Reis, Aline

Abstract Background: A previous neoadjuvant study in patients with triple negative breast cancer (TNBC) demonstrated that low tumor infiltrating lymphocytes (TILs) after neoadjuvant chemotherapy is associated with a poor outcome. Activation of RAS/MAPK pathway has been associated with reduced TILs. Preclinical studies showed that MEK inhibitor enhances immune responses and is synergistic with anti PD-1/PD-L1 therapy in TNBC. Methods: The standard Phase I 3+3 study design was used. Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Patients received single agent binimetinib for 2 weeks prior to an addition of pembrolizumab. Dose level 0 was binimetinib at 45 mg oral twice daily continuously and dose level -1 was 30 mg twice daily. Pembrolizumab was given at a fixed dose of 200 mg every 3 weeks in both dose levels. The maximum tolerated dose (MTD) was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) during the first 2 cycles in at least one-third of patients. Results: A total of 12 evaluable patients were enrolled in the phase I, 4 patients in dose level 0 and 8 patients in dose level -1. In dose level 0, among 3 out of 4 patients who were evaluable for DLT, 2 patients experienced DLTs, including grade (G) 3 nausea, vomiting, abdominal pain and G3 ALT elevation. Thus, the stopping rule was met and the dose level was adjusted to dose level -1. None of the first 3 patients in dose level -1 experienced a DLT. All three experienced other ≥ G3 AEs, including 1 G3 cardiac troponin T increased and 2 with G3 hypertension. 5 additional patients were accrued to dose level -1 and were evaluable for AEs. Three of these were evaluable for DLTs. One patient had G3 ALT/AST increase, deemed a DLT. However, this patient had liver metastasis and had G1 ALT/AST elevation at baseline. Her ALT/AST normalized in 3 weeks after treatment discontinuation and oral prednisone. Other ≥ G3 toxicities in the second group of 5 patients in dose level -1 include G3 hypertension (12.5%), nausea (12.5%), hypokalemia (12.5%), neutrophil count decrease (12.5%) dyspnea (12.5%), peripheral neuropathy (12.5%), and retinal detachment (12.5%). Since less than 1/3 of patients experienced DLT and there was no ≥ G4 AE at least possibly related to treatment over all cycles at any given dose level, the MTD was determined as dose level -1. Five patients are currently enrolled in the phase II section, and 10 more patients are needed. Objective response rate analysis will be performed once study enrollment is completed. Conclusions: The recommended phase II doses for pembrolizumab in combination with binimetinib are 200 mg every 3 weeks and 30 mg twice daily, respectively. The combination appears to be safe with manageable toxicities. Long term durable response has been observed. The phase 2 portion of this trial is currently on going. Citation Format: Saranya Chumsri, Jun He, David Hillman, Morgan Weidner, Morgan Weidner, Dana Haley, Aline Reis, Kathleen Tenner, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith Perez, Keith Knutson. Results of phase I study of pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT133.

78 Background: Previous study demonstrated that activation of RAS/MAPK pathway is associated with reduced tumor infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple negative breast cancer (TNBC). Further study showed that inhibition of MAPK pathway with a MEK inhibitor is synergistic with anti-PD1/PD-L1 therapies. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy without prior anti-PD-1/PD-L1/PD-L2 therapies were enrolled. Treatment was started with a 2-week run in period with single agent binimetinib. Dose level 0 was binimetinib at 45 mg oral twice daily continuously and dose level -1 was 30 mg twice daily. Pembrolizumab was given at a fixed dose of 200 mg every 3 weeks at both dose levels. Phase I study was based on the standard 3+3 design. Results: A total of 12 patients were enrolled and treated in the phase 1. Five patients were enrolled at dose level 0, 1 patient withdrew prior to treatment and 1 patient was not evaluable for dose limiting toxicity (DLT). Among 3 evaluable patients, 2 patients experienced DLT with grade 3 flank pain and ALT abnormality. Additional 8 patients were enrolled at dose level -1. Out of 6 evaluable patients for DLT, there was 1 DLT observed with grade 3 AST and ALT abnormality. However, this particular patient had liver metastasis with grade 1 AST and ALT abnormality at baseline and her liver function test (LFT) normalized in 3 weeks after treatment discontinuation and oral prednisone. Other grade 1-2 common AEs included rash, LFT increase, abdominal pain, mucositis, nausea, cardiac troponin T increase without EKG change. The efficacy data will be presented at the meeting after the phase II interim analysis. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe based on the initial cohort. Phase II part is currently ongoing with binimetinib 30 mg twice daily and pembrolizumab 200 mg every 3 weeks with a total of 23 patients planned where the safety and efficacy of this combination will be further evaluated. Clinical trial information: NCT03106415.