ESMO18: Novartis PI3K combo therapy boosts survival in subset of breast cancer patients

Novartis has posted positive results from its phase 3 combining its investigational oncology drug in combo with an old AstraZeneca breast cancer drug.

Drilling down into the data presented this weekend at ESMO in Germany, Novartis combined its PIK3 drug BYL719 (aka alpelisib)—a class that has seen a number of setbacks over the years—alongside the British Big Pharma's Faslodex (fulvestrant) in advanced breast cancer patients who had a specific mutation, namely PIK3CA mutated HR+/HER2 breast cancer. We had a topline posting of these data back in August, but today Novartis has released more details.

The Swiss pharma said that around 40% of HR+ advanced breast cancer patients have a PIK3CA mutation which, they said, “is associated with poor prognosis,” adding that there are currently there are no treatments that specifically target this mutation.


In this subset population, the combo nearly doubled the median progression-free survival (PFS) when pitted against AZ’s aging drug on its own and improved objective response rate (ORR). 

The so-called SOLAR-1 late-stage trial of 572 patients was treating these patients after they had seen their disease progress on or after an aromatase inhibitor and with or without a new form of drug, known as a CDK4/6 inhibitor (that includes Novartis’ own Kisqali, Pfizer’s Ibrance and Lilly’s Verzenio), versus Faslodex alone.

The numbers: PFS was 11 months for the combo treatment compared to 5.7 months for Faslodex alone, with the combo cutting the risk of death or progression in the subset of patients by an estimated 35%.

And ORR, which showed a reduction in tumor size of at least 30%, was more than doubled in patients with measurable disease who received BYL719 and Faslodex (36%) compared to those on AZ’s drug alone (16%). But the PFS improvement was not seen in patients without the mutation.

This may prove something of a reprieve for the PI3K class, which has had a torrid few years and a number of safety concerns. Back in 2016, Roche licensed out its PI3K drug to Australia's Novogen while Lilly started seeking partners in July 2017 for several midphase oncology programs, including a PI3K/mTOR dual inhibitor.

And it didn't stop there—in the summer, Roche also ditched another PI3K hopeful, taselisib, after it put up "modest" efficacy data and a risk of "considerable side effects." Safety issues have also long dogged Gilead’s blood cancer drug Zydelig (idelalisib), the first FDA-approved PI3K inhibitor, and AbbVie’s decision back in 2016 to scrap its collaboration with Infinity’s lead blood cancer candidate duvelisib, also a PI3K, after a set of poor trial results.

Back in July, Novartis itself handed over rights to another PI3K, buparlisib, to a Chinese outfit—again coming after seeing high toxicity levels.

But that's not to say that there were not adverse events (AEs) for the SOLAR-1 test: While Novartis said AEs were “mild to moderate,” the most common all-grade AEs were hyperglycemia (64% vs 10%), diarrhea (58% vs. 16%), nausea (45% vs. 22%), decreased appetite (36% vs. 11%) and rash (36% vs. 6%). Hyperglycemia was the most common grade 3/4 events (37% against <1%), something regulators will likely be taking a close look at.

Analysts at Jefferies were upbeat and not too concerned over the safety data, writing in a note to clients over the weekend, “Novartis's alpelisib could finally provide PIK3CA mutation positive endocrine resistant breast cancer patients with a viable treatment option. The results of the Phase III SOLAR-1 study indicate that unlike previous PI3K inhibitors, alpelisib's benefits outweigh its toxicities and we forecast it could achieve peak sales of $1.5B.”

Drilling down into the safety, they still see the risk/benefit as being in the drug's favor, adding, “Given the history of the class the key focus heading into the ESMO conference was on whether alpelisib's toxicity would stop it from being a viable treatment option. The SOLAR-1 study did show that alpelisib causes high rates of hyperglycemia, rash and diarrhea but these AEs were generally manageable through dose modifications. This is balanced against the meaningful PFS benefit that the combination of alpelisib and fulvestrant achieved in endocrine resistant patients.”

RELATED: Novartis hands off buparlisib to China's Adlai Noryte

“The results from SOLAR-1 are the most encouraging observed to date from a trial evaluating a PI3K inhibitor for patients with PIK3CA mutated HR+/HER2- advanced breast cancer,” said Fabrice André, M.D., Ph.D, research director and head of INSERM Unit U981, and professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France.

“These data have the potential to allow physicians to address an unmet need in this patient population by using a biomarker-driven treatment to inform their sequencing decisions.”

There are as yet no data on overall survival, the golden standard on cancer trials, though the Swiss major said this, which is being studied as a secondary endpoint, will be presented at a “future medical congress”.

Novartis said these data will be the “basis of discussions” with health authorities worldwide as it looks toward regulatory filings.

 “We are excited about the meaningful results seen in SOLAR-1 and about the possibility to reimagine what potential treatment options could look like for patients living with PIK3CA-mutated HR+/HER2-advanced breast cancer—some of which were previously treated with a CDK4/6 inhibitor,” added Samit Hirawat, M.D., head of Novartis oncology global drug development. “We are actively engaging in discussions on these results with health authorities worldwide.”