On the cyclin D1-CDK4/6-RB1 pathway, the human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER) signals merge, in cases of hormone receptor (HR)-positive, HER2-positive breast cancer. Therefore, pharmacologic interventions with individual drugs focused on HER2, estrogen receptor, and CDK4/6 targets are warranted. Elena Shagisultanova, MD, PhD, Assistant Professor, Medical Oncology, Diane O’Connor Thompson Breast Center-Anschutz, University of Colorado, Aurora, presented the safety and efficacy outcomes of the combination of tucatinib (Tukysa) with letrozole (Femara) and palbociclib (Ibrance) in patients with HR-positive, HER2-positive metastatic breast cancer.
Participants eligible to enroll in the phase 1b/2 clinical trial were HR-positive, HER2-positive metastatic breast cancer patients previously treated with ≥2 HER2-targeted therapies. Included in the study were patients with untreated asymptomatic or stable treated brain metastasis. Those patients who were treated for progressing brain metastasis joined the study after local treatment and were classified as treated stable. Treatment consisted of tucatinib 300 mg twice daily and oral letrozole 2.5 mg daily continuously, and oral palbociclib 125 mg daily 21 days on, 7 days off.
It was found that tucatinib is a strong CYP3A4 inhibitor, and due to drug–drug interaction issues found in the middle of the trial and not related to this study the dose of sensitive CYP3A4 substrate palbociclib was reduced to 75 mg for all study participants.
The primary end points were progression-free survival and assessment of safety using Common Terminology Criteria for Adverse Events version 4.03 criteria.
Secondary end points included pharmacokinetic evaluation and objective response rate. Using Response Assessment in Neuro-Oncology Brain Metastases criteria, brain metastasis response was evaluated. All patients who received ≥1 cycles of therapy were evaluated for safety.
During a time frame of approximately 29 months between November 2017 and April 2020, 40 enrolled patients were deemed evaluable. The median age was 52.5 years, and the median number of previous lines of therapy for metastatic breast cancer was 2 (range, 0-7). Fifty-eight percent of the patients had visceral disease and 38% had brain metastasis.
All patients had received previous treatment with trastuzumab (Herceptin) and pertuzumab (Perjeta), and 18 (45%) patients had received previous trastuzumab emtansine (Kadcyla) treatment. Fourteen patients were receiving active therapy while 26 were off study. The median follow-up time was 6 months.
The combination was well-tolerated with manageable and expected adverse events. Neutropenia occurred at a rate of 60%, followed by leukopenia (24%), diarrhea (19%), fatigue (14%), and infections (14%). Due to asymptomatic grade 4 elevated liver function test results that resolved without sequelae, 1 patient discontinued the study. No deaths due to adverse events were reported.
At the time of data cutoff among 26 patients with measurable disease, 31% of patients exhibited a partial response, 62% of patients had stable disease, 27% of patients had stable disease for at least 6 months, 23% of patients had not yet reached 6 months of follow-up, and 8% of patients had disease progression. Of the 14 patients with brain metastasis and evaluable disease, 1 patient had complete response in the brain, 6 patients had stable disease in the brain for at least 6 months, and 7 patients had stable disease for 2 to 6 months. Four patients receiving active therapy had not yet reached 6 months of follow-up. The median progression-free survival was 8.7 months, with 10.1 months for patients without brain metastasis and 6.0 months for those with brain metastasis.
The researchers concluded that in patients with HR-positive, HER2-positive metastatic breast cancer, the combination of tucatinib with letrozole and palbociclib showed a safety profile that was tolerable and manageable; combined with clear antitumor activity this evidence merits additional clinical studies.
Source: Shagisultanova E, Gradishar W, Brown-Glaberman U, et al. Interim safety and efficacy analysis of phase IB / II clinical trial of tucatinib, palbociclib and letrozole in patients with hormone receptor and HER2- positive metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium, December 8-11, 2020. Abstract PS10-03.
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