Bosutinib in Combination With the Aromatase Inhibitor Letrozole: A Phase II Trial in Postmenopausal Women Evaluating First-Line Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer

Abstract

Background.

Endocrine therapy resistance in hormone receptor-positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first-line endocrine therapy in locally advanced or metastatic HR+/HER2− BC.

Methods.

Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single-arm safety/dose-confirming lead-in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose-limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy.

Results.

Fifteen of 16 subjects experienced treatment-related AEs, most commonly diarrhea (69%). Treatment-related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy’s law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2.

Conclusion.

The unfavorable risk-benefit ratio did not warrant further investigation of bosutinib plus letrozole.

Discussion

This phase II study was designed to evaluate bosutinib plus letrozole versus letrozole as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic HR+/HER2− BC (Table 1). The DLT-evaluable population included all part 1 patients who received ≥21 of 28 planned cycle 1 bosutinib and letrozole doses or who experienced a DLT in cycle 1, regardless of the number of doses received. Hepatotoxicity was common in part 1. Two patients experienced serious AEs of ALT/AST elevations that led to treatment discontinuation and met DLT criteria, including one case that met Hy’s law criteria, an indicator of drug-induced hepatic injury [1]; liver function test abnormalities resolved after bosutinib discontinuation. Specific class II human leukocyte antigen alleles may play a role in tyrosine kinase inhibitor-induced hepatotoxicity [2]. One patient achieved a confirmed partial disease response. Although the safety profile for bosutinib plus letrozole was not fully determined because the upper bound of the 80% confidence interval (CI) for the 12% DLT rate (80% CI: 12%–46%) was not ≤34%, per protocol, it was decided that the observed risks exceeded potential benefits, and the study was terminated prematurely by the sponsor before part 2.

Table 1.

Treatment summary (safety population)

In another phase II trial with a similar design evaluating bosutinib at 400 mg/day plus exemestane at 25 mg/day as second-line therapy in postmenopausal women with HR+/HER2− BC (ClinicalTrials.gov identifier NCT00793546), 5 of 13 evaluable patients had a DLT, and these were all hepatic or gastrointestinal events [3]. The recommended phase II dose (RP2D) of bosutinib 300 mg/day plus exemestane 25 mg/day had a generally acceptable safety profile: 3 of 26 evaluable patients (12% [80% CI: 4%–24%]) had a DLT, and again, all were hepatic or gastrointestinal events. No hepatic toxicity met Hy’s law criteria; however, the treatment-related hepatotoxicity rate of 26% did not support further evaluation of this combination. One patient achieved a confirmed partial disease response on the RP2D; however, the 80% CI upper boundary for median progression-free survival (PFS) was below the benchmark of 16 weeks for exemestane [3].

Preclinical studies had demonstrated that bosutinib inhibits BC cell proliferation, invasion, and migration, as well as tumor growth and metastasis in vivo [4–6]. A phase II trial of bosutinib monotherapy utilizing a dose of 400 mg/day in heavily pretreated advanced BC patients unselected for HR status demonstrated a clinical benefit rate of 27% and a 16-week PFS rate of 40%; all four patients whose tumors responded had HR+ BC [7]. Common toxicities included gastrointestinal events (diarrhea [66%], nausea [55%], vomiting [47%]), and grade 3/4 ALT/AST laboratory elevations (19%) [7]. A similar safety profile was observed in a phase I study of bosutinib in advanced solid tumors [8].

Bosutinib plus letrozole has a worse safety profile than single-agent bosutinib, which is characterized by manageable events and the absence of life-threatening events [7, 8]. Given the efficacy of bosutinib monotherapy in metastatic BC, Src/Abl inhibition remains a novel treatment strategy. Alternative combination regimens with bosutinib warrant consideration in metastatic BC.

Author disclosures and references available online.