Abstract CT108: A phase 1b study of abemaciclib in combination with pembrolizumab for patients (pts) with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) (NCT02779751): Preliminary results

Abstract

Background: Abemaciclib is an orally administered, selective small molecule cyclin-dependent kinase (CDK) 4 and 6 inhibitor, approved to treat HR+, HER2- mBC pts on a continuous twice daily dosing schedule as monotherapy or in combination with endocrine therapy (ET), an aromatase inhibitor as initial endocrine based therapy, or in combination with fulvestrant. In preclinical models, abemaciclib monotherapy induced intra-tumoral immune inflammation and had a synergistically enhanced anti-tumor efficacy when administered in combination with programmed cell death protein 1 blockade. Here we report the safety and preliminary anti-tumor activity of abemaciclib plus pembrolizumab plus anastrozole in HR+, HER2- locally advanced or mBC pts. Methods: This multicenter, nonrandomized, open-label, multi-cohort phase 1b study of abemaciclib plus pembrolizumab plus anastrozole enrolled a cohort of post-menopausal HR+, HER2- pts with locally advanced or mBC. No prior CDK4/6 inhibitor, chemotherapy, or ET for locoregional advanced or mBC were allowed. Patients received 150-mg abemaciclib orally every 12 hours plus pembrolizumab 200 mg intravenously on day 1 every 21 days plus anastrozole 1 mg orally every 24 hours. The primary objective was to characterize the safety of abemaciclib plus pembrolizumab plus anastrozole. Key secondary objectives included objective response rate (ORR), progression-free survival, and overall survival. Results: Out of 26 pts enrolled, 13 (50%) had received prior systemic anti-cancer therapy, including 12 (46%) who had received ET in the adjuvant setting. The majority of pts had visceral disease (65%); 54% had 3 or more metastatic sites. The nature of adverse events (AEs) observed for the triplet therapy was overall consistent with the known side effects of abemaciclib, pembrolizumab and anastrozole. Grade 3/4 AEs in > 2 pts included increased alanine aminotransferase and neutropenia (8 pts each, 31%) and increased aspartate aminotransferase (6 pts, 23%). In general, Grade 3/4 AEs were reversible following drug holds and corticosteroid treatment. There were 2 fatal events as a result of pneumonitis. Fifteen pts (58%) discontinued treatment including 9 pts (35%) due to an AE (7 transaminase elevations). Preliminary response assessment showed 5 pts had a confirmed partial response (19% ORR), and disease control rate (CR+PR+SD) was 77%. Clinical benefit rate (CR+PR+SD persisting for ≥6 months) was 27%. Conclusions: Abemaciclib plus pembrolizumab plus anastrozole demonstrated a numerically higher rate of transaminase elevations and pneumonitis than reported for the individual treatments and 2 experienced a fatal AE. At this time, evaluation of anti-cancer activity is premature. Citation Format: Hope S. Rugo, J. Thad Beck, Guy Jerusalem, Hans Wildiers, Peter Kabos, Michael Chisamore, Rhian McNaughton, Yanyun Chen, Anwar Hossain, Sara M. Tolaney. A phase 1b study of abemaciclib in combination with pembrolizumab for patients (pts) with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) (NCT02779751): Preliminary results [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT108.

Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer

“…Gene expression analyses of biopsies from the Neo-PalAna and NeoMonarch neoadjuvant trials in luminal breast cancer suggest that this immune effect occurs in patients [37,87], but the extent to which it can be leveraged to improve patient outcomes is still unknown. Reasons for this include that: (1) ER-positive metastatic breast cancer has thus far proven unresponsive to immune-based approaches [88,89], and (2) early efforts to combine CDK4/6i and immuno-oncology therapy have been complicated by prohibitive toxicity [90,91].…”

The Immunology of Hormone Receptor Positive Breast Cancer

“…Combination therapy resulted in numerically higher rates of elevated transaminases; however, the overall safety profile was considered generally tolerable. Importantly, in another cohort (cohort D) of the JPCE trial, the safety of abemaciclib in combination with pembrolizumab and the aromatase inhibitor (AI) anastrozole was assessed in 26 patients with locally advanced or metastatic HR+/HER2- breast cancer ( 175 ). Preliminary safety results revealed a high level of grade 3/4 AEs including 8 patients with neutropenia, 6 patients with elevated alanine aminotransferase and 2 therapy-related fatalities (pneumonitis).…”

Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression

“…In the neoadjuvant setting, pembrolizumab-in combination with chemotherapyincreased the pCR rates, varying from 15 to 30%, depending on the chemotherapy backbone [131]. In the advanced setting, ORR ranges from 12% for pembrolizumab alone [132] to 34% in association with eribulin [133] and 29% when combined with the CDK4/6i, abemaciclib [134]. As maintenance therapy, durvalumab (i.e., anti-PD-L1 antibody) improved OS compared to chemotherapy in HR+ BC (21.7 vs. 17.9) [135].…”