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Clinical Trial
. 2025 May 15;31(10):1885-1893.
doi: 10.1158/1078-0432.CCR-24-3001.

Pembrolizumab in Combination with Binimetinib in Patients with Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer

Saranya Chumsri  1 , Joseph J Larson  2 , Emily Liu  2 , Kathleen S Tenner  2 , Daniel Adams  3 , Morgan T Weidner  1 , Amanda N Arnold  1 , Dana L Haley  1 , Pooja Advani  1 , Kostandinos Sideras  1 , Alvaro Moreno-Aspitia  1 , E Aubrey Thompson  4 , Edith A Perez  1 , Keith L Knutson  4   5
Affiliations
Clinical Trial

Pembrolizumab in Combination with Binimetinib in Patients with Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer

Saranya Chumsri et al. Clin Cancer Res. .

Abstract

Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors.

Patients and methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1.

Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4-69.0 months). Patients with PD-L1-positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1-negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib.

Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

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Conflict of interest statement

S. Chumsri reports grants from Merck & Co. and Pfizer during the conduct of the study, as well as personal fees from Novartis, AstraZeneca, Daiichi Sankyo, Genentech, Puma Biotechnology, Eisai, and Seagen outside the submitted work. D. Adams reports other support from Creatv MicroTech during the conduct of the study, as well as other support from Creatv MicroTech outside the submitted work and a patent for Provisional Filed pending to Creatv MicroTech. P. Advani reports other support from AstraZeneca, DSI, Pfizer/Seagen, Atossa Therapeutics, Modulation Therapeutics, Biovica, Loxo Lilly, Sermonix, Gilead, Menarini Stemline, Puma, and Elephas and personal fees from Biovica, DSI, AstraZeneca, Hesian labs, Elephas, GE HealthCare, Guardant, Menarini, Breathe BioMedical, and MJH Life Sciences outside the submitted work. K.L. Knutson reports nonfinancial support from Merck outside the submitted work, as well as a patent for PCT/US24/12603 pending. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Phase I CONSORT diagram showing the distribution of patients in the phase I portion of the trial. Thirteen patients were included in the phase I portion of this trial, including five patients treated at DL 0 and eight patients treated at DL 1. Four patients were evaluable for AE at DL 0, but one patient did not complete cycle 1 and was replaced. Two of three patients developed DLT. Therefore, eight subsequent patients were treated with DL −1. No DLT was observed in the first three-patient cohort (group 2A). Five additional patients were enrolled in DL −1 (group 2B). Two patients were not evaluable for DLT and were replaced. One of three patients in this group developed DLT.
Figure 2.
Figure 2.
Outcomes of patients treated with pembrolizumab in combination with binimetinib. A, Swimmer plot of tumor burden changes over time with pembrolizumab in combination with binimetinib. CR, complete response; PD, disease progression. B, Kaplan–Meier curve of PFS among evaluable patients. C, Kaplan–Meier curve of OS among evaluable patients.
Figure 3.
Figure 3.
A, Box plot of PD-L1 expression in the baseline tumor tissue according to ORR showing higher PD-L1 expression in patients who achieved complete response or PR. B, Box plot of sTILs in the baseline tumor tissue according to ORR showing no significant association between sTILs and ORR. CR, complete response; PD, disease progression.
See this image and copyright information in PMC

References

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