Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study

Abstract

Background: We evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients.

Methods: HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed.

Results: Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon's design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5-32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment.

Conclusion: Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit.

Trial registration: ClinicalTrials.gov and EudraCT (NCT03025880 and 2016-001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

Keywords: Advanced breast cancer; Chemotherapy; HER2-negative; MDSCs; PD-L1; Pembrolizumab; TILs.

Conflict of interest statement

L. de la Cruz-Merino received consulting or advisory role fees from Merck Sharp & Dohme (MSD)-Merck, Roche, Bristol-Myers-Squibb (BMS), Pierre-Fabre, Amgen, and Novartis; research funding from MSD-Merck, Roche, and Celgene; speaker’s honoraria from MSD-Merck, Roche, BMS, and Amgen; and grant support from Roche and BMS. M Gion received honoraria from Roche and traveled accommodation from Pfizer. J. Cruz received consulting or advisory role fees from Roche, PharmaMar, Lilly, Novartis, Eisai, Pfizer Amgen, and Celgene; travel accommodation from Roche, Novartis, and PharmaMar. V. Quiroga received speakers’ bureau honoraria from Pfizer, Novartis, and Roche; research funding from Celgene; and travel accommodation from Novartis, Roche, and Pfizer. F. Moreno received an advisory role honoraria from Pfizer, Roche, Novartis MSD, and AstraZeneca; speaker’s bureau honoraria and research funding from Pfizer; and travel accommodation from Pfizer, Roche, and Novartis. R. Andrés received travel accommodation from Roche. M. Santisteban received honoraria from Roche, Novartis, and Pfizer; and consulting or advisory role honoraria from Gilead, MSD, Novartis, Pfizer, and Biomerieux. M. Ramos received speakers’ bureau honoraria from Novartis, Roche, and Pfizer. J. Cortés has stock and other ownership interests in MedSIR and has received honoraria from Novartis, Eisai, Celgene, Pfizer, Roche, SAMSUNG, Lilly, MSD, and Daiichi Sankyo; consulting or advisory role honoraria from Celgene, Cellestia Biotech, AstraZeneca, Biothera, Merus, Roche, Seattle Genetics, Daiichi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, Servier, MSD, GlaxoSmithKline (GSK), Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, and Kyowa Kyrin; research funding from ARIAD, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai Farmaceutica, Guardanth health, MSD, Pfizer, Puma CO, Queen Mary University of London, Roche, and Piqur; and travel accommodation from Roche, Pfizer, Eisai, Novartis, and Daiichi Sankyo. E. López received consulting or advisory role honoraria from AstraZeneca, Pfizer, Roche, and Novartis; and the speaker’s bureau honoraria from Roche, Eisai, Pfizer, and Novartis. A. Cortés received consulting or advisory role honoraria from Lilly, Roche, Clovis, Ferrer, and Pfizer; speakers’ bureau honoraria from MSD, GSK, AstraZeneca, Roche and Pfizer, and research funding and travel accommodation from Pfizer. L. M. Rodríguez received honoraria from Pfizer and Pierre Fabre. I. Ceballos received consulting or advisory role honoraria from Roche and Merk KGaA; speakers’ bureau honoraria from Roche, Pfizer, BMS, and Celgene; and travel accommodation from Roche, Merck, Pfizer, and Novartis. F. Rojo received consulting or advisory role fees from Roche, AstraZeneca, Novartis, BMS, MSD, Lilly, Pfizer, Genomic Health, Guardant Health, Archer, and Pierre-Fabre; speaker bureau/expert testimony fees from Roche, AstraZeneca, Novartis, BMS, MSD, Lilly, Pfizer, and Pierre-Fabre; and travel accommodation from Roche and Novartis His institution received research grant/funding from Roche and Pfizer. The rest of authors declare no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1

Study flowchart

Fig. 2

Run-in phase design, patient inclusion, and DLTs

Fig. 3

Swimmer plot for the intention-to-treat population

Fig. 4

TILs density distribution according to tumor subtype and OR (yes/no)

Fig. 5

PD-L1 CPS distribution according to tumor subtype and OR (yes/no)

Fig. 6

Correlation of TILs density and PD-L1 expression

Fig. 7

Baseline median values of MDSCs in ABC patients and healthy cohort