Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study

Abstract

The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon's design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2-37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Keywords: MDSCs; PD-L1; TILs; biomarkers; breast cancer; immunotherapy; pembrolizumab; phase II; triple-negative.

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; speakers’ honoraria from MSD-Merck, Roche, BMS, and Amgen; and grant support from Roche and BMS. M Gion received honoraria from Roche and travel accommodation from Pfizer. J. Cruz received consulting or advisory role fees from Roche, PharmaMar, Lilly, Novartis, Eisai, Pfizer Amgen, Daichii, AstraZeneca, Seagen, GSK, 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. R. Andrés received travel accommodation from Roche. F. Moreno received advisory role honoraria from Pfizer, Roche, Novartis MSD, and AstraZeneca; speakers’ bureau honoraria and research funding from Pfizer; and travel accommodation from Pfizer, Roche, and Novartis. 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-Miranda received consulting or advisory role honoraria from AstraZeneca, Pfizer, Roche, and Novartis; and speakers’ bureau honoraria from Roche, Eisai, Pfizer, and Novartis; and travel accommodation from Roche, Novartis. 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; speakers’ 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 the authors declare no conflict of interest.

Figures

Figure 1

The best overall tumor response per each individual TNBC patient and its duration. (a) Waterfall plot. The waterfall plot presents each individual patient’s response to the study treatment based on the change of the sum of the target lesions diameters. The vertical bars are drawn from the baseline, either in the positive or negative direction to depict the change from baseline. Fourteen of the twenty patients analyzed as part of the efficacy population are represented (three patients did not have any tumor response after the beginning of the study treatment as explained in the efficacy section, and the other three patients did not have any change to be represented: two patients progressed with the development of new lesions and another patient had clinical PD). (b) Swimmer plot. The swimmer plot shows multiple pieces of each individual patient’s response; the graph includes a bar showing the length of treatment duration and indicators for the start (triangle) and end (circle) of each response episode, classified by a partial response (blue line), stable disease (green line) or progressive disease (dark yellow line), as well as an indicator showing whether the patient is a durable responder (black square) and whether the patient is still on the corresponding response (lying down triangle). In this graphic, the twenty-one TNBC patients are considered as the intention-to-treat population, however, the three patients without tumor response assessment after the beginning of the study treatment are not included.

Figure 2

Baseline median values of MDSCs (G-, M-, total; cells/µL) comparison between ABC TN patients and healthy cohort. * Wilcoxon–Mann–Whitney test. Abbreviations: MDSCs = myeloid derived suppressor cells; M-MDSCs = monocytic MDSCs; G-MDSCs = granulocytic MDSCs; ABC = advance breast cancer; TN= triple-negative; HC = healthy cohort.