Novartis’s Breast Cancer Drug Looks Promising in Phase III Trial, Despite Category’s Troubling History

Novartis announced that its BYL719 (alpelisib) met the primary endpoint of progression-free survival (PFS) in its Phase III SOLAR-1 trial. The drug is an alpha-specific PI3K inhibitor, a category of cancer drugs that has a troubling history of adverse events.

The SOLAR-1 trial studied BYL719 in combination with fulvestrant compared to fulvestrant alone in postmenopausal women and men with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) PIK3CA-mutant advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor. There are currently no approved PI3K inhibitors for HR+ advanced breast cancer.

The PI3K pathway plays a significant role in regulating cells and is, according to Novartis, “the most frequently altered pathway promoting tumor growth, disease progression and treatment resistance in HR+ advanced breast cancer.”

Specific data was not released at this time other than it showed improvement in PFS. “BYL719 is the only alpha-specific PI3K inhibitor and the first one to show potential increased benefit and acceptable tolerability for patients,” said Samit Hirawat, Head, Novartis Oncology Global Drug Development, in a statement. “We are encouraged by the results observed in the SOLAR-1 study and look forward to submitting the data to an upcoming medical congress and starting discussions with health authorities worldwide.”

Some analysts seemed to think the drug could become a blockbuster. Bruno Bulic, an analyst at Baader Helvea, said in a note to clients, “We estimate alpelisib peak sales potential at $1.9 billion, and lift our probability of success to 80 percent.”

Given the history of this class of drugs, one has to wonder if the positive analysts are being premature without seeing the actual data. In July, Novartis, according to Reuters, “unloaded rights to a similar molecule, called buparlisib, to China’s Adlai Nortye Biopharma Co. Ltd., after doctors concluded it was too dangerous to continue developing in the advanced breast cancer setting, when combined with hormone therapy.”

A month earlier, in June, Roche gave up on its own PI3K inhibitor, taselisib, after data showed that the side effects didn’t outweigh the modest PFS benefit. In their trials, almost 20 percent of breast cancer patients receiving the drug abandoned treatment early.

Novartis’ statement indicates that adverse events were “consistent” with other studies of BYL719, which is worrying.

Gilead has Zydelig, which is marketed with a black box warning concerning serious and sometimes fatal toxicities. In February, Gilead withdrew its European marketing application for Zydelig in combination with Roche’s Rituxan (rituximab) and the chemotherapy drug bendamustine for chronic lymphocytic leukemia (CLL) patients who had already had at least one line of therapy. This came after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) indicated it was unlikely to give a positive recommendation. CHMP suggested that it would need longer-term data to evaluate the drug’s benefit/risk profile.

Zydelig is otherwise approved in Europe for second-line CLL in combination with Rituxan or Novartis’ Arzerra (ofatumumab) and third-line follicular lymphoma.