61MO - Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer (mCRPC) treated with pembrolizumab (pembro) + enza in KEYNOTE-199

Background

In KEYNOTE-199 (NCT02787005), pembro + enza had durable antitumor activity in enza-refractory mCRPC. We evaluated the association between prespecified biomarkers and clinical outcomes.

Methods

Cohorts 4 (C4; RECIST-measurable disease) and 5 (C5; nonmeasurable, bone-predominant disease) enrolled men with chemotherapy-naive mCRPC, irrespective of PD-L1 status, that progressed after initial response to enza. We evaluated TMB by whole exome sequencing (n = 64), PD-L1 combined positive score (CPS) by IHC (n = 124), and 18-gene T-cell–inflamed gene expression profile (Tcell_infGEP) by NanoString (n = 51). Outcomes were DCR, PFS, PSA response, PSA progression, OS, and ORR per blinded independent review (C4 only). Significance of continuous biomarkers (CPS, TMB, GEP) was prespecified at 0.05 for 1-sided P values from logistic (ORR, DCR, PSA response) and Cox proportional hazard (PFS, OS, PSA progression) regression adjusted for ECOG PS.

Results

In C4, ORR was 10% (5/48) in pts with evaluable TMB data and 12% (10/81) in pts with CPS data. In C4 and C5, 16% (10/64) and 14% (17/124) of pts with TMB and CPS data, respectively, achieved a PSA response. TMB was significantly associated with DCR (P = 0.03) and trended toward an association with PSA response (P = 0.08). TMB (AUROC [95% CI]: 0.68 [0.51-0.86]), but not CPS (0.54 [0.41-0.67]) or Tcell_infGEP (0.55 [0.37-0.74]), enriched for PSA response. TMB (P = 0.04), but not CPS (P = 0.57) or Tcell_infGEP (P = 0.32), was significantly associated with PSA progression. There was 1 MSI-H pt (per Promega PCR assay); this pt achieved an objective and PSA response and had PFS >6 months. TMB, CPS, and Tcell_infGEP were not associated with PFS or OS. There was a low prevalence of TMB ≥175 mut/exome (11%) and Tcell_infGEP-high (≥−0.318; 16%).

Conclusions

In this biomarker analysis of KEYNOTE-199 C4-C5, PD-L1 CPS and Tcell_infGEP were not significantly associated with clinical outcome. Despite the low prevalence of TMB ≥175 mut/exome, TMB was positively associated with outcomes of pembro + enza in pts with mCRPC. The sample sizes for the exploratory analyses were small, and results should be interpreted with caution.

Clinical trial identification

NCT02787005.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J.N. Graff: Financial Interests, Personal, Other, Travel expenses: Merck, Sanofi; Financial Interests, Institutional, Research Grant: Merck, Astellas/Pfizer, Sanofi, Janssen; Non-Financial Interests, Personal, Advisory Role: Merck, Astellas, Janssen. S. Tagawa: Financial Interests, Personal, Other, Honoraria: Sanofi, Medivation/Astellas, Dendreon, Janssen, Genentech, Bayer, Endocyte, Eisai, Immunomedics, Karyopharm, AbbVie, Tolmar, Seattle Genetics, Amgen, Clovis, QED, Pfizer, AAA/Novartis, Clarity, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, AIki; Financial Interests, Institutional, Research Grant: Sanofi, Medivation, Astellas, Janssen, Amgen, Progenics, Dendreon, Lilly, Genentech, Newlink, BMS, Inovio, AstraZeneca, Immunomedics, Aveo, Rexahn, Atlab, Boehringer Ingelheim, Millennium, Bayer, Merck, AbbVie, Karyopharm, Endocyte, Clovis, Seattle Gene. C. Hoimes: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Merck, Seagen, BMS, Genentech, Bayer; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: Seagen, BMS, Genentech, Eisai. W. Gerritsen: Financial Interests, Institutional, Advisory Role, Advisory/consultancy: BMS, IqVia, Bayer, MSD, Sanofi, Janssen-Cilag; Financial Interests, Institutional, Speaker’s Bureau, Speaker Bureau/Expert Testimony: MSD; Financial Interests, Institutional, Research Grant: Astellas, Bayer, Janssen-Cilag, Sanofi. U.N. Vaishampayan: Financial Interests, Personal, Other, Honoraria: AAA, Alkermes, Bayer, Pfizer, BMS, Exelixis; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Merck, BMS, Exelixis; Financial Interests, Personal, Research Grant: Merck, BMS. C. Hwang: Financial Interests, Personal, Stocks/Shares: Johnson & Johnson; Financial Interests, Personal, Research Grant: Merck, Exelixis, Bayer, AstraZeneca, Genentech, Dendreon and Bausch; Financial Interests, Personal, Other: Sanofi/Genzyme, Bristol Myers Squibb, Astellas, Medivation, Bayer, and Janssen Scientific. A.G. Omlin: Financial Interests, Institutional, Other, Honoraria: AstraZeneca, Astellas, Bayer, BMS, Janssen, Molecular Partners, MSD, Pfizer, Roche, Sanofi Aventis; Financial Interests, Institutional, Research Grant: TEVA, Janssen; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Astellas, Bayer, Janssen, Sanofi Aventis. R.S. McDermott: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Amgen, Bayer, BMS, Clovis, Janssen, Pfizer; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: Astellas, Ipsen, MSD; Financial Interests, Institutional, Research Grant: Astellas, Bayer, BMS, Clovis, Regeneron, MSD. R. De Wit: Financial Interests, Personal, Other, Honoraria: Merck, Sanofi, Bayer, Astellas; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Merck, Sanofi, Bayer, Astellas; Financial Interests, Institutional, Research Grant: Bayer. C. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck & Co.; Financial Interests, Personal, Stocks/Shares: Merck & Co.. J. Kim: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.. L. Suttner: Financial Interests, Personal, Full or part-time Employment: Merck. R. Cristescu: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Other: Pending patent: Patent WO 2020/167619. M.J. Marton: Financial Interests, Personal, Stocks/Shares: Merck; Financial Interests, Personal, Full or part-time Employment: MSD. C. Schloss: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.. J.S. de Bono: Financial Interests, Personal, Other, Honoraria: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals; Financial Interests, Personal, Other: Patent no. WO 2005 053662; Financial Interests, Personal, Other: Patent no. US5604213. E.S. Antonarakis: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Amgen, Astellas, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Eli Lilly, ESSA, GlaxoSmithKline, Janssen, Medivation, Merck, Sanofi; Financial Interests, Personal, Research Grant: AstraZeneca, Bristol Myers-Squibb, Celgene, Clovis Oncology, Dendreon, Genentech, Janssen, Johnson & Johnson, Merck, Novartis, Sanofi, Tokai; Financial Interests, Personal, Licensing Fees, Licensing/royalties: Qiagen. All other authors have declared no conflicts of interest.