medwireNews: Adding capivasertib to fulvestrant significantly improves survival in patients with aromatase inhibitor (AI) resistant, estrogen receptor-positive, HER2-negative advanced breast cancer, particularly those with PIK3CA/AKT1/PTEN alterations, FAKTION data show.
The updated analysis of the phase 2 trial was presented by Robert Jones (Cardiff University, UK) at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA.
Jones explained that primary data from the FAKTION trial, reported in 2020, showed that progression-free survival (PFS) was significantly longer among participants randomly assigned to receive capivasertib 400 mg twice daily in a 4 days on, 3 days off schedule plus fulvestrant 500 mg every 4 weeks (n=69) than among those given placebo plus fulvestrant (n=71), at a median of 10.3 versus 4.8 months and an adjusted hazard ratio (HR) of 0.56 in favor of adding the selective AKT inhibitor.
At the time of that analysis, overall survival (OS) data were immature but suggested an improved outcome with capivasertib versus placebo (median, 26.0 vs 20.0 months).
With additional follow-up, and 77% maturity for survival data, the difference in OS between the two arms widened and reached statistical significance, reported the presenter. Specifically, median OS was 29.3 months after a median 58.5 months of follow-up in the capivasertib arm and 23.4 months after 62.3 months of follow-up in the placebo arm, equating to a significant HR of 0.66 favoring capivasertib.
Jones noted that, at primary analysis, the benefit of capivasertib did not appear to be influenced by PI3K/AKT/PTEN pathway alterations.
However, during follow-up, the researchers expanded biomarker profiling to include next-generation sequencing (NGS) which enabled them to increase the number of genetic alterations they could investigate, and more accurately determine PI3K/AKT/PTEN pathway altered status.
Indeed, the enhanced biomarker analysis revealed that 54% of participants had alterations compared with 42% in the original analysis, which used digital-droplet PCR or pyrosequencing.
Of the 20 tumors with additional alterations identified by NGS, eight carried AKT1 E17K and five had a PIK3CA activating mutation, which were not tested in the original panel.
Analyses stratified by pathway alteration status revealed that, in the pathway-altered group, median OS was 38.9 months among people who received capivasertib and 20.0 months in those who received placebo, resulting in a significant HR of 0.46 favoring capivasertib.
By contrast, there was no significant OS difference between the capivasertib and placebo arms in the pathway non-altered group, at a median of 26.0 and 25.2 months, respectively.
Jones and team also updated the PFS analysis, which was consistent with the primary analysis in the intention-to-treat population, at median of 10.3 months with capivasertib versus 4.8 months with placebo, and a significant HR of 0.56.
PFS analysis by updated biomarker subgroup showed a significant improvement in the pathway-altered group that received capivasertib versus the group that was given placebo, at a median of 12.8 and 4.6 months, respectively, and an HR of 0.44.
Conversely, there was no significant PFS difference in the pathway non-altered group, with corresponding values of 7.7 and 4.9 months.
Jones concluded that “the data support further development of capivasertib, including testing in patients who received prior CDK4/6 inhibitor therapy,” who were not enrolled in FAKTION.
He added that results of the phase 3 CAPItello-291 trial, which has recruited participants with pathway-altered and non-altered tumors “are awaited with interest.”
Discussant Claudine Isaacs, from Georgetown University Medical Center in Washington, DC, USA, said: “The investigators should be commended for re-evaluating their original findings with contemporary technology.”
She added that the “updated findings underscore the importance of having the right biomarker assays to predict who will respond to a targeted therapy.”
However, she stressed that the study was a small phase 2 trial in a CDK4/6 inhibitor-naïve population and the analyses need to be validated.
The study was simultaneously published in The Lancet Oncology.
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