1089P - Longitudinal biomarker analysis and outcomes for patients (pts) treated with neoadjuvant nivolumab (nivo) and relatlimab (rela) in surgically resectable melanoma

Background

The neoadjuvant systemic treatment (NST) platform has demonstrated improved clinical outcomes for pts with stage III, surgically resectable melanoma, and provided a unique opportunity for translational analysis into mechanistic insights and treatment (tx) personalization approaches. Our team previously reported NST outcomes with nivo (anti-PD1) + rela (anti-LAG3), which achieved a major pathologic response (MPR; ≤10% viable tumor) rate of 63% in a Ph II study (NCT02519322). Here we report the gene expression signature on the samples obtained from this study.

Methods

Baseline (BL), early on tx, and post dose 2/surgical samples were analyzed using the NanoString PanCancer IO360 panel. Differential expression was fit per signature using linear model for analysis (nSolver Advanced Analysis software). Pts were categorized into MPR vs non MPR. Event-free survival (EFS) was assessed using Kaplan-Meier estimation and differences were evaluated using log-rank test.

Results

The analysis included 53 RNA samples from 26 (17 MPR; 9 non MPR) of the 30 pts treated. The median follow up was 44 months (mos) for all pts. Among 14 BL samples, IFN- γ and tumor inflammation signatures (TIS) were significantly higher in pts with MPR vs non MPR. Conversely, BL B7-H3 was significantly lower in MPR pts vs non MPR pts. None of the 7 pts with high IFN- γ nor TIS, nor low B7-H3 have recurred, regardless of path response, with median EFS not being reached. Conversely, the median EFS for the 7 pts with low IFN- γ, TIS and high B7-H3 was 14.5 mos, p = 0.0065. At post dose 2/surgery, macrophages and mast cell populations were significantly higher in MPR vs non MPR pts.

Conclusions

The neoadjuvant platform offers unique insights into the tumor microenvironment and dynamics of the immune response over time. Our analysis reveals consistencies with previously published biomarkers associated with response to immune checkpoint inhibitors (IFN- γ) and provides insights into new biomarkers associated with response to nivo + rela, specifically B7-H3. Taken together, this work expands our insights into who may benefit from nivo + rela and provides insights into potentially actionable strategies to personalize tx approaches.

Clinical trial identification

NCT02519322.

Editorial acknowledgement

Legal entity responsible for the study

The University of Texas MD Anderson Cancer Center.

Funding

BMS.

Disclosure

D. Milton: Financial Interests, Personal, Stocks or ownership: Lilly. M.I. Ross: Financial Interests, Personal, Advisory Board, US Melanoma Advisory Board Member: Merck; Financial Interests, Institutional, Coordinating PI, Clinical Trial Support: AMGEN; Non-Financial Interests, Principal Investigator, Clinical Trials: Amgen. M.A. Postow: Financial Interests, Personal, Advisory Board: BMS, Chugai, Merck, Nektar, Pfizer; Financial Interests, Institutional, Coordinating PI: BMS; Financial Interests, Institutional, Local PI: Merck, Novartis. I.C. Glitza: Financial Interests, Advisory Role: Array Biopharma; Financial Interests, Advisory Board: BMS, Novartis, Midatech Pharma, Leal Therapeutics, Sintetica; Financial Interests, Speaker’s Bureau: Array Biopharma; Financial Interests, Invited Speaker: Amgen; Financial Interests, Institutional, Research Funding: BMS, Merck, Pfizer. M.K.K. Wong: Financial Interests, Advisory Role: Regeneron; Financial Interests, Advisory Board: Castle Biosciences, Replimune. S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Delcath, Novartis, BMS, Pfizer, Immatics, MSD; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Invited Speaker, Non-promotional speaker: BMS, MSD; Financial Interests, Personal, Other, IDMC member: Ideaya; Financial Interests, Personal, Invited Speaker: Clinical Education Alliance, Projects in Knowledge, Melanoma Research Foundation, Answers in CME; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals; Financial Interests, Institutional, Local PI: Lyvgen, InxMed, Foghorn Therapeutics, Ideaya, Novartis, Seagen, Syntrix Bio; Financial Interests, Institutional, Steering Committee Member: 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. Davies: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, BMS, Sanofi Aventis, GSK, Vaccinex, Apexigen, Eisai, Iovance, Merck, ABM Therapeutics; Financial Interests, Institutional, Coordinating PI: Pfizer; Financial Interests, Institutional, Research Grant: ABM Therapeutics, Lead Pharma, Genentech, GSK, Sanofi-Aventis, Merck, Oncothyreon; Financial Interests, Research Grant: Myriad. J.E. Gershenwald: Financial Interests, Personal, Other, consultant, advisory board, scientific advisory board: merck; Financial Interests, Personal, Other, consultant: Regeneron; Financial Interests, Personal, Royalties, author/coauthor of several melanoma chapters for this online clinical resource: UpToDate; Financial Interests, Personal, Other, I am on the scientific advisory committee for two international randomized clinical trials in melanoma -: Merck; Non-Financial Interests, Leadership Role, Chair, executive committee (voluntary position)Overall AJCC Vice Chair (voluntary position): American Joint Committee on Cancer (AJCC); Non-Financial Interests, Other, Member, ACS Cancer Surgery Standards Program (CSSP) executive committee - voluntary position: American College of Surgeons (ASC); Non-Financial Interests, Advisory Role, Member, medical advisory panel (voluntary); prior Vice-Chair and current Chair, MRA Grant Review Committee (voluntary): Melanoma Research Alliance (MRA). J. Mcquade: Financial Interests, Personal, Advisory Role: BMS, Roche; Financial Interests, Personal, Other, Travel, Accommodations: Merck; Financial Interests, Personal, Invited Speaker: Merck, Roche, BMS. V. Prieto: Financial Interests, Personal, Other, Consultant: Orlucent, Merck, Castle Biosciencies, Novartis. C.E. Ariyan: Financial Interests, Personal, Advisory Board: Merck, Iovance; Financial Interests, Personal, Stocks/Shares: Pfizer. J. Wargo: Financial Interests, Personal, Advisory Role: Daiichi Sankyo/UCB Japan, EverImmune, Gustave Roussy Cancer Center, OSE Immunotherapeutics, Peerview; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gustave Roussy Cancer Center, Peerview; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: Patent submitted regarding the role of the microbiome in response to immune checkpoint blockade; Financial Interests, Personal, Stocks or ownership: Micronoma; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo/UCB Japan, EverImmune, Gustave Roussy Cancer Center, OSE Immunotherapeutics, Peerview. 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. R.N. Amaria: Financial Interests, Institutional, Coordinating PI: Merck, Bristol Myers Squibb, OnKure, Erasca, KSQ; Financial Interests, Institutional, Local PI: Roche; Financial Interests, Institutional, Trial Chair: Obsidian. All other authors have declared no conflicts of interest.