LBA4 - Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase III KEYNOTE-522 study

Background

KEYNOTE-522 (NCT03036488) showed statistically significant and clinically meaningful improvements in pCR and EFS with the addition of pembrolizumab (pembro) to chemotherapy (chemo) in patients (pts) with early-stage TNBC. Here, we present the final OS results.

Methods

Eligible pts with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or placebo (pbo), both given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS (time from randomization to disease progression that precluded definitive surgery, local/distant recurrence, second primary cancer, or death from any cause). Overall survival is the key secondary endpoint.

Results

1174 pts were randomized to pembro (n=784) or pbo (n=390). At the prespecified data cutoff (March 22, 2024), median follow-up (range) was 75.1 mo (65.9-84.0). 115 pts (14.7%) in the pembro group and 85 pts (21.8%) in the pbo group had died; the HR was 0.66 (95% CI, 0.50-0.87; P=0.0015), meeting the prespecified significance boundary of 0.00503. The 5-yr OS rate (95% CI) was 86.6% (84.0-88.8) vs 81.7% (77.5-85.2), respectively. The benefit of pembro on OS was generally consistent across prespecified subgroups, including those defined by PD-L1 expression and nodal status. The 5-yr EFS rate (95% CI) was 81.2% (78.3-83.8) in the pembro group vs 72.2% (67.4-76.4) in the pbo group (HR 0.65 [95% CI, 0.51-0.83]). Grade ≥3 treatment-related AE rates were 77.1% in the pembro group and 73.3% in the pbo group (death incidence, 0.5% vs 0.3%, respectively); immune-mediated AEs of any grade rates were 35.0% vs 13.1%, respectively.

Conclusions

Neoadjuvant pembro + chemo followed by adjuvant pembro showed a statistically significant and clinically meaningful improvement in OS compared with neoadjuvant chemotherapy alone in pts with high-risk early-stage TNBC.

Clinical trial identification

NCT03036488.

Editorial acknowledgement

Editorial assistance in the writing of the abstract was provided by Christine McCrary Sisk, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A.

Disclosure

P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Pfizer, Roche, Gilead, Eisai, MSD, Seagen, Lilly; Financial Interests, Institutional, Research Grant: AstraZeneca, Genentech, Roche. J. Cortés: Financial Interests, Personal, Advisory Board, consulting/advisor: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp& Dohme, Leuko, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, Scorpion Therapeutics, Bridgebio, Biocon, Biontech; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca, Gilead, Steamline Therapeutics; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, (relative): Leuko; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Queen Mary University of London, Iqvia; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca, Steamline Therapeutics; Other, travel cost and expenses: Merck Sharp&Dhome. R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly; Financial Interests, Personal and Institutional, Trial Chair: Roche; Financial Interests, Personal, Steering Committee Member: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. H.L. McArthur: Financial Interests, Personal, Advisory Board: Lilly, Pfizer, Immunomedics, Merck, Seattle Genetics, Daiichi Sankyo, Bristol Myers Squibb, AstraZeneca, Puma Biotechnology, Gilead, Crown Bioscience, Roche, Novartis, Genentech; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MedImmune, AstraZeneca, Merck. L. Pusztai: Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, Stemline-Menarini, GSK, Genentech/Roche, Personalis, Daiichi, Natera, Exact Sciences; Financial Interests, Institutional, Funding: Merck & Co., Inc., Pfizer, AstraZeneca Menarini; Financial Interests, Personal, Invited Speaker: Merck & Co., Inc.; Non-Financial Interests, Personal, Local PI: Merck & Co., Inc., Pfizer, AstraZeneca, Menarini; Non-Financial Interests, Personal, Principal Investigator: Merck & Co., Inc., Pfizer, AstraZeneca; Financial Interests, Institutional, Research Funding: Exact Sciences, Bristol Myers Squibb,; Financial Interests, Institutional, Research Grant: Exact Sciences, Bristol Myers Squibb,; Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, Stemline-Menarini, GSK, Genentech/Roche, Personalis, Daiichi, Natera, Exact Sciences; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Merck & Co., Inc.; Financial Interests, Personal, Trial Chair: Pfizer, Merck & Co., Inc.; Non-Financial Interests, Personal, Writing Engagement: Merck & Co., Inc.. S. Kummel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Seagen, Pfizer, Pfizer, Roche, Somatex, Gilead, Sanofi, Hologic, PINK; Financial Interests, Personal, Invited Speaker: ExactScience, MSD, Lilly, Gilead, Roche, Sanofi, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest, Minority Ownership: WSG Study Group; Financial Interests, Personal and Institutional, Coordinating PI: Roche, Novartis; Financial Interests, Institutional, Local PI: Roche, Novartis, Lilly, Somatex, AstraZeneca, MSD. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly, Diaceutics, VmScope digital pathology software; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Myriad, German Breast Group. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo, Helsinn; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Pfizer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. R. Hui: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Eisai, Merck, Oncosec, Amgen, Takeda, Zai Lab; Financial Interests, Personal, Invited Speaker: MSD, Novartis, AstraZeneca, Eli Lilly, Janssen; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Eli Lilly, Janssen, MSD, Novartis, Oncosec, Roche, Seagen, Corvus; Financial Interests, Personal, Steering Committee Member: MSD; Financial Interests, Steering Committee Member: AstraZeneca; Non-Financial Interests, Member: ASCO, IASLC, Medical Oncology Group of Australia (MOGA); Non-Financial Interests, Other, Member of IASLC Education Committee: IASLC. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Funding: BMS, Daiichi Sankyo, MSD, Roche, Seagen, TRIO, WSG, Gilead; Financial Interests, Institutional, Steering Committee Member: Lilly, Pierre Fabre; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. M. Takahashi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Pfizer, Eisai, Daiichi Sankyo, MSD. S. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pfizer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca, Hanmi, Novartis, Roche, Pfizer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. M. 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Zhao: Financial Interests, Personal, Full or part-time Employment, United States: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. X. Zhou: Financial Interests, Institutional, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Institutional, Stocks/Shares: Merck & Co., Inc.. K.E. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. G. Aktan: Financial Interests, Institutional, Full or part-time Employment: Merck & Co., Inc; Financial Interests, Institutional, Stocks/Shares: Merck & Co., Inc.. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Eisai, G1 Therapeutics, Lilly, Merck, Novartis, Pfizer, Puma, Roche, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi, BioNtech, Byondis, Dava Oncology, Fishawack Health, Genzyme, GSK, Genentech, Loxo Oncology, Seagen, Stemline Therapeutics, Taiho Oncology, Veru; Financial Interests, Personal, Other, Advisory Board: BioNTech, Duality.