Author: By Shreeya Nanda, Senior medwireNews Reporter
medwireNews: Combining first-line paclitaxel with the AKT inhibitor capivasertib could benefit women with advanced triple-negative breast cancer (TNBC) harbouring PIK3CA/AKT1/PTEN alterations, suggest findings from the PAKT trial.
The investigators note that capivasertib addition improved outcomes in the overall cohort, but the effects were “more pronounced” in the subgroup with PIK3CA/AKT1/PTEN-altered tumours.
In the phase II study, the primary endpoint of progression-free survival (PFS) by local assessment was 5.9 months for the 70 patients with treatment-naïve locally advanced or metastatic TNBC who received a twice-daily dose of oral capivasertib 400 mg on days 2–5, 9–12 and 16–19 of each 28-day cycle alongside paclitaxel 90 mg/m2 on days 1, 8 and 15 as per the random allocation.
This was longer than the median PFS of 4.2 months achieved by their 70 counterparts who received placebo plus the same regimen of paclitaxel and the difference reached significance as per the statistical criteria of the trial.
For the primary endpoint of local assessment, the hazard ratio (HR) for progression or death was 0.74, which was higher than the prespecified HR of 0.67, but the study authors point out that central review of PFS gave an HR of 0.64.
Median overall survival (OS) in the intention-to-treat (ITT) population was 19.1 months for the capivasertib group and 12.6 months for the placebo group, giving a significant HR for death of 0.61, according to the article published in Journal of Clinical Oncology.
The presence or absence of PIK3CA/AKT1/PTEN alterations could be determined for 112 (80%) of the ITT cohort, of which 28 women were positive for either activating PIK3CA/AKT1 mutations or inactivating PTEN alterations.
In this subgroup, capivasertib addition resulted in a median PFS of 9.3 months, compared with 3.7 months with placebo, equating to a significant HR of 0.30 in favour of the highly selective AKT inhibitor.
By contrast, the median PFS durations were comparable for the capivasertib and placebo groups among women with tumours lacking these aberrations (5.3 vs 4.4 months).
The OS results were similar except that the between-group difference in patients with PIK3CA/AKT1/PTEN alterations did not reach statistical significance.
“The PAKT trial strongly suggests that the benefits of AKT inhibition might be largely limited to the subgroup of patients with PIK3CA/AKT1/PTEN alterations”, comment the authors. However, they note that “an OS benefit cannot be excluded in patients with nonaltered tumors.”
They add that “[a]lthough this subgroup is small, and results have to be interpreted with caution, the PIK3CA/AKT1/PTEN-altered and -nonaltered results are further supported by the LOTUS trial” of the AKT inhibitor ipatasertib together with paclitaxel in the same setting, which reported similar findings.
With regard to the safety profile, the incidence of adverse events of at least grade 3 was higher in the capivasertib than the placebo group, at 54.4% versus 25.7%, with diarrhoea the most common event among capivasertib-treated patients, at 13.2% versus 1.4%.
Capivasertib-treated patients were also significantly more likely than their counterparts who received placebo to require a dose interruption (34 vs 15%) or reduction (17 vs 2%).
Peter Schmid, from Barts Cancer Institute in London, UK, and co-researchers nonetheless describe the combination of capivasertib and paclitaxel as being “generally well tolerated.”
They also remark that “[o]verall, the toxicity profile seemed comparable with those of other AKT inhibitors and was largely limited to the known class effects of AKT inhibition.”
Schmid P, Abraham J, Chan S, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol; Advance online publication 11 December 2019. doi: 10.1200/JCO.19.00368
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