68TiP - KEYLYNK-009: A phase II/III, open-label, randomized study of pembrolizumab (pembro) + olaparib (ola) vs pembro + chemotherapy after induction with first-line (1L) pembro + chemo in patients (pts) with locally recurrent inoperable or metastatic TNBC

Background

Immunotherapy + chemotherapy (chemo) is a promising approach for 1L treatment of locally recurrent, inoperable TNBC or metastatic TNBC (mTNBC). An unmet need exists for effective and tolerable maintenance regimens in mTNBC to sustain clinical benefit after induction therapy and avoid potential toxicity or resistance to prolonged chemo. The PARP inhibitor ola has shown efficacy as maintenance therapy for platinum-sensitive ovarian cancer. The high prevalence of BRCAm (or “BRCAness”) in TNBC may make these tumors sensitive to DNA-damaging agents. Moreover, evidence suggests that ola + PD-1 inhibitor pembro may provide greater clinical benefit than with either agent alone. KEYLYNK-009 (NCT04191135) is a phase II/III, open-label, randomized study of pembro + ola vs chemo after induction with 1L pembro + chemo in locally recurrent, inoperable TNBC or mTNBC.

Trial design

This 2-in-1 study will enroll ∼317 pts in phase II and ∼615 additional pts in phase III if a planned efficacy boundary is met. Pts eligible for induction therapy must have measurable, locally recurrent, inoperable TNBC that cannot be treated with curative intent or mTNBC previously untreated with chemo. Pts will receive up to 6 cycles of induction therapy with pembro 200 mg Q3W + chemo (carboplatin AUC 2 + gemcitabine 1000 mg/m² on days 1 + 8 Q3W). Pts eligible for postinduction treatment must achieve CR or PR or maintain SD during induction after 4-6 treatment cycles, with ECOG PS 0/1 and no persistent grade >1 toxicities related to induction therapy (excluding alopecia, Hb ≥9.0 g/dL, grade 2 hyper-/hypothyroidism, or grade 2 hyperglycemia). These pts will be randomized 1:1 to pembro 200 mg Q3W + ola 300 mg BID or continue pembro + chemo (same as induction regimen) until completion of 35 cycles of pembro (including induction), progression, or unacceptable toxicity. Phase III primary endpoints are PFS (RECIST v1.1 by BICR) and OS. Secondary endpoints include OS and PFS in pts with BRCAm, HRQoL, and safety. Pt enrollment is ongoing and anticipated at 110 sites in 14 countries.

Clinical trial identification

NCT04191135.

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

S. Saji: Honoraria (self): AstraZeneca; Honoraria (self), Research grant/Funding (self): Chugai Pharma; Honoraria (self): Daiichi Sankyo; Honoraria (self), Research grant/Funding (self): Eisai; Honoraria (self): Eli Lilly; Honoraria (self): Kyowa Kirin; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (self): Taiho Pharmaceutical; Honoraria (self): Takeda. A. Llombart Cussac: Advisory/Consultancy, Shareholder/Stockholder/Stock options, Licensing/Royalties: MedSIR. F. Andre: Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Lilly; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: GlaxoSmithKline. M.E. Robson: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca.; Advisory/Consultancy: Change Health Care; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): InVitae; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Non-remunerated activity/ies, Physician Education Resource; Research to Practice: Clinical Care Options; Non-remunerated activity/ies, Uncompensated Relationships: Daiichi Sankyo; Non-remunerated activity/ies, Uncompensated Relationships: Merck; Non-remunerated activity/ies, Uncompensated Relationships: Pfizer. N. Harbeck: Shareholder/Stockholder/Stock options: West German Study Group; Honoraria (self): Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self): Roche; Honoraria (self): Zodiac Pharma; Advisory/Consultancy: Agendia; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; Advisory/Consultancy: Odonate Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: West German Study Group. P. Schmid: Research grant/Funding (institution), Full/Part-time employment: Genentech; Honoraria (self), Research grant/Funding (institution), Full/Part-time employment: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self): Pfizer; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Celgene; Advisory/Consultancy: Eisai; Honoraria (self): Genentech/Roche; Advisory/Consultancy: Merck; Advisory/Consultancy: Puma Biotechnology; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Oncogenex. D.W. Cescon: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Agendia; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Genomic Health; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Licensing/Royalties, Patent Pending: Biomarkers of TTK inhibitors : University of Toronto. J.S. Ahn: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb-Ono Pharmaceutical; Honoraria (self): Eisai; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche; Advisory/Consultancy: Samsung Bioepis. R. Nanda: Advisory/Consultancy: Aduro; Advisory/Consultancy: Athenex; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: Ionis; Advisory/Consultancy: Macrogenics; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Corcept Therapeutics; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Odonate Therapeutics; Non-remunerated activity/ies: G1 Therapeutics. L. Fan: Full/Part-time employment: li_fan2@merck.com. J.A. Mejia: Full/Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. V. Karantza: Shareholder/Stockholder/Stock options, Full/Part-time employment: erck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. A. Bardia: Advisory/Consultancy: Biotheranostics Inc.; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Travel/Accommodation/Expenses: Phillips; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy: Puma; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Radius Health; Advisory/Consultancy: Diiachi Pharma/AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunomedics; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Taiho. H.S. Rugo: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Sermonix; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): OBI; Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Odonate; Advisory/Consultancy: Puma; Advisory/Consultancy: Samsung.