Abstract 640TiP
Background
Standard-of-care therapies for mCRPC are abiraterone, enzalutamide, or docetaxel, but these are not curative. Moreover, ∼20% of pts develop t-NE, which has no standard of care. Pembro monotherapy showed promising antitumor activity in docetaxel-pretreated pts with adenocarcinoma mCRPC in the phase II KEYNOTE-199 trial. The VEGF/FGFR inhibitor lenvatinib inhibits proliferation and angiogenesis in prostate cancer cells in vitro and in mice. Combining PD-1 and VEGF/FGFR inhibition may have enhanced benefit in adenocarcinoma mCRPC and t-NE mCRPC.
Trial design
This nonrandomized, open-label, multicohort, phase Ib/II KEYNOTE-365 study (NCT02861573) will be conducted to evaluate several pembro combination therapies in different pt populations with mCRPC. Pts enrolled in cohort E must have confirmed adenocarcinoma of the prostate without small cell histology. Pts enrolled in cohort F must have t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort of 40-100 pts includes adults with ECOG 0/1 who had previously received docetaxel for mCRPC. Prior treatment with ≤2 NHAs (hormone-sensitive metastatic prostate cancer or mCRPC) and 1 other chemotherapy for mCRPC were permitted. Pts enrolled in cohort F must have t-NE that progressed within <6 months of starting an NHA and <6 cycles of docetaxel. Both cohorts will receive pembro 200 mg IV Q3W + oral lenvatinib 20 mg QD. Treatment will continue until disease progression, withdrawal of consent, prespecified ALT or AST elevation, or other discontinuation event. CT/MRI will be performed at screening, Q9W through week 54, and Q12W thereafter. AEs will be monitored throughout the trial through 30 days after discontinuation (90 for serious AEs), graded using CTCAE v4.0. Primary end points are safety and tolerability, PSA response rate, and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression, ORR, and rPFS per PCWG3-modified RECIST v1.1 by BICR; DOR and DCR per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and OS.
Clinical trial identification
NCT02861573, August 10, 2016.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD of ApotheCom (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
G. Kramer: Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Sanofi Genzyme; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Institutional, Research Grant: Bayer. N.D. Shore: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Aurora Oncology; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Personal, Advisory Role: Clovis Oncology; Financial Interests, Personal, Advisory Role: Cold Genesys; Financial Interests, Personal, Advisory Role: Dendreon; Financial Interests, Personal, Advisory Role: Exact Imaging; Financial Interests, Personal, Advisory Role: Exact Science; Financial Interests, Personal, Advisory Role: FerGene; Financial Interests, Personal, Advisory Role: Foundation Medicine; Financial Interests, Personal, Advisory Role: GenesisCare; Financial Interests, Personal, Advisory Role: Invitae; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: MDxhealth; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Myovant; Financial Interests, Personal, Advisory Role: Myriad; Financial Interests, Personal, Advisory Role: Nymox; Financial Interests, Personal, Advisory Role: Pacific Edge; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Phosphorous; Financial Interests, Personal, Advisory Role: PreView Medical; Financial Interests, Personal, Advisory Role: Propella; Financial Interests, Personal, Advisory Role: Sanofi Genzyme; Financial Interests, Personal, Advisory Role: Sesen Bio; Financial Interests, Personal, Advisory Role: Specialty Network; Financial Interests, Personal, Advisory Role: Tolmar; Financial Interests, Personal, Advisory Role: Urogen; Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Clovis Oncology; Financial Interests, Personal, Speaker’s Bureau: Foundation Medicine; Financial Interests, Personal, Speaker’s Bureau: Guardant; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Myovant; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Tolmar. A.M. Joshua: Financial Interests, Institutional, Other, Honoraria: Merck. X.T. Li: Financial Interests, Personal, Full or part-time Employment: MSD. C.H. Poehlein: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Leadership Role: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. C. Schloss: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. J.S. de Bono: Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Honoraria: Astellas; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Other, Honoraria: Bioxcel Therapeutics; Financial Interests, Personal, Other, Honoraria: Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria: Cellcentric; Financial Interests, Personal, Other, Honoraria: Daiichi; Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Other, Honoraria: Genentech Roche; Financial Interests, Personal, Other, Honoraria: Genmab; Financial Interests, Personal, Other, Honoraria: GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria: Harpoon; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Other, Honoraria: Menarini Silicon Biosystems; Financial Interests, Personal, Other, Honoraria: Merck Serono; Financial Interests, Personal, Other, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Other, Honoraria: Orion Pharma; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Qiagen; Financial Interests, Personal, Other, Honoraria: Sanofi Aventis; Financial Interests, Personal, Other, Honoraria: Sierra Oncology; Financial Interests, Personal, Other, Honoraria: Taiho; Financial Interests, Personal, Other, Honoraria: Terumo; Financial Interests, Personal, Other, Honoraria: Vertex Pharmaceuticals; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Bioxcel Therapeutics; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Cellcentric; Financial Interests, Personal, Advisory Role: Daiichi; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Genentech Roche; Financial Interests, Personal, Advisory Role: Genmab; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Harpoon; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Menarini Silicon Biosystems; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Orion Pharma; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Qiagen; Financial Interests, Personal, Advisory Role: Sanofi Aventis; Financial Interests, Personal, Advisory Role: Sierra Oncology; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Advisory Role: Terumo; Financial Interests, Personal, Advisory Role: Vertex Pharmaceuticals; Financial Interests, Personal, Other, Travel expenses: Amgen; Financial Interests, Personal, Other, Travel expenses: Astellas; Financial Interests, Personal, Other, Travel expenses: AstraZeneca; Financial Interests, Personal, Other, Travel expenses: Bayer; Financial Interests, Personal, Other, Travel expenses: Bioxcel Therapeutics; Financial Interests, Personal, Other, Travel expenses: Boehringer Ingelheim; Financial Interests, Personal, Other, Travel expenses: Cellcentric; Financial Interests, Personal, Other, Travel expenses: Daiichi; Financial Interests, Personal, Other, Travel expenses: Eisai; Financial Interests, Personal, Other, Travel expenses: Genentech Roche; Financial Interests, Personal, Other, Travel expenses: Genmab; Financial Interests, Personal, Other, Travel expenses: GlaxoSmithKline; Financial Interests, Personal, Other, Travel expenses: Harpoon; Financial Interests, Personal, Other, Travel expenses: Janssen; Financial Interests, Personal, Other, Travel expenses: Menarini Silicon Biosystems; Financial Interests, Personal, Other, Travel expenses: Merck Serono; Financial Interests, Personal, Other, Travel expenses: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel expenses: Orion Pharma; Financial Interests, Personal, Other, Travel expenses: Pfizer; Financial Interests, Personal, Other, Travel expenses: Qiagen; Financial Interests, Personal, Other, Travel expenses: Sanofi Aventis; Financial Interests, Personal, Other, Travel expenses: Sierra Oncology; Financial Interests, Personal, Other, Travel expenses: Taiho; Financial Interests, Personal, Other, Travel expenses: Terumo-Vertex Pharmaceuticals; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Cellcentric; Financial Interests, Institutional, Research Grant: Daiichi; Financial Interests, Institutional, Research Grant: Genentech Roche; Financial Interests, Institutional, Research Grant: Genmab; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Harpoon; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Merck Serono; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Orion Pharma; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Sanofi Aventis; Financial Interests, Institutional, Research Grant: Sierra Oncology; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Vertex Pharmaceuticals; Non-Financial Interests, Personal, Royalties, DNA damage repair inhibitors for treatment of cancer (patent no. WO 2005 053662; licensee: AstraZeneca): Patent; Non-Financial Interests, Personal, Royalties, 17-substituted steroids useful in cancer treatment (patent no. US5604213; licensee: Janssen): Patent; Financial Interests, Personal, Other, Travel expenses: Vertex Pharmaceuticals. E. Yu: Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Clovis Oncology; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Myovant Sciences; Financial Interests, Institutional, Funding: Dendreon; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Seattle Genetics; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Taiho Pharmaceutical; Financial Interests, Institutional, Funding: Pharmacyclics; Financial Interests, Institutional, Funding: Blue Earth Diagnostics; Financial Interests, Institutional, Funding: Bayer.