Neoadjuvant pembro + chemo had manageable safety and promising antitumor activity in participants (pts) with early TNBC in KEYNOTE-173 and I-SPY 2. KEYNOTE-522 (NCT03036488) is a pbo controlled phase III study of neoadjuvant pembro + chemo followed by adjuvant pembro in pts with early TNBC.
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 pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin, then with 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Pts were stratified by nodal status (+ vs -), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (Q3W vs QW). Dual primary endpoints were pCR defined as ypT0/Tis ypN0 and event-free survival (EFS). Secondary endpoints included pCR defined as ypT0 ypN0 and ypT0/Tis, OS, and efficacy in the PD-L1+ population.
Median follow-up was 15.5 mo (range, 2.7-25.0). 784 pts were randomized to pembro, 390 to pbo. Among 602 pts evaluable for the definitive pCR analysis, pembro + chemo showed a statistically significant improvement in pCR (ypT0/Tis ypN0) vs pbo + chemo: 64.8% (95% CI, 59.9-69.5) vs 51.2% (95% CI, 44.1-58.3), P = 0.00055; results were consistent for the secondary pCR definitions, ypT0 ypN0 (59.9% vs 45.3%) and ypT0/Tis (68.6% vs 53.7%). For pembro vs pbo, pCR (ypT0/Tis ypN0) was 68.9% vs 54.9% in the PD-L1+ population and 45.3% vs 30.3% in the PD-L1- population. The addition of pembro to chemo followed by pembro showed a favorable trend in EFS (HR 0.63 [95% CI, 0.43-0.93]). Across phases, grade 3 or higher treatment-related AE rates were 78.0% in the pembro + chemo group and 73.0% in the pbo + chemo group (death incidence, 0.4% vs 0.3%, respectively).
Addition of pembro to neoadjuvant chemo significantly increased the pCR rate in pts with early TNBC. Neoadjuvant pembro + chemo followed by adjuvant pembro showed a favorable trend in EFS. AEs were consistent with the known safety profiles of each agent.
NCT03036488.
Writing assistance was provided by Christine McCrary Sisk and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
P. Schmid: Honoraria (self): Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Advisory / Consultancy: Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Research grant / Funding (institution): AZ, Genetech, Roche, Oncogenex, Novaris, Astellas; Spouse / Financial dependant: Spouse is a consultant for Genetech/Roche. J. Cortés: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharpe & Dohme; Advisory / Consultancy: Cellestia; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biothera Pharmaceuticals; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Advisory / Consultancy: Servier; Research grant / Funding (institution): Ariad Pharmaceuticals; Research grant / Funding (institution): Baxalta GMBH/Servier Affaires; Research grant / Funding (institution): Bayer Healthcare; Research grant / Funding (institution): Guardian Health; Research grant / Funding (institution): Piqur Therapeutics ; Research grant / Funding (institution): Puma C; Research grant / Funding (institution): Queen Mary University of London; Research grant / Funding (institution): Seagen; Shareholder / Stockholder / Stock options: MedSIR. R. Dent: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. L. Pusztai: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pieris; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Almac; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Syndax. H.L. McArthur: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Spectrum Pharm; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Puma Biotechnology. S. Kuemmel: Advisory / Consultancy: F. Hoffmann-La Roche Ltd; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Somatex; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma Biotechnology; Advisory / Consultancy: PFM Medical; Advisory / Consultancy: Lilly; Research grant / Funding (institution): WSG; Travel / Accommodation / Expenses: Roche Pharma. J. Bergh: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi Aventis. C. Denkert: Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen ; Advisory / Consultancy: MSD; Advisory / Consultancy: Daiichi Sankyo; Shareholder / Stockholder / Stock options: Sividon (Myriad); Licensing / Royalties: VmScope. Y.H. Park: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Research grant / Funding (self): AstraZeneca. R. Hui: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Eli Lilly. N. Harbeck: Honoraria (institution): only research grants; Advisory / Consultancy: Agendia; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Odonate; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Sandoz/Hexal; Advisory / Consultancy: Seattle Genetics; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Nanostring; Leadership role: German AGO Breast Committee; Research grant / Funding (institution): several phase II-III trials; Shareholder / Stockholder / Stock options: CO-Director West German Study Group; Full / Part-time employment: LMU Munich; Spouse / Financial dependant: West German Study Group. M. Takahashi: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly ; Honoraria (self), Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Research grant / Funding (self): Kyowa-Hakko Kirin; Research grant / Funding (self): Nippon Kayaku . T. Foukakis: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Research grant / Funding (institution): Pfizer; Licensing / Royalties: Wolters Kluwer Health (UpToDate). P.A. Fasching: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy: TEVA; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp&Dohme; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics; Honoraria (self), Advisory / Consultancy: Macrogenics; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Puma; Honoraria (institution), Research grant / Funding (institution): Biontech; Honoraria (institution), Research grant / Funding (institution): Cepheid. F. Cardoso: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Astellas/Medivation; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Daiichi-Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: GE Oncology; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Macrogenics; Advisory / Consultancy: Medscape; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Merus BV; Advisory / Consultancy: Mylan; Advisory / Consultancy: Mundipharma; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Pierre-Fabre; Advisory / Consultancy: prIME Oncology; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Teva; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Fresenius GmbH; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Nerviano; Research grant / Funding (institution): Medigene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Sonus; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tigris; Research grant / Funding (institution): Wilex; Research grant / Funding (institution): Wyeth; Officer / Board of Directors: ESMO Board of Directors. L. Jia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. V. Karantza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. Zhao: Full / Part-time employment: Merck & Co., Inc.. G. Aktan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. O’Shaughnessy: Honoraria (self): AbbVie Inc; Honoraria (self): Agendia; Honoraria (self): Amgen Biotechnology; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene Corporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeautics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Puma Biotechnology; Honoraria (self): Prime Oncology; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Syndax Pharmaceuticals.