The addition of ipatasertib to paclitaxel failed to improve progression-free survival (PFS) and objective response rates (ORRs) versus placebo plus paclitaxel in patients with PIK3CA/AKT1/PTEN-altered hormone receptor (HR)–positive, HER2-negative advanced breast cancer, according to findings from the phase 3 IPATunity130 trial that were presented at the 2020 ESMO Virtual Congress.
At a median follow-up of 12.9 months, the investigator-assessed PFS was 9.3 months with the combination (95% CI, 8.0-11.0) versus 9.3 months with placebo/paclitaxel (95% CI, 7.2-12.2), failing to meet the primary end point of the study (HR, 1.00; 95% CI, 0.71-1.40; log-rank P = .9965).
“The results are consistent with the phase 1/2 BEECH trial of paclitaxel with or without the AKT inhibitor capivasertib,” said Nicholas Turner, PhD, lead study author and consultant medical oncologist at The Royal Marsden Hospital, in a virtual presentation of the data. “In contrast, an AKT inhibitor in combination with fulvestrant improved PFS in the phase 2 FAKTION trial, suggesting that endocrine blockade is critical to the activity of AKT inhibitors in hormone receptor–positive breast cancer.”
The PI3K/AKT pathway plays a critical role in HR–positive, HER2-negative breast cancer, and AKT activation is responsible for resistance to endocrine therapy.
Ipatasertib is an oral ATP-competitive selective inhibitor of AKT1/2/3, which is the central node of the PI3K/AKT pathway. In preclinical models, HR–positive cell lines with PI3K3CA mutations or PTEN loss were shown to be sensitive to single-agent ipatasertib. Additionally, phase 1b data demonstrated clinical activity with the combination of ipatasertib and taxane chemotherapy in HR–positive metastatic breast cancer.
In cohort B of the double-blind, placebo-controlled trial, patients with at least 1% HR–positive, HER2-negative measurable advanced breast cancer who harbored a PIK3CA/AKT1/PTEN alteration were randomized 2:1 to 400 mg of ipatasertib once daily on days 1-21 plus 80 mg/m2 of paclitaxel on days 1, 8, and 15 of every 28-day cycle (n = 146) versus placebo plus paclitaxel (n = 76) on the same schedule. Treatment was continued until disease progression, intolerable toxicity, or elective withdrawal. Crossover from placebo to ipatasertib was not permitted.
Cohort A, which is comparing the same 2 regimens in triple-negative breast cancer, will be analyzed independently, and cohort C is evaluating the combination plus atezolizumab (Tecentriq) in patients with PIK3CA/AKT1/PTEN-non-altered tumors.
Eligible patients were not considered appropriate for endocrine-based therapy and had not received prior chemotherapy for advanced breast cancer. Patients were candidates for taxane therapy and had an ECOG performance status of 0 or 1. Prior CDK4/6 inhibition and/or mTOR inhibition was permitted.
The analysis of the primary end point was planned after approximately 150 events occurred. The study had 80% power to detect a hazard ratio of 0.62, at a 2-sided alpha of 0.05.
Regarding baseline characteristics, just over 50% of patients received prior neoadjuvant or adjuvant chemotherapy, and approximately half of patients had not received prior endocrine therapy for advanced breast cancer. The majority of patients (≥ 80%) had a PIK3CA/AKT1 activating mutation, while the remainder of patients had a PTEN alteration without a PIK3CA/AKT1 activating mutation.
Regarding secondary end points, the combination led to an ORR of 47% (95% CI, 38%-55%) versus 47% with placebo/paclitaxel (95% CI, 35%-59%). The median duration of response was 9.2 months in the combination arm (95% CI, 7.2-11.3) versus 9.2 months in the placebo/paclitaxel arm (95% CI, 6.8-12.5).
More deaths were reported in the combination arm (n = 33; 23%) compared with the placebo/paclitaxel arm (n = 22; 29%). The median overall survival (OS), which was immature at the clinical cut-off date, was not estimable (NE) in the combination arm (95% CI, 19.2-NE); the median OS was 20.9 months in the placebo/paclitaxel arm (95% CI, 17.3-NE; OS HR, 0.72, 95% CI, 0.42-1.24).
From the treatment exposure and safety analysis, diarrhea was shown to be the main adverse effect (AE) that was associated with the addition of ipatasertib. However, the AE resolved in 94% of patients, with a median resolution time of 15 days. Nausea was also reportedly higher with ipatasertib but resolved in the majority of patients (87%), with a median resolution time of 22.5 days.
“Focusing on potential AKT inhibitor [adverse] effects, there was only a minor increase in rash, and no clear increase in hyperglycemia with ipatasertib,” said Turner.
AEs leading to discontinuation from ipatasertib or placebo occurred in 11% of patients in the ipatasertib arm (n = 16) versus 4% of those in the placebo arm (n = 3). AEs leading to discontinuation from paclitaxel occurred in 26% of patients (n = 38) versus 13% (n = 10), respectively.
Serious AEs were reported in 19% of patients in the ipatasertib arm (n = 28) versus 12% of patients in the placebo arm (n = 9). Grade 5 AEs occurred in 3% (n = 5) versus 1% (n = 1) of patients, respectively.
Overall, the mean treatment duration was similar in the ipatasertib and placebo arms, at approximately 5 months, and 21% of patients in both arms remain on treatment.
Ongoing and planned studies in HR-positive HER2-negative advanced breast cancer are evaluating ipatasertib in combination with endocrine-based regimens, concluded Turner.
Turner N, Dent R, O’Shaughnessy J, et al. Ipatasertib + paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomised trial. Presented at: 2020 ESMO Virtual Congress. September 19-21, 2020. Abstract 283MO.