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Randomized Controlled Trial
. 2023 Nov 1;6(11):e2342107.
doi: 10.1001/jamanetworkopen.2023.42107.

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Masato Takahashi  1 , Javier Cortés  2   3   4 , Rebecca Dent  5 , Lajos Pusztai  6 , Heather McArthur  7 , Sherko Kümmel  8   9 , Carsten Denkert  10 , Yeon Hee Park  11 , Seock-Ah Im  12 , Jin-Hee Ahn  13 , Hirofumi Mukai  14 , Chiun-Sheng Huang  15 , Shin-Cheh Chen  16 , Min Hwan Kim  17 , Liyi Jia  18 , Xin Tong Li  18 , Konstantinos Tryfonidis  18 , Vassiliki Karantza  18 , Hiroji Iwata  19 , Peter Schmid  20
Affiliations
Randomized Controlled Trial

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Masato Takahashi et al. JAMA Netw Open. .

Abstract

Importance: In the phase 3 KEYNOTE-522 study, addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly increased pathologic complete response (pCR) and event-free survival (EFS) vs neoadjuvant chemotherapy in patients with early triple-negative breast cancer.

Objective: To evaluate efficacy and safety outcomes for patients enrolled in East/Southeast Asia (Asia) in KEYNOTE-522.

Design, setting, and participants: KEYNOTE-522, a multicenter, double-blind, randomized clinical trial, enrolled 1174 patients between March 7, 2017, and September 13, 2018. For interim EFS and overall survival (OS) analyses (data cutoff, March 23, 2021), median follow-up was 39.8 months (range, 30.4-46.9 months) for pembrolizumab plus chemotherapy and 40.8 months (range, 30.1-46.9 months) for placebo plus chemotherapy. Data cutoff for pCR analysis was September 24, 2018. This secondary analysis included adults enrolled in Asia with newly diagnosed, previously untreated, nonmetastatic triple-negative breast cancer (tumor stage T1c and nodal stage N1-2 or tumor stage T2-4 and nodal stage N0-2) and Eastern Cooperative Oncology Group performance status of 0 to 1, regardless of programmed cell death ligand 1 (PD-L1) status.

Intervention: Patients were randomized 2:1 to 4 cycles of pembrolizumab (200 mg every 3 weeks) or placebo plus carboplatin and paclitaxel and another 4 cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide before surgery. After definitive surgery, patients received pembrolizumab or placebo every 3 weeks for 9 cycles or until recurrence or unacceptable toxic effects.

Main outcomes and measures: The main outcome was pCR (no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy) at the time of definitive surgery and EFS.

Results: A total of 216 of 1174 randomized patients (all female; median [range] age, 46.0 [24.0-71.0] years) were from Korea, Japan, Taiwan, and Singapore (136 in the pembrolizumab plus chemotherapy group and 80 in the placebo plus chemotherapy group). Of these patients, 104 (76.5%) in the pembrolizumab plus chemotherapy group and 60 (75.0%) in the placebo plus chemotherapy group had a tumor PD-L1 combined positive score of 1 or greater. Pathologic complete response was 58.7% (95% CI, 46.7%-69.9%) with pembrolizumab plus chemotherapy and 40.0% (95% CI, 26.4%-54.8%) with placebo plus chemotherapy; benefit was observed regardless of PD-L1 status. Thirteen patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 patients (25.0%) in the placebo plus chemotherapy group had EFS events (hazard ratio, 0.35; 95% CI, 0.17-0.71). The 36-month EFS rate was 91.2% (95% CI, 85.0%-94.9%) with pembrolizumab plus chemotherapy and 77.2% (95% CI, 66.3%-85.0%) with placebo plus chemotherapy. Grade 3 to 4 treatment-related adverse events occurred in 109 patients (80.1%) receiving pembrolizumab plus chemotherapy and 64 patients (81.0%) receiving placebo plus chemotherapy.

Conclusions and relevance: In this subgroup analysis of patients enrolled in Asia in KEYNOTE-522, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements in pCR and EFS vs neoadjuvant chemotherapy alone. These findings support the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a standard-of-care therapy for patients in Asian countries with early triple-negative breast cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT03036488.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Takahashi reported receiving nonfinancial support from Merck & Co Inc during the conduct of the study and personal fees from AstraZeneca, Eli Lilly, Pfizer, and Eisai and grants from Eisai, Kyowa-Hakko Kirin, Nippon Kayaku, and Taiho outside the submitted work. Dr Cortés reported receiving personal fees from Merck Sharp & Dhome LLC, a subsidiary of Merck & Co Inc, Rahway, New Jersey (MSD), during the conduct of the study and personal fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipeses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, AbbVie, Novartis, Eisai, Pfizer, and Samsung Bioepis, receiving grants from Ariad Pharmaceuticals, Baxalta GMBH/Servier Affaires, Bayer HealthCare, Guardant, Piqur Therapeutics, Iqvia, and Queen Mary University of London, and having capital stock in MAJ3 outside the submitted work; in addition, Dr Cortés had patents for pharmaceutical combinations of a Pi3k inhibitor and microtubule destabilizing agent and for HER2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Dr Dent reported receiving personal fees from MSD, AstraZeneca, Roche, Novartis, Pfizer, and DKSH during the conduct of the study and receiving personal fees from MSD, AstraZeneca, Roche, Novartis, Pfizer, and DKSH outside the submitted work. Dr Pusztai reported receiving personal fees from Merck & Co Inc during the conduct of the study and receiving consulting fees for advisory board participation from Pfizer, AstraZeneca, Novartis, Bristol Myers Squibb, Stemline-Menarini, GSK, Genentech/Roche, Personalis, Daiichi Sankyo, Natera, and Exact Sciences. Dr McArthur reported receiving personal fees and grants from MSD outside the submitted work. Dr Kümmel reported receiving personal fees from Roche, AstraZeneca, Eli Lilly, Pfizer, Gilead, Stryker, Novartis, Somatex, Exact Science, Agendia, Daiichi Sankyo, MSD, and Seagen and travel support from Eli Lilly, Roche, and Daiichi Sankyo during the conduct of the study and having leadership or fiduciary roles with Arbeitsgemeinschaft Gynäkologische Onkologie, European Society for Medical Oncology, and West German Study Group outside the submitted work. Dr Denkert reported receiving personal fees from MSD Oncology during the conduct of the study and personal fees from Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Eli Lilly, and Diaceutics and grants from European Commission, German Cancer Aid Translational Oncology, and German Breast Group outside the submitted work; in addition, Dr Denkert had a patent for VNscope digital pathology with royalties paid, a patent for WO2020109570A1 pending, a patent for WO2015114146A1 pending, and a patent for WO2010076322A1 pending. Dr Park reported receiving nonfinancial support from MSD during the conduct of the study and grants from Pfizer, AstraZeneca, Roche, Novartis, Genomie Insight, and NGenBio, personal fees from AstraZeneca, Roche, Novartis, Eli Lilly, and Daiichi Sankyo, and nonfinancial support from Pfizer, Roche, Novartis, Daiichi Sankyo, Eisai, and Gilead outside the submitted work. Dr Im reported having an advisory role with MSD during the conduct of the study and receiving grants from AstraZeneca, Daewoong Pharm, Boryung Pharm, Eisai, Pfizer, and Roche and having advisory roles with AstraZeneca, Hanmi, Bertis, Novartis, Eli Lilly, Pfizer, Roche, and Daiichi Sankyo outside the submitted work. Dr Mukai reported receiving grants from MSD during the conduct of the study. Dr Huang reported receiving grants from MSD during the conduct of the study and grants from AstraZeneca, Daiichi Sankyo, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, Novartis, Seagen, Gilead, and Aston Sci, personal fees from AstraZeneca, Daiichi Sankyo, EirGenix, Eli Lilly, Pfizer, Roche, Novartis, and Gilead, and nonfinancial support from AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, and Novartis outside the submitted work. Dr Jia reported receiving personal fees from Merck & Co Inc for full-time employment and stock outside the submitted work. Dr Li reported being an employee of the Merck Research Lab during the conduct of the study and outside the submitted work. Dr Tryfonidis reported being an employee of MSD, and holding stock/stock options in Merck & Co Inc during the conduct of the study. Dr Karantza reported being an employee of MSD and holding stock/stock options in Merck & Co Inc during the conduct of the study and outside the submitted work. Dr Iwata reported receiving grants from MSD during the conduct of the study and personal fees from MSD, Daiichi Sankyo, Chugai, AstraZeneca, Pfizer, Taiho, Eisai, and Kyowa Kirin and grants from AstraZeneca, Pfizer, and Daiichi Sankyo outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Disposition and Analysis Populations: Subgroup of Patients Enrolled in Asia
AC indicates doxorubicin-cyclophosphamide; AE, adverse event; EC, epirubicin-cyclophosphamide; and EFS, event-free survival. aPatients did not have to complete all neoadjuvant therapy to undergo surgery. bIncludes all patients who received at least 1 dose of study treatment or underwent surgery.
Figure 2.
Figure 2.. Pathologic Complete Response (pCR) in the Overall Subgroup of Patients Enrolled in Asia and by Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS)
Pathologic complete response was defined as no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy. Data cutoff date was September 24, 2018.
Figure 3.
Figure 3.. Event-Free Survival (EFS) in the Overall Subgroup of Patients Enrolled in Asia and by Pathologic Complete Response (pCR)
Pathologic complete response was defined as no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy. Data cutoff date was March 23, 2021.
See this image and copyright information in PMC

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