A Phase 1b Study of Abemaciclib plus Pembrolizumab for Patients with HR-Positive, HER2-Negative Metastatic Breast Cancer

Abemaciclib is a selective and potent small-molecule inhibitor of CDK4/6, with evidence of single-agent antitumor activity and a safety profile that enables dosing on a continuous schedule. In patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer refractory to endocrine therapy, abemaciclib demonstrated clinical activity as monotherapy (MONARCH 1).¹ In the phase 3 MONARCH 2 study, which evaluated patients with HR-positive/HER2-negative breast cancer whose disease progressed while receiving endocrine therapy, abemaciclib plus fulvestrant resulted in a 7.2-month extension in median progression-free survival (PFS) compared with the placebo arm (hazard ratio, 0.553; 95% confidence interval, 0.449-0.681; P ≤.001).² Patients in the abemaciclib arm with measurable disease achieved an objective response rate (ORR) of 48.1% compared with 21.3% in the placebo arm.² In the phase 3 MONARCH 3 study, abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving PFS and ORR (59% vs 44%; P = .004), and demonstrating a tolerable safety profile in women with HR-positive/HER2-negative advanced breast cancer.³

The current report was from a multicenter, nonrandomized, open-label phase 1b study of abemaciclib plus pembrolizumab for patients with HR-positive/HER2-negative metastatic breast cancer or non–small-cell lung cancer. The study had 3 disease-specific cohorts, each with approximately 25 patients; the HR-positive/HER2-negative metastatic breast cancer cohort (part C) was presented at SABCS 2017.⁴ The primary objective was to characterize the safety of the combination of abemaciclib plus pembrolizumab. The secondary objective was to assess the preliminary efficacy of the combination of abemaciclib plus pembrolizumab by ORR per tumor assessment via Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1). Patients received 150 mg of abemaciclib orally every 12 hours, plus pembrolizumab 200 mg as a 30-minute intravenous infusion on day 1 every 21 days. Eligible patients included women with confirmed HR-positive/HER2-negative metastatic breast cancer who had previously received 1 or 2 prior chemotherapy regimens for metastatic breast cancer; had measurable disease via RECIST v1.1 and Eastern Cooperative Oncology Group performance status of 0 or 1; had no history or evidence of central nervous system metastasis; and had not received treatment with CDK4/6 inhibitors.

At the time of abstract presentation, the HR-positive/HER2-negative metastatic breast cancer cohort was fully enrolled, at 28 patients. The median age of patients was 55 years. Of the patients, 78.6% had visceral metastases and 60.7% had bone metastases; 17.9% had 1 metastatic site, 14.3% had 2 metastatic sites, and 64.3% had ≥3 metastatic sites. Prior therapy for metastatic disease consisted of endocrine therapy, of which 32.1% had 1 regimen, 25% had 2 regimens, 14.3% had 3 regimens, and 3.6% had ≥4 regimens. Prior therapy for metastatic disease also consisted of chemotherapy, of which 53.6% had 1 regimen, 32.1% had 2 regimens, and 3.6% had 3 regimens. The most common adverse events of all grades included diarrhea (78.6%), fatigue (50.0%), headache (39.3%), and neutropenia (39.3%). All patients experienced increased creatinine; 74.1% had decreased white blood cell count; 66.7% had anemia; and 63% had decreased lymphocyte count.

The combination of abemaciclib plus pembrolizumab demonstrated a tolerable safety profile in patients with HR-positive, HER2-negative metastatic breast cancer. At the 16-week analysis, abemaciclib plus pembrolizumab demonstrated a confirmed ORR of 14.3%. Additional time will be necessary to properly evaluate the efficacy of the abemaciclib plus pembrolizumab combination.

References
1. Dickler MN, et al. Clin Cancer Res. 2017;23:5218-5224.
2. Sledge GW Jr, et al. J Clin Oncol. 2017;35:2875-2884.
3. Goetz MP, et al. J Clin Oncol. 2017;35:3638-3646.
4. Rugo HS, et al. SABCS 2017. Abstract P1-09-01.