Ipatasertib, Paclitaxel Combo Does Not Improve PFS in PIK3CA/AKT1/PTEN-Altered TNBC


Treatment with ipatasertib plus paclitaxel (Abraxane) failed to show a significant improvement in progression-free survival versus placebo plus paclitaxel in patients with PIK3CA/AKT1/PTEN-altered locally advanced, unresectable, or metastatic triple-negative breast cancer.

According to findings from cohort A of the phase 3 IPATunity trial that were presented during the 2020 San Antonio Breast Cancer Symposium, combination treatment with ipatasertib and paclitaxel (Abraxane) failed to show a significant improvement in progression-free survival (PFS) versus placebo plus paclitaxel in patients with PIK3CA/AKT1/PTEN-altered locally advanced, unresectable, or metastatic triple-negative breast cancer (TNBC).

With a median follow-up time of 8.3 months, the investigator-assessed PFS was 7.4 months (range, 5.6-8.5) in the ipatasertib-paclitaxel combination arm versus 6.1 months (range, 5.5-9.0) in the placebo-paclitaxel arm (stratified HR, 1.02; 95% CI, 0.71-1.45; log-rank P = .9237), failing to demonstrate statistical significance.

“Results from this trial differ from findings in both randomized phase 2 trials of AKT inhibition in advanced TNBC. Most notably the LOTUS trial, looking at ipatasertib and the PAKT trial, looking at capivasertib,” Rebecca C. Dent, MD, senior consultant and head of Medical Oncology Department, National Cancer Center, Singapore, said in a virtual presentation of the data.

Ipatasertib is a highly selected ATP-competitive AKT inhibitor, which was first evaluated in the phase 2 LOTUS trial. In the study, the combination of ipatasertib and paclitaxel, given in the first-line setting, led to an improvement in PFS versus placebo plus paclitaxel in an unselected population of patients with locally advanced TNBC (stratified HR, 0.60; 95% CI, 0.37-0.98). The PFS benefit was even more evident in patients with PIK3CA/AKT1/PTEN alterations (unstratified HR, 0.44; 95% CI, 0.20-0.99), serving as the rationale for the IPATunity trial in a biomarker-selected population.

The double-blind, placebo-controlled trial enrolled patients with measurable TNBC and a PIK3CA/AKT1/PTEN alteration who had not received prior chemotherapy for advanced disease. If patients received neoadjuvant or adjuvant chemotherapy, it had to have been at least 12 months prior to enrollment. Eligible patients were also candidates for taxane therapy and had a an ECOG performance status of 0 or 1.

Patients were randomized 2:1 to 80 mg/m2 of paclitaxel on days 1, 8, and 15 plus 400 mg of ipatasertib once a day on days 1 to 21 of every 28-day cycle (n = 168), or paclitaxel plus placebo (n = 87) given in the same schedule.

Treatment was continued until disease progression, intolerable toxicity, or elective withdrawal, and crossover from placebo to ipatasertib was not allowed.

Patients were stratified by prior neoadjuvant or adjuvant chemotherapy (yes vs no), geographic region (Asia-Pacific vs Europe vs North America vs rest of the world), and tumor alteration status (PIK3CA/AKT1-activating mutation vs PTEN alteration without PIK3CA/AKT1-activating mutation).

Investigator-assessed PFS served as the primary end point of the study and was planned after 125 PFS had occurred.

Regarding baseline characteristics, 55% of patients in the placebo arm had received prior chemotherapy versus 48% in the ipatasertib arm. A total of 13% of patients in the placebo arm had locally advanced unresectable disease versus 21% in the ipatasertib arm. Moreover, PD-L1 assessment per the SP142 assay demonstrated that 40% of patients in the placebo arm were PD-L1 positive versus 29% in the ipatasertib arm. A total of 51% and 49% of patients in both arms had a PIK3CA/AKT1-activating mutation or PTEN alteration without a PIK3CA/AKT1-activating mutation, respectively.

Additional findings showed the investigator-assessed objective response rate was 39% (95% CI, 31%-47%) in the ipatasertib arm versus 35% in the placebo arm (95% CI, 25%-46%). The clinical benefit rates were 47% (95% CI, 39%-55%) and 45% (95% CI, 35%-56%), respectively.

Across all clinical subgroups assessed for PFS, none derived benefit with the addition of ipatasertib, with the exception of patients with PD-L1–positive tumors (n = 28; unstratified HR, 0.61; 95% Wald CI, 0.34-1.09).

“Dose intensity, treatment duration, and discontinuation appear similar between the 2 arms. Most notably, no difference in terms of serious adverse effects [AEs] [was observed] between the 2 arms,” said Dent.

No new AEs were reported. More than double the rate of diarrhea was seen in patients in the ipatasertib arm vs the placebo arm. Rates of alopecia, nausea, constipation, vomiting, anemia, neutropenia, asthenia, peripheral sensory neuropathy, peripheral neuropathy, hyperglycemia, fatigue, and decreased appetite were otherwise comparable between arms.

Further analyses of IPATunity cohort A regarding potential biomarkers of response to ipatasertib and overall survival follow-up are ongoing, concluded Dent.


Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04. https://bit.ly/3n6wrMp

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