Clinically meaningful survival advantage to adding alpelasib to fulvestrant in HR+, HER2-, PIK3CA-mutated breast cancer

By oncoXchange

September 22nd 2020

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By Wayne Kuznar for oncoXchange

The PI3K inhibitor alpelasib added to hormonal therapy conferred an 8-month advantage in overall survival (OS) compared with hormonal therapy alone in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with PI3KCA mutations.

Updated findings from the phase 3 SOLAR-1 trial revealed that at a median follow up of 30.8 months, median OS was 39.3 months in patients randomized to alpelasib plus fulvestrant compared with 31.4 months in the placebo plus fulvestrant arm, a difference that did not achieve significance (HR, 0.86; 95% CI, 0.64–1.15; P=0.15), but is considered clinically relevant. The data were presented by lead investigator Fabrice André, MD, PhD, during the virtual 2020 ESMO Congress.

Approximately 40% of patients with HR-positive, HER2-negative breast cancer harbour PI3KCA gene mutations, resulting in PI3K pathway hyperactivation and endocrine resistance, said Prof. André, from the Breast Cancer Unit, Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.

Alpelasib is an alpha-selective inhibitor of PI3K. As reported previously, alpelasib plus fulvestrant demonstrated a significant improvement in progression-free survival in the cohort with PIK3CA-mutated HR+, HER2- advanced breast cancer, the primary endpoint of SOLAR-1 trial, compared with placebo plus fulvestrant (11.0 months versus 5.7 months),

SOLAR-1 trial evaluated alpelasib (300 mg orally) plus fulvestrant (500 mg intramuscularly) or placebo plus fulvestrant in 572 postmenopausal chemotherapy-naïve patients with disease progression on, or following treatment with, an aromatase inhibitor. PIK3CA mutations were identified in 341 patients (169 in the alpelasib plus fulvestrant arm and 172 in the placebo plus fulvestrant arm).

At data cutoff (April 23, 2020), after median follow-up of 42.4 months, “three times as many patients were still on treatment in the alpelasib versus placebo arm [12.4% vs. 4.1%],” said Andre.

A key secondary endpoint of the trial was to evaluate OS in the cohort of patients with PI3KCA mutations as assessed in tumor tissue. In addition to the improvement in OS in the experimental arm in the entire cohort with PIK3CA mutations, the HR for death was 0.68 in the subset with lung or liver metastases (95% CI, 0.46-1.00) in favor of alpelasib plus fulvestrant, with a median OS of 37.2 versus 22.8 months.

In the 186 patients with PIK3CA mutation in plasma ctDNA, an exploratory analysis found median to be 34.4 months in the alpelasib/fulvestrant arm versus 25.2 months in the placebo/fulvestrant arm (HR, 0.74; 95% CI, 0.51-1.08).

Some 78.4% in the alpelasib/fulvestrant arm and 81.7% in the placebo/fulvestrant arm received antineoplastic therapy following discontinuation of study treatment. A CDK4/6 inhibitor was the first new antineoplastic medication after discontinuation of study in 11.5% of the alpelasib/fulvestrant arm and 13.4% in the placebo/fulvestrant arm.

“In a post hoc exploratory analysis, time to first chemotherapy was delayed with the addition of alpelasib to fulvestrant,” said André. Median time to chemotherapy was 23.3 versus 14.8 months in the alpelasib/fulvestrant and placebo/fulvestrant arms, respectively (HR 0.72; 95% CI, 0.54–0.95).

No new safety signals with alpelasib were observed.

Alongside the known significant improvements in PFS with alpelasib plus fulvestrant, the OS data further support the use of alpelasib plus fulvestrant for patients with HR-positive, HER2-negative advanced breast cancer and PI3KCA mutations, a setting in which treatment options are limited, according to André.