1812 - KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Clinical trial identification

NCT03036488.

Editorial acknowledgement

Writing assistance was provided by Christine McCrary Sisk and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

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

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.