Abstract OT1-18-06: KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer
Authors: Schmid Peter , Baccan Carlos , Guo Zifang , Tryfonidis Kostas , Rugo Hope S. 
Published: March 2022

Abstract
Background: For patients with HR+/HER2− advanced breast cancer who experience disease progression on endocrine therapy, cytotoxic chemotherapy (chemo) regimens are standard of care. Adding immunotherapy to chemo may improve patient outcomes. The anti-PD-1 antibody pembrolizumab (pembro) has demonstrated efficacy in patients with triple-negative breast cancer, including those with metastatic disease (KEYNOTE-355) and with early-stage disease (KEYNOTE-522). The phase 1b KEYNOTE-028 trial showed durable activity with pembro monotherapy among patients with previously treated HR+/HER2−, PD-L1-positive (ie, combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study comparing pembro plus chemo vs placebo plus chemo in patients with PD-L1-positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer who progressed on prior endocrine therapy. Methods: Approximately 800 patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer who are candidates for chemo (no prior chemo for metastatic disease) and who have a PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line plus CDK4/6 inhibitor treatment with relapse within 24 months of surgery in the adjuvant setting. Patients without CDK4/6 inhibitor treatment may enroll if they have progression within 6 months of starting endocrine therapy for metastatic disease and within 24 months of surgery while on adjuvant endocrine therapy. Patients are randomized 1:1 to receive pembro 200 mg IV or placebo Q3W, each in combination with investigator’s choice of 1 of 4 chemo regimens: paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or capecitabine 1000 mg/m2 PO BID on days 1-14 Q3W. Randomization is stratified by tumor PD-L1 expression (CPS 1-9 vs ≥10), visceral metastases (yes vs no), and chemo (taxanes vs liposomal doxorubicin vs capecitabine). Participants, investigators, and study personnel are blinded to treatment assignment and tumor PD-L1 status. Treatment is continued until radiographic disease progression, unacceptable toxicity, withdrawal, or, for pembro/placebo, completion of 35 administrations (~2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed every 9 weeks through the first 54 weeks and then every 12 weeks thereafter to detect evidence of progression. AEs occurring from randomization until 30 days after treatment discontinuation (90 days for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review in patients with PD-L1 CPS ≥10 and ≥1 tumors, separately. A key secondary endpoint is OS; additional secondary endpoints are investigator-assessed PFS, ORR, disease control rate, duration of response, and health-related quality of life using EORTC QLQ-C30 (each assessed in patients with PD-L1 CPS ≥10 and ≥1 tumors), as well as safety in the overall population. The family-wise type-I error rate is controlled at 0.025 (one-sided) across the PFS and OS endpoints. PFS and OS will be estimated using the Kaplan-Meier method. Treatment differences will be assessed using a stratified log-rank test, and HRs and 95% CIs will be determined using a stratified Cox proportional hazards model. Enrollment is ongoing.
Citation Format: Peter Schmid, Carlos Baccan, Zifang Guo, Kostas Tryfonidis, Hope S. Rugo. KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-06.