VP7_2021 - KEYNOTE-522: Phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer (TNBC)

Abstract

P. Schmid¹, J. Cortes², R. Dent³, L. Pusztai⁴, H. McArthur⁵, S. Kümmel⁶, J. Bergh⁷, C. Denkert⁸, Y.H. Park⁹, R. Hui¹⁰, N. Harbeck¹¹, M. Takahashi¹², M. Untch¹³, P.A. Fasching¹⁴, F. Cardoso¹⁵, Y. Ding¹⁶, K. Tryfonidis¹⁷, G. Aktan¹⁷, V. Karantza¹⁷, J. O’Shaughnessy^18
1Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University London, London, UK, ²International Breast Cancer Center, Quirón Group, Madrid and Barcelona, Spain, and Vall d'Hebron Institute of Oncology, Barcelona, Spain, ³National Cancer Center Singapore, Duke–National University of Singapore Medical School, Singapore, ⁴Yale School of Medicine, Yale Cancer Center, New Haven, CT, USA, ⁵Breast Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA, ⁶Breast Unit, Kliniken Essen-Mitte, Essen, Germany, ⁷Department of Oncology-Pathology, Karolinska Institutet and Breast Cancer Centre, Cancer Theme, Karolinska University Hospital, Solna, Sweden, ⁸Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, Germany, ⁹Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, ¹⁰Westmead Breast Cancer Institute, Westmead Hospital and the University of Sydney, Sydney, NSW, Australia, ¹¹Breast Center, LMU University Hospital, Munich, Germany, ¹²Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan, ¹³Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin, Germany, ¹⁴University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany, ¹⁵Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal, ¹⁶Biostatistics, Merck & Co., Inc., Kenilworth, NJ, USA, ¹⁷Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA, ¹⁸Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, USA

Background: KEYNOTE-522 (NCT03036488) is a phase III study of neoadjuvant pembrolizumab (pembro) + chemotherapy (chemo) vs. placebo (pbo) + chemo followed by adjuvant pembro vs. pbo in patients (pts) with early-stage TNBC. In prior interim analyses, pembro + chemo showed a significant improvement in pCR and a favorable trend in EFS. We present results from a prespecified interim analysis of KEYNOTE-522.

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 neoadjuvant pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin, then with 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. Pts were stratified by nodal status (+ vs. -), tumor size (T1/T2 vs. T3/T4), and carboplatin schedule (Q3W vs. QW). Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS.

Results: 1174 pts were randomized to pembro (n=784) or pbo (n=390). At the March 23, 2021 data cutoff (median follow-up, 37.8 mo [range, 2.7-48.0]), 123 pts (15.7%) in the pembro group and 93 pts (23.8%) in the pbo group had an EFS event, defined as disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR 0.63 [95% CI, 0.48-0.82]; P=0.0003). The 36-mo EFS rate was 84.5% (95% CI, 81.7-86.9) in the pembro group vs. 76.8% (95% CI, 72.2-80.7) in the pbo group; median was not reached in either group. The most common EFS event was distant recurrence, in 60 pts (7.7%) in the pembro group vs. 51 pts (13.1%) in the pbo group. Pembro showed a favorable trend in OS (HR 0.72 [95% CI, 0.51-1.02]); follow-up is ongoing. 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 occurred in 43.6% vs. 21.9%, respectively.

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

Clinical trial identification: NCT03036488.

Editorial acknowledgement: Medical writing and/or editorial assistance was provided by Christine McCrary Sisk. This assistance was 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: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure:
P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca; Bayer; Boehringer Ingelheim; Merck; Novartis; Pfizer; Puma; Roche; Eisai; Celgene; Financial Interests, Personal, Other, Spouse: Roche; Financial Interests, Institutional, Research Grant: Astellas; AstraZeneca; Genentech; Novartis; Oncogenex; Roche; Medivation.
J. Cortes: Financial Interests, Personal, Invited Speaker: Roche; Novartis; Celgene; Eisai; Pfizer; Samsung Bioepis; Lilly; Merck Sharp & Dohme; Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Roche; Celgene; Cellestia; AstraZeneca; Biothera Pharmaceutical; Merus; Seattle Genetics; Daiichi Sankyo; Erytech; Athenex; Polyphor; Lilly; Servier; Merck Sharp & Dohme; GSK; Leuko; Bioasis; Clovis Oncology; Boehringer Ingelheim; Kyowa Kirin; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche; Ariad Pharmaceuticals; AstraZeneca; Baxalta GMBH/Servier Affaires; Bayer Healthcare; Merck Sharp & Dohme; Pfizer; Piqur Therapeutics; Puma C; Queen Mary University of London; F. Hoffman-La Roche; Guardant Health; Eisai; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Roche; Novartis; Eisai; Pfizer; Daiichi Sankyo.
R. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca; Eisai; Eli Lilly; Genentech; Merck; Novartis; Pfizer; Financial Interests, Personal, Other, Consultant: Genentech; Financial Interests, Personal, Other, Travel expenses: Genentech; Merck; Pfizer.
L. Pusztai: Financial Interests, Personal, Advisory Board: Seagen; Pfizer; AstraZeneca; Merck; Novartis; Bristol-Myers Squibb; Genentech; Eisai; Pieris; Immunomedics; Clovis; Syndax; H3Bio; Radius Health; Daiichi; Non-Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Non-Financial Interests, Institutional, Principal Investigator: Merck; Pfizer; AstraZeneca; Seagen.
H. McArthur: Financial Interests, Personal, Advisory Board: Amgen; Bristol-Myers Squibb; Eli Lilly; Genentech/Roche; Immunomedics; Merck; Pfizer; Puma; Daiichi Sankyo; Seattle Genetics; AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; MedImmune; AstraZeneca; BTG; Merck.
S. Kümmel: Financial Interests, Personal and Institutional, Invited Speaker: Roche; Genomic Health; Exact Science; Seagen; Novartis; Amgen; Celgene; Daiichi Sankyo; AstraZeneca; Somatex/Hologic; MSD; Pfizer; PFM Medical; Lilly; Financial Interests, Personal and Institutional, Advisory Board: Roche; Genomic Health; Exact Science; Seagen; Novartis; Amgen; Celgene; Daiichi Sankyo; AstraZeneca; Somatex/Hologic; MSD; Pfizer; PFM Medical; Lilly; Non-Financial Interests, Personal, Member of the Board of Directors: WSG - Westdeutsche Studiengruppe - co Director; Financial Interests, Institutional, Research Grant: Somatex/Hologic; Financial Interests, Personal and Institutional, Principal Investigator: Roche; Novartis; Somatex/Hologic; Non-Financial Interests, Personal, Member: ESMO; ASCO; DGS; DGGG; WSG; AGO; AGImed; Non-Financial Interests, Personal, Member of the Board of Directors: AGO.
J. Bergh: Other, Institutional, Invited Speaker, Agreement with Karolinska Institutet: AstraZeneca; Roche; Non-Financial Interests, Institutional, Member of the Board of Directors: Karolinska Comprehensive Cancer Center; Cancer Core Europe; Cancer Research Karolinska Institutet; Financial Interests, Personal, Full or part-time Employment: Karolinska Institutet; Karolinska University Hospital, Karolinska CCC; Financial Interests, Personal and Institutional, Ownership Interest: Asklepios Medicin HB; Financial Interests, Institutional, Royalties, For participation in writing for UpToDate: Asklepios Medicin HB; Financial Interests, Institutional, Research Grant, Prior to last 3 years: AstraZeneca; Amgen; Bayer; Merck; Pfizer; Roche; Sanofi-Aventis; Financial Interests, Institutional, Funding: Swedish Cancer Society; Cancer Society in Stockholm; Knut and Alice Wallenberg Society; Swedish Research Council; Financial Interests, Institutional, Principal Investigator: Prospective academic studies; Non-Financial Interests, Personal and Institutional, Member: ASCO; AACR; ESMO; Nobel Assembly; Non-Financial Interests, Personal and Institutional, Member, Founding member: ECCO Academy; Non-Financial Interests, Personal and Institutional, Member, Fellow: Royal College of Physicians; Non-Financial Interests, Personal and Institutional, Member, Adjunct member: Nobel Committee; Non-Financial Interests, Personal and Institutional, Affiliate, Visiting Professor: Oxford University; Non-Financial Interests, Personal and Institutional, Advisory Role: European Medicines Agency; Swedish Medicine Products Agency; Non-Financial Interests, Institutional, Leadership Role: Cancer Research KI.
C. Denkert: Financial Interests, Personal, Advisory Board, (Oncology): MSD; Daiichi Sankyo; Molecular Health; AstraZeneca; Merck; Novartis; Roche; Financial Interests, Personal, Ownership Interest, (until 2016): Sividon Diagnostics; Financial Interests, Personal, Royalties: VMscope digital pathology software; Financial Interests, Institutional, Funding: Myriad; Roche; GBG.
Y.H. Park: Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Pfizer; Roche; Novartis; Merck; Financial Interests, Institutional, Research Grant: AstraZeneca; Pfizer; Roche; Merck; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca; Pfizer; Roche; Daiichi Sankyo; Novartis; Merck; Financial Interests, Personal, Other, Speaker fee: Roche; Novartis; Non-Financial Interests, Personal, Other, Medical writing support: F. Hoffmann-La Roche Ltd.
R. Hui: Financial Interests, Personal, Invited Speaker: MSD; Novartis; AstraZeneca; Roche; Non-Financial Interests, Personal, Writing Engagements: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; BMS; Eli Lilly; Merck; MSD; Novartis; Oncosec; Pfizer; Roche; Seagen.
N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca; Daiichi Sankyo; Lilly; MSD; Novartis; Pfizer; Pierre Fabre; Roche; Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca; Daiichi Sankyo; Lilly; MSD; Novartis; Pfizer; Pierre Fabre; Roche; Sandoz/Hexal; Seagen; Non-Financial Interests, Personal, Officer: ESMO Guideline Committee; Financial Interests, Personal, Full or part-time Employment: LMU University Hospital; Financial Interests, Personal, Ownership Interest: WSG; Non-Financial Interests, Personal, Member: AGO, Germany; ESO/ESCO.
M. Takahashi: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Eli Lilly; Eisai; Pfizer.
M. Untch: Financial Interests, Institutional, Invited Speaker: AstraZeneca; Celgene; Amgen; Pfizer; Roche; Lilly; Daiichi Sankyo; Mylan; Novartis; MSD; Seagen; Pierre Fabre; GSK; Financial Interests, Personal, Writing Engagements: AstraZeneca GmbH; Daiichi Sankyo; Exact Sciences Deutschland; Lilly; Mylan Germany; Pierre Fabre; Veracyte, Inc; Financial Interests, Institutional, Advisory Board: AbbVie; AstraZeneca; Celgene; Amgen; Pfizer; Roche; Lilly; GSK; Daiichi Sankyo; Novartis; MSD; Seagen; Celgene; Pierre Fabre; Agendia; Mylan; Financial Interests, Institutional, Advisory Role: AbbVie; AstraZeneca; Celgene; Amgen; Pfizer; Roche; Lilly; GSK; Daiichi Sankyo; Novartis; MSD; Seagen; Pierre Fabre; Agendia.
P.A. Fasching: Financial Interests, Personal, Advisory Board: Agendia; AstraZeneca; Daiicho Sankyo; Eisai; Hecal; Lilly; Merck Sharp & Dohme; Novartis; Pfizer; Pierre Fabre; Roche; Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Daiichi Sankyo; Eisai; Lilly; Merck Sharp & Dohme; Novartis; Seagen; Non-Financial Interests, Institutional, Principal Investigator: BionTech; Cepheid; Non-Financial Interests, Personal, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.v.; ASCO; Deutsche Gesellschaft für Senologie e.v.; Translational Research in Oncology.
F. Cardoso: Financial Interests, Personal, Advisory Board: Amgen; Astellas/Medivation; AstraZeneca; Celgene; Daiichi Sankyo; Eisai; GE Oncology; Genentech; GlaxoSmithKline; Macrogenics; Medscape; Merck Sharp & Dohme; Merus BV; Mundipharma; Mylan Pharmaceuticals Inc.; Novartis Pharma; Pfizer; Pierre Fabre; prIME Oncology; Roche; Samsung Bioepis; Sanofi; Seattle Genetics; Teva Pharmaceutical Industries.
Y. Ding: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
K. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
G. Aktan: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
V. Karantza: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
J. O’Shaughnessy: Financial Interests, Personal, Speaker’s Bureau: Lilly; Pfizer; Seagen; Financial Interests, Personal, Advisory Board: AbbVie Inc.; Agendia; Amgen Biotechnology; Aptitude Health; AstraZeneca; Bayer; Bristol-Myers Squibb; Celgene Corporation; Clovis Oncology; Daiichi Sankyo; Eisai; G1 Therapeutics; Genentech; Gilead Sciences; GRAIL; Halozyme Therapeutics; Heron Therapeutics; Immunomedics; Ipsen Biopharmaceuticals; Lilly; Merck; Myriad; Nektar Therapeutics; Novartis; Pfizer; Pharmacyclics; Pierre Fabre Pharmaceuticals; Puma Biotechnology; Prime Oncology; Roche; Samsung Bioepis; Sanofi; Seagen; Syndax Pharmaceuticals; Taiho Oncology; Takeda; Synthon.