Safety and Efficacy of Tucatinib, Letrozole, and Palbociclib in Patients with Previously Treated HR+/HER2+ Breast Cancer

Abstract

Purpose: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC).

Patients and methods: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS).

Results: Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year.

Conclusions: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.

Figure 1.

Estrogen receptor and HER2 signaling converge at the cyclin D1–CDK4/6 complex. (Created with BioRender.com.)

Figure 2.

CONSORT diagram. *, Both patients discontinued the study due to patient decision. **, For patients remaining on study after first CNS PD, PFS is calculated at the time of first CNS progression, whereas duration of time on study is calculated at the time of a second progressive event and discontinuation of study.

Figure 3.

PFS and time on study. A, Kaplan–Meier plot of progression-free survival. B, Duration of time on study, each bar represents individual patient; blue represent patients with CNS disease; green represent patients without CNS disease; lighter bars represent patients previously treated with trastuzumab and pertuzumab; darker bars represent patients previously treated with trastuzumab, pertuzumab and T-DM1. *, Patient received fam-trastuzumab deruxtecan. **, Patient received margetuximab. Diamonds, time (in parentheses) of the first CNS progression; arrows represent ongoing treatment.

Figure 4.

Change in size of target lesions (%) per RECIST and RANO-BM in patients with measurable lesions (N = 27). Each bar represents an individual patient. On the basis of the change in size of target lesions, the dotted line at 20% represents progressive disease, and at −30% represents partial response; solid line at −100% represents complete response.