In the phase III, randomized, open-label KEYNOTE-119 (NCT02555657) study, second- or third-line treatment with pembro monotherapy did not significantly improve OS vs single-agent chemo treatment of physician’s choice (TPC) in patients (pts) with mTNBC, although the pembro treatment effect increased with increasing PD-L1 enrichment. In this exploratory analysis, we evaluated the association of T-cell-inflamed gene expression profile (GEP) with clinical outcomes from KEYNOTE-119.
Pts with centrally confirmed mTNBC, ECOG PS ≤1, and 1-2 prior systemic treatments for metastatic breast cancer were randomized 1:1 to pembro 200 mg Q3W for up to 35 cycles or TPC (capecitabine, eribulin, gemcitabine, or vinorelbine) per local guidelines. Tumor RNA profiling was conducted on the RNA-seq platform (Illumina, San Diego, CA). Association of GEP with clinical outcomes was evaluated by logistic regression (best objective response [BOR] per RECIST v1.1) and Cox proportional hazards models (PFS and OS) with baseline adjustment for ECOG PS; 95% CIs for BOR were estimated using the Clopper and Pearson method.
As of April 11, 2019, GEP data for 333 pts (pembro, n=177; TPC, n=156) were available for analysis. GEP was significantly associated with improved BOR, PFS, and OS in pts treated with pembro but not TPC (Table). HR for OS was 0.77 (95% CI, 0.58–1.04) in pts with GEP non-low (≥1st tertile) and 1.72 (1.15–2.55) in pts with GEP low (<1st tertile). No association was seen between
These findings suggest a positive association between GEP and clinical outcomes in pts with mTNBC who are treated with pembro, with a more favorable treatment effect in the GEP-enriched population. Results may help inform future analyses of outcomes by biomarker status in this population.
aHypothesis=nonzero (2-tailed test); bHypothesis=positive (1-tailed test); cNominal statistical significance (α=0.05).
BOR PFS OS TPC,a n=156 0.205 0.146 0.752 Pembro,b n=177 <0.001c <0.0001c <0.0001c Low (<1st tertile) - TPC, n=59 8.5 (2.8–18.7) 3.1 (2.2–4.3) 3.63 (2.31–5.70) 11.5 (7.1–15.2) 1.72 (1.15–2.55) - Pembro, n=52 0.0 (0.0–6.8) 1.9 (1.6–2.0) 5.6 (4.2–7.0) Non-low (≥1st tertile) - TPC, n=97 13.4 (7.3–21.8) 3.6 (2.3–4.6) 1.40 (1.02–1.93) 11.1 (7.3–13.7) 0.77 (0.58–1.04) - Pembro, n=125 15.2 (9.4–22.7) 2.1 (2.1–3.4) 12.7 (9.9–15.5)
NCT02555657.
Medical writing assistance was provided by Sonia Mohinta, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
J. Cortés: Financial Interests, Personal and Institutional, Other, Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Financial Interests, Personal, Other, Honoraria (self), Travel / Accommodation /Expenses: Novartis; Financial Interests, Personal, Other, Honoraria (self), Advisory /Consultancy: Celgene, Eisai; Financial Interests, Personal and Institutional, Other, Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Financial Interests, Personal, Other, Honoraria (self): Samsung; Financial Interests, Personal, Other, Advisory / Consultancy: Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Financial Interests, Personal, Other, Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Financial Interests, Institutional, Other, Research grant / Funding (institution): Ariad Pharmaceuticals, Baxalta, GMBH/Servier Affaires, Bayer Healthcare, F. Hoffman-La Roche, Guardanth Health, Merck Sharp & Dohme, Piqor Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Other, Shareholder / Stockholder / Stock options: MedSIR. S. Im: Financial Interests, Personal, Other, Advisory / Consultancy, Research grant / Funding (self): AstraZeneca, Pfizer; Financial Interests, Personal, Other, Advisory / Consultancy: Amgen, Eisai, Hanmi, Ildong, MediPactor, Novartis, Roche. A. Gonçalves: Financial Interests, Institutional, Other, Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Financial Interests, Institutional, Other, Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Financial Interests, Institutional, Other, Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Financial Interests, Institutional, Other, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Roche; Financial Interests, Personal, Invited Speaker, Travel / Accommodation / Expenses: Celgene. K.S. Lee: Financial Interests, Personal, Invited Speaker, Advisory / Consultancy: Roche, Lilly, Pfizer, Novartis; Financial Interests, Personal and Institutional, Invited Speaker, Research grant / Funding (institution), (support of drug): Dong-A Pharm. P. Schmid: Financial Interests, Personal, Other, Honoraria (self), Advisory / Consultancy: Pfizer, Merck, BI, Bayer, Esai, Puma, Celgene; Financial Interests, Personal and Institutional, Other, Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ, Novartis, Roche; Financial Interests, Institutional, Other, Research grant / Funding (institution): Genentech, Oncogenex, Astellas; Financial Interests, Personal, Other, Spouse / Financial dependant, Spouse is a consultant for Genentech/Roche: Genentech/Roche. K. Tamura: Financial Interests, Personal and Institutional, Other, Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer, Cyugai, Eisai, Eli Lilly; Financial Interests, Personal and Institutional, Other, Research grant / Funding (self), Research grant / Funding (institution): Daiich-Sankyo, MSD, AstraZeneca, Ono, Kyowa Hakko, Novartis, Clovis, Sanofi; Financial Interests, Institutional, Other, Research grant / Funding (institution): Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Taiho. L. Testa: Financial Interests, Institutional, Other, Advisory / Consultancy, Research grant / Funding (institution): Lilly, Novartis; Financial Interests, Institutional, Other, Research grant / Funding (institution): Roche; Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Libbs, Pfizer. S. Ohtani: Financial Interests, Institutional, Other, Honoraria (institution): Chugai, Eisai, Pfizer, AstraZeneca. N. Harbeck: Financial Interests, Personal, Other, Advisory / Consultancy: Agendia, Celgene, Genomic Health, Odonate, Sandoz/Hexal, Seattle Genetics; Financial Interests, Personal, Other, Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Other, Speaker Bureau / Expert testimony: Amgen, Nanostring; Financial Interests, Personal, Other, Shareholder / Stockholder / Stock options, Spouse / Financial dependant, Codirector of West German Study Group (self): West German Study Group; Financial Interests, Personal, Other, Full / Part-time employment: LMU Munich. S. Loi: Financial Interests, Institutional, Other, Consulting or Advisory Role: Aduro Biotech, AstraZeneca/MedImmune, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, and Seattle Genetics; Financial Interests, Institutional, Other, Research Funding: Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Puma Biotechnology, Roche/Genentech, and Seattle Genetics. J. Lunceford, V. Karantza, J.A. Mejia, R. Cristescu, M. Nebozhyn, P. Jelinic, L. Huang: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. E.P. Winer: Financial Interests, Personal, Other, Advisory / Consultancy: Genentech, Lilly, Carrick Therapeutics, GSK, Seattle Genetics, LEAP. All other authors have declared no conflicts of interest.