PAM Inhibitor Doubles Time to Progression in Advanced Breast Cancer Subset

CHICAGO — A second-line triplet regimen involving the novel intravenous drug gedatolisib significantly reduced the risk of progression or death in PIK3CA-mutant hormone receptor (HR)-positive breast cancer, a phase III study showed.

Among patients previously treated with CDK4/6 inhibition and an aromatase inhibitor (AI), median progression-free survival (PFS) reached 11.1 months with gedatolisib plus palbociclib (Ibrance) and fulvestrant, as compared with 5.6 months in a control arm that included fulvestrant plus alpelisib (Piqray), an approved drug for PIK3CA-mutant disease (HR 0.50, 95% CI 0.37-0.68, P<0.0001).

Though not formally tested, a third study arm found that the doublet of gedatolisib plus fulvestrant resulted in a similarly high PFS of 11.3 months. Treatment discontinuation due to toxicity was low in the two investigational arms, Sara Hurvitz, MD, of the University of Washington and Fred Hutch Cancer Center in Seattle, reported at the American Society of Clinical Oncology (ASCO) annual meeting.

“Gedatolisib plus fulvestrant, with or without palbociclib, represents a potential new standard of care for patients with this disease that has progressed on or after treatment with a CDK4/6 inhibitor,” she said during a late-breaking presentation.

After CDK4/6 inhibitors, patients with PIK3CA-mutant advanced breast cancer generally derive modest benefit from existing PI3K pathway inhibitors and AKT inhibitors and may experience significant toxicity, said Hurvitz.

Gedatolisib is an investigational inhibitor of PI3K, AKT, and mTORC1/2 (PAM), a complex multi-node pathway that drives breast cancer growth and contributes to endocrine and CDK4/6 inhibitor resistance. The drug is currently under review at the FDA for an indication based on other findings from the study, where the same two gedatolisib regimens more than tripled median PFS versus fulvestrant alone for previously treated PIK3CA wild type, HR-positive advanced breast cancer. A decision is expected next month.

Combined, the results validate the PAM pathway as a molecular driver in HR-positive/HER2-negative advanced breast cancer, “regardless of PIK3CA mutation status,” said Hurvitz.

Gedatolisib demonstrated impressive antitumor activity in the current study, but the rationale for the triplet regimen is not entirely clear, according to ASCO discussant Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minnesota.

“Palbociclib plus fulvestrant is neither approved nor proven to be effective following first-line AI plus CDK4/6,” he said. “So right now I find no evidence that three drugs is better than two drugs. Three drugs clearly provide more toxicity.”

Serious treatment-related adverse events (AEs) occurred in 10.5% of the gedatolisib triplet arm, 3.8% of the gedatolisib doublet arm, and 13.2% of the control arm, though certain PI3K pathway inhibitor-related toxicities such as hyperglycemia and diarrhea were lower with the novel drug.

Goetz pointed to past evidence from advanced breast cancer trials suggesting that giving more drugs at once versus sequentially does not generally improve overall survival.

He also asked where gedatolisib fits among PIK3-targeting agents when it comes to sequencing, an answer not provided by the study design: “Is upfront comprehensive targeting of the pathway better than strategic, selective upstream PI3K targeting followed later by comprehensive PAM inhibition?”

Study Details

Hurvitz presented findings from Study 2 of VIKTORIA-1, an international open-label phase III study. Patients in this part of the trial were enrolled if they had PIK3CA-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer.

Participants were required to have progressed on or after a CDK4/6 inhibitor and nonsteroidal AI. Up to two prior lines of endocrine therapy for advanced disease were allowed, but patients had to be naive to prior PI3K pathway inhibitors and chemotherapy in the advanced setting. The study also had an HbA1c cutoff of 6.4%, given the risk for hyperglycemia.

The 362 participants were randomized in a 3:3:1 ratio (gedatolisib triplet, alpelisib-fulvestrant control arm, and gedatolisib doublet), and the current analysis had a median follow-up of 12.8 months.

Baseline demographics and disease characteristics were well-balanced, said Hurvitz. Median age was around 60 years, and over three-fourths were white. Roughly 75% of patients had liver or lung metastases and about 15% appeared to have endocrine-resistant disease.

The primary endpoint was PFS for the gedatolisib triplet arm versus the control arm, and Hurvitz said the PFS benefit extended to all subgroups.

An interim analysis of overall survival, a secondary endpoint, was immature but showed a median not reached with the gedatolisib triplet versus 31.1 months with fulvestrant plus alpelisib (HR 0.76, 95% CI 0.50-1.14). Median OS in the gedatolisib doublet arm was 22.8 months.

Objective response rates were highest with the gedatolisib triplet, at 49%, followed by 36% with the gedatolisib doublet and 26% in the control arm. Median durations of response were 15.7 months, 24.2 months, and 7.5 months, respectively. Disease control rates with the two gedatolisib regimens topped 92%, as compared with 78% for fulvestrant plus alpelisib.

Fewer than 4% of patients discontinued gedatolisib due to toxicity versus 7% in the control arm. The most common AEs with the triplet regimen were neutropenia (related to palbociclib use) and stomatitis (61% in both gedatolisib arms), although most of these events were grade 1/2, said Hurvitz.

PI3K pathway inhibitor-related toxicities were notably low with gedatolisib, including hyperglycemia (15% with triplet, 11.5% with doublet) and diarrhea (15% and 9.6%, respectively), and, as expected, higher with alpelisib (hyperglycemia in 57.9%, diarrhea in 40.1%), said Hurvitz.

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