARM A. In the biomarker analysis, pts with high tumor mutational burden (TMB, ≥10 mut/mb) had an improved BMFS compared with pts with low TMB [HR 0.20 (0.05-0.95)]. JAK mutated pts had a better BMFS compared to wild type pts [HR 0.26 (0.06-1.12)].

Conclusions

Patients in ARM B and C had a longer BMFS compared with pts who started treatment with T-T. BMFS rate at 4 years was better in TMB high and in JAK mutated pts. At the time of the meeting it will also be reported the 5-years OS data.

Clinical trial identification

NCT02631447.

Legal entity responsible for the study

Fondazione Melanoma.

Funding

This study was supported by unconditioned grants from Bristol Myers Squibb (Princeton, NJ) and Array Biopharma Inc./Pfizer (Boulder, CO).

Disclosure

P.A. Ascierto: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna. All other authors have declared no conflicts of interest.

Background

The phase III NIBIT-M2 study showed a 41% 5-year overall survival (OS) of melanoma patients (pts) with asymptomatic brain metastases (BM) treated with ipilimumab (I) plus nivolumab (N) (I+N) ( Di Giacomo AM, CCR 2021 ). In spite of the significant efficacy of I combined with N, no data are available on long-term survival, and patient-reported outcomes (PROs) and quality of life (QoL) in this patient population. Here, we report the 7-year efficacy outcomes and HRQoL analyses of the NIBIT-M2 study.

Methods

The NIBIT-M2 study recruited melanoma pts with active, untreated, asymptomatic BM from 9 Italian Centers that were randomized (1:1:1) to fotemustine (F) (Arm A), I+F (Arm B), or I+N (Arm C). Primary endpoint was OS; among secondary endpoints were intracranial progression-free survival (iPFS) and HRQoL. PROs were assessed at week (W) 1 and W12 using the EORTC Quality of Life Questionnaire (QLQ)-C30 Version 3.

Results

From Jan 2013 to Sept 2018 , 80 pts were enrolled: 76 received F (23), I+F (26), or I+N (27). As of May 1, 2023, at a median follow-up of 67 months (mo), median OS was 8.5 (95% CI: 6.6-10.3), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-69.9) mo for Arm A, B, and C respectively. The 7-y OS rate was 10.0% (95% CI: 0-22.5) in Arm A, 10.3% (95% CI: 0-22.6) in Arm B, and 42.8% (95% CI: 23.4-62.2) in Arm C. Median iPFS was 3.0 (95% CI: 2.3-3.6), 3.3 (95%CI: 1.2-5.4) and 8.7 (95% CI: 0-19.9) for Arm A, B, and C, respectively. The 7-year iPFS rate was 4.3% (95% CI: 0-12.7) in Arm A, 7.7% (95% CI: 0-17.9) in Arm B, and 28.6% (95% CI: 11.2-46.0) in Arm C. Seventy-two pts (compliance 95%) and 34 pts (compliance 45%) completed the baseline and the W12 QLQ C-30 assessment. HRQoL was preserved in all treatment arms; no significant differences were observed in global health score. Most functional scales evaluated were preserved from baseline to W12, with a lower mean score decrease in pts receiving I+N.

Conclusions

The 7-year results of the NIBIT-M2 study, with the longest follow-up available to date in melanoma pts with asymptomatic BM treated with I+N, continue to show persistent therapeutic efficacy. HRQoL was preserved in all treatment arms and I+N induced a lower decrease in mean functional scales.

Clinical trial identification

NCT02460068.

Legal entity responsible for the study

NIBIT Foundation ONLUS.

Funding

Bristol Myers Squibb.

Disclosure

A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: Sanofi. V. Chiarion Sileni: Financial Interests, Personal, Advisory Board, analysis of treatment modality (diagnosis, stanging, surgery, radiotherapy, systemic therapy for Merkel cell carcinoma in Italy: Merck-Serono; Financial Interests, Institutional, Invited Speaker, Treatment option for BRAF mutated melanoma: Novartis; Financial Interests, Institutional, Invited Speaker, Treatment choices for BRAF mutated melanoma, evidence-based, and biologically supported: Pierre Fabre; Financial Interests, Institutional, Invited Speaker, Immunotherapy for melanoma treatment present and future: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, registration, and accommodation to attend ASCO annual meetings: Pierre Fabre. M. Del Vecchio: Financial Interests, Personal, Advisory Board: BMS, MSD, Sanofi, Pierre Fabre, Novartis. P.F. Ferrucci: Financial Interests, Personal, Advisory Board: BMS, Roche, Pierre Fabre, MSD, Novartis. M. Guida: Financial Interests, Personal, Advisory Board: Bristol Meyer Squibb, Novartis, Merck Sharp & Dohme. P. Quaglino: Non-Financial Interests, Personal, Advisory Board: BMS, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, MSD. M. Guidoboni: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre; Financial Interests, Personal, Research Grant: Merck Sharp & Dohme. P. Marchetti: Other, Personal, Advisory Board: BMS, Roche, MSD, Novartis, AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pfizer, Merck Sharp & Dohme, AstraZeneca, Boehringer Ingelheim, Celgene, Roche. A. Covre: Other, Personal, Advisory Board: EpiGen Therapeutics srl. R. Camerini: Financial Interests, Personal, Advisory Board: Bristol Meyer Squibb; Other, Personal, Advisory Board: Reithera srl, Alfasigma SPA, Cosmo Nbv, EpiGen Therapeutics. L. Calabro: Other, Personal, Advisory Board: BMS, AstraZeneca, MSD, Sanofi, Roche. M. Mandalà: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. D. Giannarelli: Financial Interests, Personal, Other, Educational Course in Biostatistics: Amgen; Financial Interests, Personal, Other, Course on GRADE system in Hematology: AstraZeneca. M. Maio: Financial Interests, Personal, Advisory Board: BMS, Roche, GSK, Sanofi, Alfasigma, Amgen, Sciclone, Eli Lilly, MSD, Incyte, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Stocks/Shares: EpiGen, Theravance. All other authors have declared no conflicts of interest.

Background

Metastatic uveal melanoma (mUM) has a historically poor 1-yr overall survival (OS) rate of 52%. Tebentafusp (tebe), a bispecific (gp100 x CD3) ImmTAC, is approved for adult HLA-A*02:01+ patients (pts) with unresectable or mUM. In the primary analysis of the Phase (Ph) 3 IMCgp100-202 study in previously untreated mUM [NCT03070392], tebentafusp significantly improved OS compared to investigator’s choice (IC) [HR 0.51] with a 1-yr OS rate of 73% versus 59%, respectively. Deeper ctDNA reductions were associated with longer OS. Here we present the 3-yr updated analyses of the Ph3 study.

Methods

In this randomized, open-label, Ph3 trial, HLA-A*02:01+ first-line mUM pts were randomized 2:1 to receive tebe or IC of pembrolizumab, ipilimumab or dacarbazine, stratified by LDH. Primary endpoint was OS. Secondary endpoints included overall response rate (ORR), progression free survival (PFS) and disease control rate (DCR) and safety. An exploratory endpoint was ctDNA reduction.

Results

378 pts were randomized to tebe (252) or IC, including pembrolizumab (103), ipilimumab (16) or dacarbazine (7). After a minimum follow-up of 36 months, the estimated 3-yr OS of tebe was 27% (95% CI 22-33%) vs 18% (95% CI 11-25%) for IC with maintained separation of the OS KM curves. The OS benefit of tebe was also observed in pts with known poor prognostic factors in the metastatic setting. 1-yr and 2-yr PFS rates were 17% vs 9% and 8% vs 3%, for tebe vs IC, respectively. ORR remained in favor of tebe vs IC (11% vs 5%). A third of tebe responders were still in response at 18 months. The DCR rates (CR/PR/SD ≥12 weeks) were 46% for tebe and 27% for IC. Of 45 ctDNA evaluable pts in the tebe arm who cleared their ctDNA by week 9, 32 (71%) survived ≥2 yrs and 17 (38%) survived ≥3 yrs. No new safety signals were identified. The rate of treatment discontinuation due to related AEs continued to be lower in the tebe arm (2% vs 5%). There were no treatment related deaths.

Conclusions

This is the longest OS follow-up in a randomized trial in mUM. Tebentafusp continues to provide long-term survival benefit in first line HLA-A*02:01+ pts, with estimated 3-yr OS rate of 27%, further solidifying tebentafusp as first line standard of care in this population.

Clinical trial identification

NCT03070392.

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

S. Piperno-Neumann: Financial Interests, Personal, Advisory Board: Immunocore, Pierre Fabre, Atlanthera. 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. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfizer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Member of Board of Directors: Polish Society of Surgical Oncology; Non-Financial Interests, Member of Board of Directors, President: Polish Oncological Society. M. Schlaak: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb, Novartis, Merck/MSD, Roche, Pierre Fabre, Kyowa Kirin, Immunocore, Sanofi Genzyme; Financial Interests, Personal, Other, Travel expenses: Sun Pharma. M.O. Butler: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, Bristol Myers Squibb, Novartis, Sanofi, Pfizer, Adaptimmune, GSK, Immunocore, EMD Serono, Sun Pharma; Financial Interests, Personal and Institutional, Research Grant: Merck; Financial Interests, Personal, Research Grant: Takara Bio; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Novartis, Sanofi, Adaptimmune, Immunocore, Regeneron, Lilly, Amgen, OncoSeq. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune, Marengo; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Invited Speaker: GSK, Pfizer, Sanofi, Moderna, Roche-Genentech, BiomedValley DIscoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Simcha Therapeutics, OnKure, Synthekine, Marengo. 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, Simcere. J.M. Kirkwood: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Amgen, Harbour BioMed, ISTARI Oncology, Scopus BioPharma, Pfizer, AXIO Research, Immunocore, Natera, DermTech, Ankyra Therapeutics, Becker Pharmaceutical Consulting, Fenix Group International, IQVIA, Merck, Replimune, SR One Capital Management, Iovance Biotherapeutics, Checkmate Pharmaceuticals, OncoSec, OncoCyte, Cancer Network, Takeda, Applied Clinical Intelligence, PATHAI, Magnolia Innovation, iOnctura, Jazz Pharmaceuticals, Regeneron; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Checkmate Pharmaceuticals, Bristol-Myers Squibb, Regeneron, Ankyra Therapeutics, Iovance Biotherapeutics; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Institutional, Research Funding: Amgen, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapeutics, Novartis, Immvira, Harbour BioMed, Takeda, Verastem, Lion Biotechnologies. M. Orloff: Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Speaker, Consultant, Advisor: IDEAYA Biosciences, Immunocore, Trisalus Life Sciences, Delcath Systems; Financial Interests, Institutional, Research Funding: Bristol-Myers Squibb, Immunocore, Delcath Systems, Plexxikon, IDEAYA Biosciences, Linnaeus Therapeutics. J.J. Sacco: Financial Interests, Personal, Speaker, Consultant, Advisor: Immunocore, Bristol Myers Squibb, MSD, Delcath, Amgen; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: Immunocore, Bristol Myers Squibb, MSD, Amgen, AstraZeneca, Replimune. S. Ochsenreither: Financial Interests, Personal, Advisory Board: MSD, BMS, Janssen, Ipsen, Immunocore, Genemab, Pfizer; Financial Interests, Personal, Invited Speaker: MSD, Merck, Immunocore, Janssen; Financial Interests, Personal, Other, Support for travel / meeting: Janssen, Pfizer; Financial Interests, Personal, Invited Speaker, Patent of T-cell therapy target: Fred Hutchinson cancer Research Center. A.M. Joshua: Financial Interests, Personal, Stocks/Shares: Pricillium Therapeutics; Financial Interests, Institutional, Invited Speaker: Neolukin, Janssen, Ipsen, AstraZeneca, Sanofi, Noxopharm, Iqvia, Pfizer, Novartis, Bristol-Myers Squibb, Merck Serono, Eisai; Non-Financial Interests, Advisory Role: Bristol-Myers Squibb, Janssen, Merck, Mayne, Roche, Bayer, Macrogenics, Pfizer, AstraZeneca, Corvus, Eli-Lilly. B. Curti: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Biomarkers for OX40 response; Financial Interests, Personal, Other, Honoraria: Clinigen Group, Sanofi; Financial Interests, Institutional, Research Funding: Bristol-Myers Squibb, Clinigen Group. R.D. Carvajal: Financial Interests, Personal, Speaker, Consultant, Advisor: Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Sanofi Genzyme, Trisalus; Financial Interests, Personal, Speaker’s Bureau: Regeneron; Financial Interests, Personal, Advisory Board: Aura Biosciences, Chimeron, Rgenix. O. Hamid: Financial Interests, Personal, Advisory Board: Alkermes, Amgen, BMS, Bactonix, Beigene, Bioatla, Esai, GSK, Georgiamune, GigaGen, Grit Bio, IO Biotech, Idera, Idera, Immunocore, Incyte, Instil Bio, Iovance, Janssen, KSQ, Merck, Nextcure, Novartis, Obsidian, Pfizer, Roche Genentech, SEAGEN, Sanofi / Regeneron, Tempus, Vial, Zelluna; Financial Interests, Personal, Invited Speaker: BMS, Immunocore, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Stocks/Shares: Bactonix; Financial Interests, Institutional, Invited Speaker: Aduro, Akeso, Amgen, Arcus, BMS, Bioatla, CytomX, Exelixis, GSK, Idera, Immunocore, Incyte, Iovance, Merck, Merck Serono, Moderna, Nextcure, Novartis, Pfizer, Roche Genentech, Rubius, SEAGEN, Sanofi / Regeneron, Torque, Zelluna. L. Collins: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. C. Holland: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore, Amgen, MacroGenics. P. Nathan: Financial Interests, Personal, Advisory Board: BMS, Immunocore, Novartis, Merck, Pfizer, 4SC, IDEAYA; Financial Interests, Institutional, Other, research support: Immunocore; Financial Interests, Personal, Invited Speaker: novartis, 4SC; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, Ipsen, Immunocore, Merck, Pfizer. All other authors have declared no conflicts of interest.

Background

Advanced mucosal melanoma is rare and difficult to treat, with worse outcomes after anti–PD-1 therapy than nonmucosal melanoma (median ORR: 19%–23%; median OS: 11.3–13.4 mo in large pooled analyses [ D’angelo JCO 2017 , Mignard J Oncol 2018 , Hamid Br J Can 2018 ]). Lifileucel, a one-time autologous TIL cell therapy, had an ORR of 31.4% in 153 pts with heavily pretreated advanced melanoma (only uveal excluded) in the C-144-01 study (NCT02360579; Chesney JITC 2022 ). We report outcomes of pts with advanced mucosal melanoma treated with lifileucel in C-144-01.

Methods

Pts (coh 2+4) must have progressed after anti–PD-1/PD-L1 therapy. Pts had ≥1 lesion resected for lifileucel manufacturing, then received lymphodepleting chemotherapy (cyclophosphamide 60 mg/kg/d × 2d; fludarabine 25 mg/m²/d × 5d), a single lifileucel infusion, and up to 6 doses of high-dose IL-2. Responses were assessed by IRC per RECIST v1.1.

Results

Fifteen pts with mucosal melanoma were enrolled; lifileucel was manufactured for all 15 (100%), and lymph nodes were the most common source (47%). Twelve pts received lifileucel (median target lesion SOD: 118.9 mm; median prior lines of therapy: 2 [range: 1–6]; LDH >ULN: 42%; liver and/or brain metastases: 42%). Median number of TIL infused was 26 × 10⁹ cells. ORR was 50% (95% CI: 21%–79%). At median study follow-up of 35.7 months, median DOR was not reached (NR; 95% CI: 12.5 mo–NR), median PFS was NR (95% CI: 1.4 mo–NR), and median OS was 19.4 mo (95% CI: 7.9–NR). TEAEs were consistent with known safety profiles of lymphodepleting chemotherapy and IL-2. The most common (≥30%) G3/4 non-hematologic TEAEs were febrile neutropenia (58%) and hypotension (33%). Translational data will be presented.

Conclusions

In C-144-01, the activity of lifileucel in this small subset of pts with the difficult-to-treat mucosal melanoma subtype was clinically meaningful and durable (ORR: 50%; median DOR: NR) with anti-tumor activity that was consistent with the overall post-anti–PD-1/PD-L1 advanced melanoma population. These data further support the potential benefit of lifileucel as a one-time treatment that is differentiated from other immunotherapies.

Editorial acknowledgement

Writing assistance was provided by Amanda Kelly (Iovance Biotherapeutics, Inc.).

Legal entity responsible for the study

Iovance Biotherapeutics, Inc.

Funding

Iovance Biotherapeutics, Inc.

Disclosure

H. Kluger: Financial Interests, Institutional, Research Funding: Apexigen, BMS, Merck; Financial Interests, Personal, Advisory Role: BMS, Clinigen, Shionogi, Chemocentryx, Calithera, Signatero, Merck, Iovance. S. Thomas: Financial Interests, Personal, Speaker’s Bureau: BMS, Merck, Pfizer, Ipsen, Amgen, Genentech, Foundation One; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS, Merck, Pfizer, Ipsen, Amgen, Genentech, Foundation One; Financial Interests, Personal, Advisory Role: BMS, Merck, Pfizer, Ipsen, Amgen, Genentech, Foundation One; Financial Interests, Institutional, Research Funding: BMS, Merck, Pfizer, Ipsen, Amgen, Genentech, Foundation One. J.A. Chesney: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen; Financial Interests, Institutional, Research Funding: Replimune, Amgen, Iovance Biotherapeutics, Inc., FATE. E. Domingo-Musibay: Financial Interests, Institutional, Other, Grants or contracts: Instil Bio. M.F. Sanmamed: Non-Financial Interests, Personal, Advisory Board: Numab, BMS, Pieris; Non-Financial Interests, Institutional, Research Funding: Roche, BMS; Financial Interests, Personal, Speaker’s Bureau: MSD, Replimune; Financial Interests, Personal, Other, Grant travel: Roche, BMS, AZ. T. Medina: Financial Interests, Personal, Advisory Role: Merck, Bristol Myers Squibb, Iovance Biotherapeutics, Inc., Moderna, Nektar, Regeneron, Exicure, Checkmate, BioAtla, Xencor, Replimune, Day One Pharmaceuticals, Pfizer, Taiga. E. Whitman: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Speaker, Consultant, Advisor: Merck; Financial Interests, Personal, Speaker’s Bureau: Merck, Bristol Myers Squibb, Regeneron, Castle BioSciences. F. Graf Finckenstein: Financial Interests, Personal, Leadership Role: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Officer: Iovance Biotherapeutics, Inc. J. Chou, X. Wu, G. Sulur, W. Shi: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, Inc. A. Sarnaik: Non-Financial Interests, Institutional, Non-financial benefits: Iovance Biotherapeutics, Inc.; Financial Interests, Institutional, Royalties: Iovance Biotherapeutics, Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor: Iovance Biotherapeutics, Inc., Guidepoint, Defined Health, Boxer Capital, Huron Consulting Group, Keyquest Health, Istari, Rising Tide, Gerson Lehram Group; Financial Interests, Personal, Speaker’s Bureau: Society for ImmunoTherapy of Cancer, Physicians' Education Resource, Medscape, WebMD, MedStart Health; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Iovance Biotherapeutics, Inc., Provectus Biopharmaceuticals; Financial Interests, Personal, Other, Patents: Moffitt Cancer Center, Provectus Biopharmaceuticals; Financial Interests, Institutional, Other, Receipt of equipment, materials, drugs, medical writing, gifts or other services: Bristol Myers Squibb, Genentech. All other authors have declared no conflicts of interest.

Background

NIVO+RELA demonstrated significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922). Exploratory biomarker analyses were conducted to elucidate mechanisms underlying NIVO+RELA activity and identify patients (pts) more likely to derive benefit from the combination.

Methods

Blood samples at baseline and 4 weeks post dose were analyzed by flow cytometry for pharmacodynamic changes in immune cell populations, eg lymphocyte activation gene-3 (LAG-3)- or programmed death-1 (PD-1)-expressing CD4+ and CD8+ T cells, natural killer (NK) cells. Baseline tissue samples were analyzed by immunohistochemistry (IHC) for major histocompatibility complex (MHC) class I/II expression and CD8 infiltration. HALO image analysis of LAG-3+ and LAG-3− CD8+ T cells was conducted by multiplex IHC. Association between biomarkers and treatment response was assessed.

Results

Multiple peripheral immune cell types significantly increased with NIVO+RELA vs NIVO (Table). Response to NIVO+RELA was associated with increased LAG-3+ CD4+ T cells at week 4, but on-treatment modulation of peripheral CD8+ T cells was not associated with NIVO+RELA efficacy. Baseline PD-1+ CD8+ and ICOS+ CD8+ T cell numbers were higher in responders to NIVO+RELA but not NIVO. In the tumor microenvironment (TME), higher baseline MHC-I and MHC-II were associated with improved efficacy in both arms. A PFS benefit with NIVO+RELA vs NIVO was observed in pts with low/medium TME CD8 infiltration; benefit of NIVO+RELA vs NIVO was seen for high TME CD8 infiltration only when LAG-3 was also expressed.

Conclusions

TME analysis suggests RELA activity is particularly robust in tumors with lower CD8+ T-cell infiltration; peripheral data suggest CD4+ T-cell modulation may be key to its distinct mechanism of action. Further exploratory biomarker analyses are warranted to identify pts who may derive maximal benefit from NIVO+RELA. Table: LBA51

Select changes in peripheral blood 4 weeks post first dose suggesting RELA-specific activity

Clinical trial identification

NCT03470922, EudraCT 2017-003583-12.

Editorial acknowledgement

Editorial support was provided by Keri Wellington, PhD, and Agata Shodeke, PhD, of Spark Medica Inc., according to Good Publication Practice guidelines, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

E.J. Lipson: Financial Interests, Personal, Advisory Board: Bristol Myers-Squibb, Merck, Sanofi, Regeneron, Genentech, Eisai, Instil Bio, Natera, Nektar Therapeutics, Pfizer, Rain Therapeutics, CareDx, Immunocore, Novartis, Replimune, HUYA Bioscience International; Financial Interests, Personal, Other, Consultant: OncoSec; Financial Interests, Institutional, Coordinating PI: Bristol-Myers Squibb; Financial Interests, Institutional, Local PI: Regeneron, Merck, Sanofi. S. Dolfi: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. H. Tang: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. H. Gogas: Financial Interests, Institutional, Principal Investigator: Amgen, Array BioPharma, BMS, Genentech, Merck, Novartis; Financial Interests, Institutional, Advisory Board: BMS. H.A. Tawbi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis, Genentech, Eisai, Karyopharm, Iovance, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Merck, Rapt Pharmaceuticals; Financial Interests, Institutional, Steering Committee Member: Novartis, Genentech; Financial Interests, Institutional, Funding: GSK, Eisai. F..S. Hodi: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, Genentech/Roche, Gossamer, Catalym, Immunocore, Kairos, Zumuto, Corner Therapeutics, Curis, AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Novartis; Financial Interests, Personal, Advisory Board: Surface, Compass Therapeutics, Apricity, Bicara, Checkpoint Therapeutics, Bioentre, Iovance, Rheos; Financial Interests, Personal, Stocks/Shares: Apricity, Bicara, Checkpoint Therapeutics. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant and Advisory Role.Travel support: Pfizer/Array; 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 and travel support: Bio-AI Health; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: iTeos; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role.Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Institutional, Funding, Clinical Trial: Pfizer/Array, Roche Genentech, Sanofi; Financial Interests, Personal, Advisory Board: Erasca; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; 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, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, SMR, AIOM. E.C. Gutierrez: Non-Financial Interests, Institutional, Principal Investigator: FAICIC S. DE R.L. DE C.V. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG. F.A. Medina Soto: Non-Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb. P. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfzer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Member of Board of Directors: Polish Society of Surgical Oncology; Non-Financial Interests, Member of Board of Directors, President: Polish Oncological Society. M. Maio: Financial Interests, Personal, Advisory Board: bms, roche, GSK, Sanofi, ALFASIGMA, Amgen, SCICLONE, Eli Lilly, MSD, INCYTE, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Stocks/Shares: Epigen, Theravance. Y. Xu: Non-Financial Interests, Institutional, Other: Bristol Myers Squibb. K. Desai: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. A. Yu: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb. K. Demers: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. K. Miller-Moslin: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. G.V. Long: Financial Interests, Personal, Advisory Role: Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. C. Garnett-Benson: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

In cutaneous squamous cell carcinoma (cSCC), both PD-1 and EGFR-inhibitors are effective, but durable tumor control, especially in anogenital cSCC, is still limited. For the latter, and refractory patients (pts), there is an unmet medical need.

Methods

Pts with unresectable stage III/IV cSCC were treated with PD-L1 inhibitor avelumab (10 mg/kg q2w) plus EGFR-inhibitor cetuximab (500 mg/m² q2w) for up to 1 year. The Safety Analysis (SAF) set was defined as pts who received at least 1 administration of study treatment, the per protocol (PP) set if treated for at least 12 weeks.

Results

54 pts were registered (SAF Set: 51 pts; PP Set: 37 pts). Two-thirds of pts had prior systemic treatment for cSCC, i.e. chemotherapy or PD-1 inhibition. 31.4% (SAF) and 21.6% (PP) of primaries were anogenital cSCC. Within a median follow up of ∼ 2.5 years, median PFS/OS were 8.4/17.4 months in the SAF and 9.2/25.4 months in the PP set, respectively. No significant differences in PFS and OS were observed when subgroups for tumor stage (III vs. IV), location of primary (anogenital vs. elsewhere), or prior treatment (yes vs. no) were analyzed. Adverse events (AE) >= grade 3 were common, but adverse drug reactions (ADR) >= grade 3 occurred only in ∼ 20% of pts, which is explained by the frailty of pts with advanced cSCC. Only two pts discontinued treatment due to ADR (abnormal ECG, sarcoid-like lesions). Table: 1087MO

Conclusions

Avelumab plus cetuximab is a feasible treatment option in patients with cSCC. This combination shows remarkable activity even in patients in whom PD-1 blockade has low efficacy, such as anogenital cSCC, or after failure of anti-PD-1 monotherapy.

Clinical trial identification

EudraCT 2018-001708-12.

Legal entity responsible for the study

Dermatologic Cooperative Oncology Group (DeCOG/ADO).

Funding

Merck KGaA/EMD.

Disclosure

J.C. Becker: Financial Interests, Personal, Advisory Board: Amgen, Merck, Recordati, Sanofi, Boehringer Ingelheim, InProTher, Almirall; Financial Interests, Personal, Other, Member of a DMSB: 4SC; Financial Interests, Institutional, Research Grant: IQVIA, Alcedis, Merck; Non-Financial Interests, Institutional, Product Samples: 4SC. L. Zimmer: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, MSD, Sun Pharma, Pierre Fabre, Sanofi; Financial Interests, Personal, Other, Travel Support: Bristol Myers Squibb, MSD, Sun Pharma, 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. J.C. Hassel: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Sanofi, MSD, Sun Pharma, Almirall, Roche, Amgen, GSK, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, Pierre Fabre, Sun Pharma, GSK; Financial Interests, Institutional, Advisory Board: Novartis, BMS, Immunocore, Nektar, Philogen; Financial Interests, Institutional, Research Grant: BMS, Sun Pharma; Financial Interests, Institutional, Local PI: Philogen, Genentech, 4SC, BioNTech, Idera, Iovance, Nektar, Pierre Fabre, Regeneron, Sanofi; Financial Interests, Institutional, Coordinating PI: BMS, Immunocore, Novartis; Financial Interests, Institutional, Steering Committee Member: Immunocore; Non-Financial Interests, Leadership Role: DeCOG; Non-Financial Interests, Member: ASCO. All other authors have declared no conflicts of interest.

Background

We previously reported a high rate of pathologic complete response (pCR) or major pathologic response (MPR) to neoadjuvant (neoadj) cemiplimab (anti-programmed cell death-1) among 79 patients (pts) with locoregionally advanced, resectable CSCC. Here, we present 1-year follow-up data, with event-free, disease-free and overall survival (EFS, DFS, OS; NCT04154943).

Methods

This non-randomised multicentre phase II study had 2 parts. In part 1, pts with resectable stage II–IV (M0) CSCC received neoadj cemiplimab 350 mg every 3 weeks (Q3W) for up to 4 doses followed by curative-intent surgery. In Part 2, per investigator discretion, pts received adjuvant cemiplimab for up to 48 weeks or radiotherapy (RT) or observation only. EFS (time from first dose of neoadj cemiplimab to progressive disease precluding surgery, inability to undergo complete resection, disease recurrence, or death due to any cause); DFS (time from surgery until CSCC recurrence or death due to any cause) and OS were summarised by the Kaplan-Meier method.

Results

At December 1, 2022 data cut-off, median duration of follow-up was 18.7 months (range: 1.3–30.4) for all 79 pts. Among 70 pts who had surgery, the most common choices for subsequent care were observation only (n=29), cemiplimab (n=16), or RT (n=12) or other (Table). None of 40 pts with pCR and 1 of 10 pts with MPR experienced recurrence. Estimated 12-month EFS was 89% (95% confidence interval [CI]: 79–94%) for all pts and 95% (95% CI: 81–99%) for pts with pCR. Of 70 pts who completed surgery, 12-month DFS was 92% (95% CI: 82–97%). For all 79 pts: estimated 12-month OS rate was 92% (95% CI: 83–96%). Of 16 pts who received cemiplimab in part 2, there were 2 serious adverse events: grade 3 cardiomyopathy and grade 3 hypophysitis. Table: 1088MO

Conclusions

In pts with resectable stage II–IV CSCC, neoadj cemiplimab demonstrated favourable EFS, DFS and OS rates, and no recurrences in pts with pCR at a median follow-up of 18.7 months. There were no new safety signals with cemiplimab.

Clinical trial identification

NCT04154943.

Editorial acknowledgement

Medical writing support was provided by Jenna Lee, MSc, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., Sanofi.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc., and Sanofi.

Funding

Regeneron Pharmaceuticals, Inc., and Sanofi.

Disclosure

N. Gross: Financial Interests, Institutional, Funding: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Board: PDS Biotechnology, Shattuck Labs, DragonFly Therapeutics, Sanofi, Merck, Genzyme; Financial Interests, Personal, Advisory Role: PDS Biotechnology, Shattuck Labs, DragonFly Therapeutics, Sanofi, Merck, Genzyme. D.M. Miller: Financial Interests, Personal, Advisory Role: Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dohme, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme; Financial Interests, Personal, Stocks/Shares: Checkpoint Therapeutics, Avstera Therapeutics Corp; Financial Interests, Institutional, Funding: Kartos Therapeutics, NeoImmune Tech, Inc., Regeneron Pharmaceuticals, Inc. N.I. Khushalani: Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, Merck, Novartis, Iovance, Instil Bio, Castle Biosciences, Nektar, Incyte (data safety monitoring committee), AstraZeneca (data safety monitoring committee), Jounce Therapeutics; Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, Merck, Novartis, Replimune, GSK, HUYA, Celgene; Financial Interests, Personal, Other, Honoraria: Genzyme, NCCN (from Pfizer), Nektar (study steering committee); Financial Interests, Personal, Stocks or ownership: Bellicum Pharmaceuticals, Amarin, Transenetrix. V. Divi: Financial Interests, Institutional, Research Funding: Genentech; Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals, Inc. E. Ruiz: Financial Interests, Personal, Advisory Board: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Advisory Role: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Member of Board of Directors: Checkpoint Therapeutics. E.J. Lipson: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Sanofi, Regeneron, Genentech, Eisai, Instil Bio, Natera, Nektar Therapeutics, Pfizer, Rain Therapeutics, CareDx, Immunocore, Novartis, Replimune, HUYA Bioscience International; Financial Interests, Personal, Other, Consultant: OncoSec; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Regeneron, Merck, Sanofi. 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, Sanofi; Financial Interests, Institutional, Research Funding: Novartis, Roche. P.L. Swiecicki: Financial Interests, Institutional, Research Grant: Ascentage Pharma, Pfizer; Financial Interests, Personal, Advisory Board: Elevar Therapeutics, Prelude Therapeutics, Regeneron Pharmaceuticals, Inc. J.L. Atlas: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi. J.L. Geiger: Financial Interests, Institutional, Research Funding: Alkermes, Merck, Regeneron Pharmaceuticals, Inc., Roche/Genentech; Financial Interests, Institutional, Sponsor/Funding: EMD Serono; Financial Interests, Personal, Advisory Board: Astellas, Exelixis, Merck, Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Role: Astellas, Exelixis, Merck, Regeneron Pharmaceuticals, Inc. A. Hauschild: Financial Interests, Personal, Advisory Board: BMS, MSD, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi, Novartis, Eisai, Immunocore, Replimune, Seagen, Dermagnostix, Neracare, IO Biotech, Incyte, Highlight Therapeutics, Agenus; Financial Interests, Personal, Invited Speaker: Merck, Pfizer; Financial Interests, Institutional, Local PI: BMS, MSD, Pierre Fabre, Amgen, Roche, Agenus; Financial Interests, Institutional, Coordinating PI: Regeneron, Novartis. J.H. Choe: Financial Interests, Personal, Advisory Role: Exelixis, Coherus Biosciences, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc.; Financial Interests, Institutional, Research Funding: Genmab A/S, Arcus Biosciences. B.G.M. Hughes: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer, Roche; Financial Interests, Institutional, Research Funding: Amgen. S. Yoo, M.D. Mathias, H. Han, 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, GSK, ALX Oncology; Non-Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GSK, Bristol Myers Squibb; Non-Financial Interests, Personal, Steering Committee Member: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GSK, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

AXL has been linked with both a reduced response to PD-1 blockade and resistance to BRAF directed therapies in melanoma. Bemcentinib (Bem) is a first-in-class, orally bioavailable, highly selective AXL inhibitor. BGBIL006 (NCT02872259) is an open label Phase Ib/II clinical study designed to explore whether combinations with Bem are safe and improve overall response rate (ORR) relative to standard of care therapies in metastatic melanoma.

Methods

Six patients were enrolled in the dabrafenib/trametinib (D/T) + Bem dose finding part 1. In part 2, 68 patients received D/T or pembrolizumab (Pem) based on BRAF mutation status and tumour load and were randomized 2:1 to receive D/T or Pem with or without Bem. Upon progression, 17 BRAF+ patients switched from D/T to Pem or vice versa in part 3. Safety was assessed by NCI CTCAE v 4.03 and tumour responses were assessed using RECIST v1.1.

Results

Patients were enrolled between 2017 and 2022. At the interim database lock on August 21 2023, median follow time was 53 months (10-78). A daily dose of 200 mg Bem was well tolerated in combinations with Pem or D/T; 24% (18/73) of Grade ≥ 3 AEs were regarded as related to Bem. Most frequent Bem-related AEs were rash, diarrhoea, fatigue and increased transaminases. In the efficacy population (n=70), we did not observe significant differences in ORR, PFS or OS between standard treatments and the combinations with Bem. In pre-planned analyses of baseline biomarkers, we did not identify subgroups of patients with increased response to combinations with Bem compared to standard treatment. The following biomarkers predicted improved ORR to Pem; high CD8+ count (p<0.01), high FOXP3 count (p<0.01), high PD-L1 in TIL (p=0.02), high AXL expression in inflammatory cells (p=0.04). High FOXP3 count (above median) in tumours, compared with low, predicted increased PFS in Pem treated patients (HR 0.2, p<0.01).

Conclusions

Bem was well tolerated in combinations with Pem or D/T in melanoma, but did not increase responses or survival in the efficacy population nor in biomarker defined subgroups. High FOXP3 count in tumour infiltrating inflammatory cells was a strong predictive marker for response to Pem.

Clinical trial identification

NCT02872259.

Legal entity responsible for the study

Department of Oncology, Haukeland University Hospital, Bergen, Norway.

Funding

KlinBeForsk, Program for treatment research Norway. The Norwegian Cancer Society. The Norwegian Research Council. BerGenBio ASA provided the study drug bemcentinib free of charge and provided pharmacovigilance.

Disclosure

C. Schuster: Financial Interests, Personal, Other, Travel Grant: BerGenBio; Financial Interests, Personal, Invited Speaker: BMS, Pierre Fabre. K. Davidsen: Financial Interests, Personal, Invited Speaker: BMS. J. Karlsen: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Novartis, Pierre Fabre. A.J. Rayford: Financial Interests, Personal, Full or part-time Employment, Part time: BergenBio ASA. H. Løvendahl Svendsen: Financial Interests, Personal, Stocks/Shares: BerGenBio ASA. B.T. Gjertsen: Financial Interests, Personal, Leadership Role: Alden Cancer Therapy II, Kinn Therapeutics; Financial Interests, Personal, Advisory Role: BerGenBio, Novartis, AbbVie, Pfizer, Jazz Pharma; Financial Interests, Personal, Funding: Mendus; Financial Interests, Personal, Licencing Fees or royalty for IP: Alden Cancer Therapy II. L. Akslen: Financial Interests, Personal, Stocks/Shares: BerGenBio. J. Lorens: Financial Interests, Personal, Stocks/Shares: BerGenBio; Financial Interests, Personal, Other, Previously employed by BerGenBio: BerGenBio. All other authors have declared no conflicts of interest.