Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer

Ami N Shah, Lisa Flaum, Irene Helenowski, Cesar A Santa-Maria, Sarika Jain, Alfred Rademaker, Valerie Nelson, Dean Tsarwhas, Massimo Cristofanilli, William Gradishar, Ami N Shah, Lisa Flaum, Irene Helenowski, Cesar A Santa-Maria, Sarika Jain, Alfred Rademaker, Valerie Nelson, Dean Tsarwhas, Massimo Cristofanilli, William Gradishar

Abstract

Background: Response rates to single agent immune checkpoint blockade in unselected pretreated HER2-negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy.

Methods: We conducted a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. The primary end point was median progression-free survival (mPFS) compared with historic controls and secondary end points were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2-month improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone.

Results: Thirty patients, 16 TN and 14 HR+ MBC, were enrolled from 2017 to 2018. Patients had a median age of 51 years and received a median of 1 (range 0-6) prior lines of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.0 (95% CI 2.0 to 6.4) months and was not significantly longer than historic controls of 3 months. The median overall survival was 15.4 (95% CI 8.2 to 20.3) months. The ORR was 14% (n=4), stable disease (SD) was 41% (n=12) and clinical benefit rate (CBR=partial response+SD>6 months) was 28% (n=8). The ORR and CBR were not significantly different between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and HR+, respectively). The 1-year PFS rate was 20.7% and three patients have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases.

Conclusions: Compared with historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control.

Trial registration number: NCT03044730.

Keywords: breast neoplasms; immunology; oncology; programmed cell death 1 receptor.

Conflict of interest statement

Competing interests: No, there are no competing interests.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
(A) Progression-free (PFS) and (B) overall survival (OS) in all patients and by breast cancer subtype. ER+, endocrine-refractory-positive; HR+, hormonereceptor-positive endocrine-refractory; TNBC, triple negative breast cancer.
Figure 2
Figure 2
Response to capecitabine and pembrolizumab by RECIST V.1.1 criteria. HR+, hormonereceptor-positive endocrine-refractory; TN, triple negative.

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