No Benefit Adding Ipatasertib to First-Line Paclitaxel for PIK3CA-Altered TNBC

Results from the IPATunity130 phase 3 trial showed that adding ipatasertib to paclitaxel did not improve progression-free survival (PFS) in patients with PIK3CA/AKT1/PTEN-altered, locally advanced, unresectable or metastatic triple-negative breast cancer (aTNBC). 

“In the randomized phase II LOTUS trial, adding [ipatasertib] to paclitaxel improved [PFS], with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors,” explained Rebecca Dent, MD, National Cancer Center, Singapore, and colleagues.

With this in mind, researchers conducted a double-blind, placebo-controlled, randomized trial comprising eligible PIK3CA-, AKT1-, or PTEN-altered measurable aTNBC patients. They also had to have an ECOG performance status 0/1 and no prior chemotherapy for TNBC.

Between February 2018 and April 2020, a total of 255 patients were enrolled and randomized in a 2:1 ratio to receive oral ipatasertib 400 mg or placebo (days 1-21), both combined with IV paclitaxel 80 mg/m2 (days 1, 8, & 15). The cycle was repeated every 28 days until disease progression, unacceptable toxicity, or patient withdrawal.

Investigator-assessed PFS was the primary end point, while secondary end points included overall survival (OS), objective response rate (ORR), duration of response, clinical benefit rate (CBR), patient-reported outcomes, and safety. Stratification factors included prior (neo)adjuvant chemotherapy (yes vs no); geographic region (Asia-Pacific vs Europe vs North America vs the rest of world); and tumor alteration status (PIK3CA/AKT1-activating mutation vs PTEN alteration without PIK3CA/AKT1-activating mutation). 

Of the 255 participating patients, 51% received (neo)adjuvant chemotherapy, and 59% had visceral disease, 51% had PIK3CA/AKT1-activating mutations, and the remaining 49% had PTEN alterations (without PIK3CA/AKT1-activating mutations). The median follow-up was 8.3 months (range 0-26.8 months), 33% of patients continued treatment. The mean duration of paclitaxel was 5.5 months in the ipatasertib and 5.4 in the placebo arm. There was no difference in PFS between either treatment groups overall or any subgroups. The OS results were immature due to deaths reported for 20% of patients.

Grade ≥3 adverse events (AEs) were of similar proportions in both the ipatasertib and placebo arms (46% and 44% respectively), fatal AEs were 1% in both groups, and AEs resulting in discontinuation of any treatment was 14% and 15%, respectively. AEs resulting in dose reduction was more common amongst the ipatasertib arm (35%) compared to the placebo arm (14%). 

“In contrast to results from the phase II LOTUS trial, this trial showed no PFS improvement with the addition of ipatasertib to first-line paclitaxel in patients with PIK3CA/AKT1/PTEN-altered aTNBC," Dr Dent et al wrote.

"Biomarker analyses are ongoing to evaluate potential markers of ipatasertib benefit. Safety was consistent with previously reported results for this combination,” they concluded.—Alexandra Graziano
Dent R, Kim SB, Oliveira M, et al. Double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC): primary results from IPATunity130 Cohort A. Presented at: the 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract GS3-04.

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