LBA3 - Phase III study of neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer (TNBC): KEYNOTE-522 Korean subgroup analysis

Background

KEYNOTE-522 (NCT03036488) is a global, phase 3, randomized, double-blind study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant therapy followed by adjuvant pembro vs pbo for early-stage TNBC. Pembro-chemo/pembro demonstrated clinically meaningful and statistically significant improvements in pathologic complete response (pCR at IA2; 65% vs 51%; P < 0.001]) and event-free survival (EFS at IA4; HR, 0.63 [95% CI, 0.48‒0.82]; P < 0.001) vs pbo-chemo/pbo. We report outcomes at IA4 for patients (pts) enrolled in the Republic of Korea in this study.

Methods

Pts with previously untreated, nonmetastatic, centrally confirmed TNBC (T1c N1/N2 or T2–4 N0–N2 per AJCC) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or pbo, each with 4 cycles of paclitaxel + carboplatin, then with 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received 9 cycles of adjuvant pembro or pbo. Dual primary endpoints were pCR (ypT0/Tis ypN0) and investigator-assessed EFS. Overall survival (OS) was a secondary endpoint. Adverse events (AEs) were graded per NCI CTCAE v4.0. No alpha was assigned to this post hoc exploratory subgroup analysis.

Results

A total of 86 pts were randomized (pembro-chemo/pembro, n = 56; pbo-chemo/pbo, n = 30). Median time from randomization to data cutoff (Mar 23, 2021) was 38.6 mo (range, 30.4–45.5). pCR (95% CI) was 68% (54%–80%) with pembro-chemo/pembro and 47% (28%–66%) with pbo-chemo/pbo. 4 (7%) and 10 pts (33%), respectively, had EFS events (HR, 0.19 [95% CI, 0.06–0.60]). 3-y EFS rates were 93% vs 70%; median EFS was not reached in either arm. 3-y OS rates were 98% vs 68%. Grade ≥3 treatment-related AEs (TRAEs) occurred in 82% of pts with pembro-chemo/pembro and 87% with pbo-chemo/pbo. No grade 5 TRAEs were reported.

Conclusions

Neoadjuvant pembro + chemo followed by adjuvant pembro led to improved efficacy vs pbo-chemo/pbo and manageable safety in pts with previously untreated, early-stage, nonmetastatic TNBC enrolled in KEYNOTE-522 in the Republic of Korea. Results are consistent with overall study population findings.

Clinical trial identification

NCT03036488.

Editorial acknowledgement

Medical writing assistance was provided by Susan Tyree, PhD, CMPP, of ICON plc (Blue Bell, PA, USA).

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

Y.H. Park: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Eisai, Roche, Daiichi Sankyo, MENARINI, Bixink, Everest, Novartis, Inc.; Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, AstraZeneca, Novartis, Genome Insight, NGenBio, Roche. S. Im: Financial Interests, Personal, Advisory Role: AstraZeneca, Novartis, Roche/Genentech, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Daiichi Sankyo; Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical; Financial Interests, Personal, Other: Roche. M.H. Kim: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boryung Pharmaceutical, Celltrion, Daiichi Sankyo, Eisai, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Institutional, Research Funding: AstraZeneca, Boryung Pharmaceutical. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, BridgeBio; Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daiichi Sankyo, AstraZeneca, Gilead, Steamline Therapeutics; Financial Interests, Institutional, Research Funding: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, Guardant Health, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Piqur Therapeutics, IQVIA, Queen Mary University of London, F. Hoffman-La Roche; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, Relative: Leuko; Financial Interests, Personal, Other, Travel, accommodation, expenses: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Other, (1) Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED and (2) Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/ 0338368 A1. LICENSED: Patents. R.A. Dent: Financial Interests, Personal, Advisory Role: AstraZeneca, Eisai, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Roche; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Eisai, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Roche. L. Pusztai: Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Novartis, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Almac, Syndax; Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Seattle Genetics; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Novartis, Genentech, Eisai, Pieris, Immunomedics, Almac, Syndax, Seattle Genetics; Financial Interests, Personal, Other, Honoraria (self): Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Novartis, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Almac, Syndax. H.L. McArthur: Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Bristol Myers Squibb, Spectrum Pharm, Lilly, Amgen, Immunomedics, Pfizer, Genentech, AstraZeneca; Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Bristol Myers Squibb; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Bristol Myers Squibb, Spectrum Pharm, Lilly, Amgen, Immunomedics, Pfizer, Genentech, AstraZeneca, Puma Biotechnology. S. Kummel: Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting Fees: Roche; Genomic Health; Novartis; Amgen; Celgene; Daiichi Sankyo; AstraZeneca; Somatex; Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Pfizer; PFM Medical; Lilly; Sonoscape; Financial Interests, Institutional, Research Funding: Roche, Somatex; Financial Interests, Personal, Ownership Interest, Minority ownership: WSG Study Group; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Daiichi Sankyo, Sonoscape. C. Denkert: Financial Interests, Personal, Other, Honoraria (Self): Teva, Novartis, Pfizer, Roche, Amgen; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Sividon (Myriad); Financial Interests, Personal, Other, Licensing/Royalties: VmScope. J. O'Shaughnessy: Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting fees: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bayer, BMS, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Myriad, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Pierre Fabre, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Syndax Pharmaceuticals, Sy. M. Mouret-Reynier: Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. M.I.R. Ferreira: Financial Interests, Institutional, Local PI: AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Taiho Oncology; Financial Interests, Institutional, Other, Sub-investigator: AstraZeneca, Daiichi Sankyo, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Roche; Non-Financial Interests, Personal, Member of Board of Directors, Board member (treasurer): Grupo de Estudos Oncológicos. M. Gion Cortes: Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. J. Boileau: Financial Interests, Personal, Other, Speaking honoraria: Roche, Novartis, Genomic Health, Pfizer, Allergan, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Advisory Board: Roche, Genomic Health, Nanostring Technologies, Pfizer, Lilly, Novartis, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Other, Travel support: Roche, GSK, Novartis, Pfizer, LifeCell; Financial Interests, Institutional, Research Funding: Roche, Novartis, Pfizer, AbbVie, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, RNA Diagnostics Inc., Lilly, Bristol Myers Squibb, Genomic Health. R. Hui: Financial Interests, Personal, Advisory Board, Received personal fees for advisory boards: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, BMS, Eisai, Eli Lilly, Merck KGaA, Novartis, Oncosec, Pfizer, Roche, Seagen; Financial Interests, Personal, Other, Speaker honoraria: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Roche; Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, BMS, Corvus, Eli Lilly, Janssen, Novartis, Olema, Oncosec, Roche, Seagen. Y. Zhu, W. Pan, V.V. Karantza: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. P. Schmid: Financial Interests, Personal, Other, Has been a consultant to/received honoraria from: AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Puma, Roche, Eisai, Celgene; Financial Interests, Institutional, Research Funding: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Other, Spouse is Roche employee: Roche. All other authors have declared no conflicts of interest.