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Novartis' Piqray Effective in Breast Cancer Subset; Bayer's Aliqopa Gives Limited Signals in NCI-MATCH

NEW YORK – A study presented at the American Society of Clinical Oncology's virtual annual meeting demonstrated promising efficacy for Novartis PI3K inhibitor alpelisib (Piqray) in PIK3CA-mutated advanced breast cancer patients who have previously progressed on CDK4/6 inhibitors.

Meanwhile, in an arm of the NCI-MATCH trial, researchers exploring Bayer's PI3K inhibitor copanlisib (Aliqopa) for signs of efficacy in a variety of PIK3CA-mutated cancers, failed to find a robust signal.

Hope Rugo from the University of California, San Francisco's Helen Diller Family Comprehensive Cancer Center, presented the results from cohort A of the prospective Phase II non-comparative open-label BYLieve study. In that cohort, 127 patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer received alpelisib in combination with fulvestrant after they had received CDK4/6 and aromatase inhibitors.

In the BYLieve study, PIK3CA status was determined in patients by PCR analysis. In cohort A, 121 patients had their PIK3CA mutation status centrally confirmed and were included in the primary efficacy analysis.

PIK3CA is mutated in 40 percent of hormone receptor-positive, HER2-negative advanced breast cancers, and studies have shown that breast cancer patients with these mutations can have worse outcomes. PI3K pathway hyperactivations due to PIK3CA mutations can also contribute to endocrine resistance. 

In the earlier Phase III SOLAR-1 trial, combining alpelisib and fulvestrant was effective in hormone receptor-positive, HER2-negative PIK3CA-mutated breast cancer patients that progressed on or after aromatase inhibitor therapy. In that study, median progression-free survival was 11 months in the arm containing alpelisib and 5.7 months in the placebo arm.

Investigators in that study had some indication that patients who had progressed on a CDK inhibitor might benefit from alpelisib. But only 20 patients had received prior CDK inhibitor treatment, since at the time these drugs had just started becoming commercially available. Still, in this cohort, median progression-free survival was 5.5 months in the arm with alpelisib and 1.8 months in the placebo arm.

Last year, the US Food and Drug Administration approved alpelisib for PIK3CA-mutated breast cancer patients who have progressed on an endocrine-based regimen based on the results of SOLAR-1. 

"For patients with PIK3CA-mutated hormone receptor-positive advanced disease who progress on CDK inhibitor-based treatment, alpelisib and fulvestrant is a treatment option," said Rugo. "However, there is limited clinical data available to inform treatment decisions in this setting."

Cohort A of BYLieve met its primary endpoint of progression-free survival with 50.4 percent of patients alive without disease progression at the six-month follow-up. The median progression-free survival was 7.4 months. The overall response rate was 21 percent.

Comparatively, in the SOLAR-1 trial, 44.4 percent of PIK3CA-mutated patients who received prior CDK inhibitor treatment were alive without disease progression at the six-month follow-up after treatment with alpelisib and fulvestrant.

In cohort A, 26 percent of patients experienced a serious treatment-related adverse event, and 20.5 percent of patients discontinued treatment due to an adverse event. There were no new safety signals seen in this study. The most common side effect was rash, which Rugo noted could be moderately managed with prophylactic antihistamines.

To compare cohort A with a control group, matched analyses were performed against a real-world cohort of patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer patients in the US who had previously received CDK inhibitor therapy. The 95-patient cohort was obtained using de-identified profiles from the Flatiron Health-Foundation Medicine clinico-genomics database. There were 33 unique treatment regimens reported in this synthetic control cohort, with the most common treatments being capecitabine monotherapy and fulvestrant monotherapy. In this group, median progression-free survival was about 3.6 months.

Rugo concluded that the data from the BYLieve study supports the use of alpelisib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer in the post-CDK inhibitor setting. Further, she said that this study confirmed the preliminary findings noted in the SOLAR-1 study.

Another study presented at ASCO involving a different PI3K inhibitor, copanlisib, had quite different aims: to hunt for a signal in a variety of PIK3CA-mutated tumors. Copanlisib is already approved by the FDA for treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies.

At the meeting, Senthil Damodaran from the MD Anderson Cancer Center presented data from the Phase II NCI MATCH EAY131-Z1F study, which investigated the efficacy of the pan-PI3K inhibitor in patients with PIK3CA-mutated solid tumors, myeloma, and lymphoma who have progressed following at least one line of systemic therapy. Patients who have a KRAS mutation or have been previously treated with a PI3K, AKT, or mTOR inhibitor were excluded from the trial.  

Overall, 35 patients were enrolled in the NCI MATCH study, and 28 were assessable for response. There were 25 different tumor histologies represented in the study. The most common types of tumors were genitourinary tumors, gynecological tumors, and gastrointestinal tumors.

More than half the patients had grade 3 or 4 adverse events. Five patients died during the study due to factors unrelated to treatment. Due to disease progression, 64 percent of patients discontinued treatment.

The overall response rate was 11 percent. The median time of treatment was 1.7 months. Partial responses were seen in uterine cancer, clear cell carcinoma of anterior abdominal wall, and liposarcoma. Two patients remained on treatment at the time of data cutoff: one patient with head and neck cancer, and another sarcoma patient.

The median progression-free survival is 4.3 months with an estimated six-month progression-free survival rate of 38 percent. The median overall survival is 7.2 months with an estimated six-month overall survival rate of 54 percent.

Damodaran said that while the study did not meet its primary endpoint of response, copanlisib was effective in various PIK3CA-mutated tumors in the late-line refractory setting. He suggested further studies to explore the drug either alone or in combination with other agents in these tumors may be warranted.

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