Triplet therapy confers benefit among certain patients with advanced breast cancer
CHICAGO — The combination of ribociclib, everolimus and exemestane conferred clinical benefit and appeared tolerable among patients with endocrine therapy-refractory, hormone receptor-positive, HER2-negative advanced breast cancer that progressed on a CDK 4/6 inhibitor, according to data from the TRINITI-1 trial presented at ASCO Annual Meeting.
“Preclinical evidence suggests that the addition of everolimus (an mTOR inhibitor) to ribociclib (a CDK 4/6 inhibitor) and exemestane (an aromatase inhibitor) may restore sensitivity to both CDK 4/6 inhibitor and endocrine-based therapy,” Aditya Bardia, MD, MPH, assistant professor of medicine at Harvard Medical School and one of the study’s co-authors, told HemOnc Today.
The phase 1/phase 2, multicenter, open-label TRINITI-1 trial evaluated triplet therapy with ribociclib (Kisqali, Novartis), everolimus (Afinitor, Novartis) and exemestane (Aromasin, Pfizer) among men and postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer who received previous CDK 4/6 inhibitor therapy and up to three lines of therapy. Phase 1 of the trial determined the maximum tolerated dose of the triplet. Phase 2 evaluated the safety and efficacy of the daily regimen of 200 mg or 300 mg ribociclib, 2.5 mg or 5 mg everolimus and 25 mg exemestane.
Ninety-five patients (median age, 58 years; 81% white) who were refractory to endocrine-based therapy and progressed after receiving CDK 4/6 inhibitors were evaluable as of Oct. 24, 2018, including 17 patients in phase 1 and 78 patients in phase 2.
Clinical benefit rate at week 24, per RECIST version 1.1 criteria, served as the primary endpoint, with a predefined threshold of greater than 10%.
Average follow-up was 5.3 months (maximum, 22 months).
The triplet therapy demonstrated a clinical benefit rate of 41.1% (95% CI, 31.1-51.6) at 24 weeks, which was four times the minimum threshold for the study. The disease control rate was 61.1% (95% CI, 50.7-70.9), and the overall response rate was 8.4% (95% CI, 3.7-15.9), including one complete response and seven partial responses.
Median PFS was 5.7 months (95% CI, 3.6-9.1), with a 1-year PFS rate of 33.4% (95% CI, 22.8-44.4).
Researchers noted differences in PFS among patients with certain tumor molecular alterations.
“The most common gene alterations found in circulating tumor DNA at randomization were PIK3CA and ESR1,” Bardia told HemOnc Today. “Among the patients with a PIK3CA or ESR1 mutation, concomitant PIK3CA and ESR1 mutations were detected in 46.7% of patients. Patients with ESR1 or PIK3CA mutations at baseline had a numerically shorter median PFS vs. those with wild-type status.”
Bardia said that adverse events in this trial “were consistent with known safety profiles” of the drugs used in the study.
The most common hematologic adverse events included neutropenia (64.6%), thrombocytopenia (29.2%) and anemia (28.1%). The most common nonhematologic adverse events were stomatitis (41.7%), nausea (31.3%) and diarrhea (27.1%).
Most patients (72.9%) experienced grade 3 or grade 4 adverse events, the most frequent of which included neutropenia (47.9%), decreased white blood cell count (11.5%) and anemia (10.4%).
“TRINITI-1 met its primary efficacy endpoint and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with endocrine-based therapy plus an mTOR inhibitor plus a CDK 4/6 inhibitor in patients with endocrine therapy-refractory, hormone receptor-positive, HER2-negative advanced breast cancer after progression on a CDK 4/6 inhibitor,” Bardia said. “The biomarker data suggest that certain tumor molecular alterations may confer therapeutic advantage, and their presence at baseline may be associated with a better outcome with triplet therapy. Additional research is warranted to guide rational therapy selection.” – by Drew Amorosi
Bardia A, et al. Abstract 1016. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Bardia reports consultant/advisory roles with or research funding from bioTheranostics, Genentech/Roche, Immunomedics, Innocrin Pharma, Merck, Novartis, Pfizer, Radius Health, Radius Pharma, Sanofi and Spectrum Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.