Sep 18, 2024
By Dibash Kumar Das, PhD
The CAPItello-290 Phase III trial, long-awaited by the oncology community, delivered mixed results for the combination of capivasertib and paclitaxel as a first-line treatment for metastatic triple-negative breast cancer (mTNBC). Although the trial did not achieve its primary endpoint of improving overall survival (OS) in both the general mTNBC population and those with specific tumor mutations, the combination treatment showed a notable progression-free survival (PFS) advantage. These findings offer important insights into the potential therapeutic role of capivasertib in managing this aggressive and challenging form of breast cancer.
At the ESMO Conference 2024, Heather L. McArthur, Clinical Director of the Breast Cancer Program at UT Southwestern Medical Center, presented the results (Abstract LBA19) from the CAPItello-290 trial (NCT03997123). The study explored the efficacy and safety of capivasertib, a pan-AKT inhibitor, combined with paclitaxel as a first-line treatment for mTNBC patients. As a leading breast cancer expert, McArthur explained that the trial was grounded in the promising findings from the earlier Phase II PAKT trial, which had demonstrated significant improvements in both PFS and OS when capivasertib was added to paclitaxel.
“Capivasertib is an oral, potent, and selective inhibitor of all three AKT isoforms (AKT1/2/3), recommended in combination with fulvestrant as a treatment option for patients with ER-positive/HER2-negative advanced breast cancer with one or more PIK3CA/AKT1/PTEN tumor alterations after disease progression or recurrence following one or more prior lines of endocrine therapy,” McArthur explained. “The PI3K/AKT signaling pathway is often overactivated in cancer, promoting breast cancer cell survival and resistance to chemotherapy or endocrine therapy. About one-third of patients with TNBC harbor PIK3CA/AKT1/PTEN tumor alterations.”
In the CAPItello-290 trial, 812 patients were enrolled between July 2019 and February 2022. Participants were randomized to receive either paclitaxel with capivasertib or paclitaxel with placebo. The dual primary endpoints were OS across all participants and in a subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors.
Despite the rigorous study design, the trial did not meet the predefined OS targets. Median OS in the overall population was 17.7 months for the capivasertib-paclitaxel group compared to 18.0 months for the placebo group (HR: 0.92; 95% CI; 0.78-1.08, P=.324). Similarly, among patients with PIK3CA/AKT1/PTEN-altered tumors, median OS was identical at 20.4 months for both groups (HR: 1.05; 95% CI: 0.77-1.43, P=.760).
While OS did not show a significant benefit, the secondary endpoint of PFS offered more encouraging results. The overall population treated with capivasertib had a median PFS of 5.6 months compared to 5.1 months in the placebo group (HR: 0.72; 95% CI: 0.61-0.84). In the subset of patients with PIK3CA/AKT1/PTEN-altered tumors, median PFS was 7.5 months for the capivasertib group versus 5.6 months in the placebo arm (HR: 0.70; 95% CI: 0.52-0.95).
In terms of safety, the trial confirmed that the combination of capivasertib and paclitaxel was generally well tolerated. Common adverse events (AEs) including diarrhea (76.4% in the capivasertib group versus 26.0% in the placebo group) and anemia (39.3% vs 30.7%). Grade 3 or higher AEs included diarrhea (12.7% vs 0.7%) and neutropenia (7.2% vs 6.6%).
"The safety profile of capivasertib was broadly consistent with known data on the drug, and no new safety signals were identified," McArthur emphasized.
“CAPItello-290 did not meet the predefined threshold for improving OS in either the overall population or in patients with PIK3CA/AKT1/PTEN-altered tumors, although PFS numerically favored first-line capivasertib—paclitaxel over placebo—paclitaxel in patients with mTNBC,” MrArthur concluded.
Dibash Kumar Das is a contributing writer.