Abstract
PurposePI3K/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).MethodsCohort 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).ResultsOverall, 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%).ConclusionAdding 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.
Highlights
The phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently upregulated in cancer [1, 2]
Between January 6, 2018 and March 29, 2019, 782 patients were screened for the trial, of whom 560 were considered screen failures, most commonly because of absence of PIK3CA/AKT1/PTEN alteration (n = 303)
The majority of samples for determination of PIK3CA/AKT1/ PTEN status were from primary tumor tissue (143 [64%] primary, 66 [30%] metastatic, 10 [5%] unknown, three [1%] enrolled based on local testing with no central confirmation available)
Summary
The phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently upregulated in cancer [1, 2]. Activation of AKT, the central node of the PI3K/AKT pathway, promotes cell survival, proliferation, metabolism and growth [1, 3], and is implicated in resistance to endocrine therapy [4]. PIK3CA/AKT1/PTEN alterations are frequently observed in breast cancer, including approximately 50% of patients with hormone receptor-positive (HR+) breast cancers, and contribute towards a negative prognosis and resistance to endocrine therapies [5,6,7,8,9]. Phase 2 LOTUS trial, the addition of ipatasertib to paclitaxel improved progression-free survival (PFS) compared with paclitaxel alone in metastatic triple-negative breast cancer (TNBC), especially in patients whose tumors harbored alterations in PIK3CA, AKT1 and/or PTEN [15]
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