Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

Abstract

Purpose PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects. Trial registration NCT03337724.

Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial

“…NGS testing has been previously used to identify PI3K/AKT/PTEN pathway-altered tumours. [18][19][20] Here, we present the first mature analysis of overall survival and an updated progression-free survival analysis in the intent-to-treat population of FAKTION after an additional 34 months of follow-up. In a prespecified exploratory analysis, we considered the benefit of capivasertib by tumour PI3K/AKT/PTEN pathway-altered status after expanding testing of the originally collected tumour or plasma samples to include NGS assays.…”

“…NGS testing has been previously used to identify PI3K/AKT/PTEN pathway-altered tumours. 18 , 19 , 20 …”

Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer

“…IPATunity130 (NCT03337724) was a phase III trial evaluating the efficacy of the combination of ipatasertib and paclitaxel compared to a placebo and paclitaxel in locally advanced or metastatic breast cancers [ 46 ]. Surprisingly, this trial failed to demonstrate a benefit in PFS among the B HR+/HER-2-negative cohort (mPFS was 9.3 in both arms, HR 1.00, 95% CI 0.71–1.40), and the OS data are still immature [ 47 ]. We do not have results for cohort A, the TNBC population, to see if there is a subgroup of PIK3CA/AKT1/PTEN-altered TNBC that would derive benefits from the combination of ipatasertib and paclitaxel [ 48 ].…”

The Molecular Predictive and Prognostic Biomarkers in Metastatic Breast Cancer: The Contribution of Molecular Profiling

“…In two small phase II randomized trials with 140 and 124 patients, the addition of capivasertib [ 35 ] or ipatasertib [ 36 ] to paclitaxel in a first-line setting for metastatic TNBC was associated with a median improvement in PFS of 5 months in patients with a PIK3CA or AKT mutation or low PTEN status. However, these alterations failed to predict the benefit of ipatasertib in the largest prospective phase III clinical trial, IPATunity130 [ 37 ], which enrolled 255 mTNBC patients, so they have not yet attained ESCAT I targetability.…”