Novel PI3K inhibitor for Breast Cancer: Success at Last?

Zosia Chustecka

October 21, 2018

MUNICH — A new and highly selective inhibitor of phosphatidylinositol-3-kinase (PI3K) has shown benefit in advanced breast cancer and may succeed where two previous drugs aimed at the same target failed.  

Fabrice André, MD, PhD

The new investigational drug alpelisib (Novartis) is an alpha-specific PI3K inhibitor and blocks only the alpha-isoform of the enzyme, which is the one that is mutated in breast cancer.

"Previous PI3K inhibitors targeted all four isoforms, so there were a lot of toxicities," explained Fabrice André, MD, PhD, professor of medical oncology at the Institut Gustave Roussy, Villejuif, France.

He was lead investigator of the phase 3 SOLAR-1 trial, conducted in postmenopausal women and men with advanced breast cancer that was hormone-receptor positive (HR+) and HER2 negative, and who tested positive for PIK3CA mutations (314 of 572 of trial participants, 54.8%).

The PIK3CA mutation activates the PI3 kinase pathway leading to cancer progression and resistance to endocrine therapy, he explained.

In the patients who had the mutation, the combination of alpelisib plus endocrine therapy with fulvestrant almost doubled progression-free survival (PFS) compared with fulvestrant alone.

Median PFS was 11.0 months in the alpelisib group vs 5.7 months in the control group (hazard ratio, 0.65; P = .00065) at a median follow-up of 20.0 months.

There was no benefit seen in patients who did not have the mutation.

"Alpelisib is the first drug to show a benefit in a genomic subgroup of breast cancer patients," André said in an ESMO press release.  

"For now, the follow-up is short so we cannot say whether there is a long-term survival benefit. But alpelisib increased PFS and that will hopefully translate to improvement in outcome," he commented.

Toxicity a Problem With Earlier Drugs

The most frequent side effects of alpelisib were hyperglycemia, which André said could be managed with metformin, and nausea, decreased appetite, and rash.

Overall, most frequent all-grade adverse events were hyperglycemia (in 64% of patients on the combination vs 10% on fulvestrant alone), diarrhea (58% vs 16%), nausea (45% vs 22%), decreased appetite (36% vs 10%), and rash (36% vs 6%).

The majority of side effects were grade 1-2, he noted. Grade 3-4 hyperglycemia was reported in 36.6% of patients on the combination, and Grade 3 rash in 9.9%.

Discontinuation because of side effects was seen in 6.3% of patients because of hyperglycemia and by 3.2% of patients because of rash.

"There is no life-threatening toxicity or major toxicity that would be expected to affect quality of life," André commented.

Toxicity has been a problem with earlier drugs in this class, which were not as specific in their PI3K inhibition.

Earlier this year, Roche stopped development of the PI3K inhibitor taselisib, after seeing only a modest improvement in PFS (of 2 months), but side effects led 16.8% of patients with breast cancer to discontinue the drug (in the SANDPIPER trial, as reported by Medscape Medical News).

Novartis stopped its development of an earlier generation PI3K inhibitor, buparlisib, after concerns about the toxicity of the drug when combined with endocrine therapy in the advanced breast cancer setting.

Where Will Alpelisib Fit?

Patients in the SOLAR-1 trial had previously received one or more prior lines of endocrine therapy, but had not received chemotherapy for advanced breast cancer.

They were randomized to oral alpelisib (300 mg/day) or placebo plus intramuscular fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle 1).

Commenting on the study for ESMO, Angelo Di Leo, MD, head of medical oncology at the Hospital of Prato, Italy, said: "This is the first trial to show a clinically relevant benefit with a PI3K inhibitor combined with endocrine therapy in patients with HR+ HER2- advanced breast cancer with PIK3CA mutations."

"The next critical step will be to understand when, and how, this compound should be incorporated into the current treatment algorithm — upfront, in combination with endocrine therapy and a CDK4/6 inhibitor, or sequentially, after disease progression on the combination of endocrine therapy and a CDK4/6 inhibitor."

He noted that only a few patients in this trial had received treatment with a CDK4/6 inhibitor, which is becoming a new standard of care in patients with endocrine therapy resistance, and this is a limitation of the study, as it does not reflect current clinical practice.

The same question about where this drug will fit into clinical practice alongside the CDK4/6 inhibitors was raised by discussant for this study Rebecca Dent, MD, from the National Cancer Centre in Singapore.

The results from SOLAR-1 show a "clinically meaningful absolute benefit in PFS," she commented.

Alpelisib is the "best in class," she said.

However, we need to wait for overall survival data as well as patient-reported outcomes and quality of life data, she said. Although the toxicity seen with this drug is less than was seen with earlier-generation unselective PI3K inhibitors, she noted that there was nevertheless "significant clinical toxicity that is not unexpected given this metabolically driven pathway."

"Would different dosing schedules, pharmacodynamics endpoint, and/or novel prophylactic measures ameliorate these toxicities?" she wondered. 

Widespread Testing Will Be Needed

The study could have wide implications for clinical practice, André suggested. If PI3K inhibitors become a treatment option for patients with advanced breast cancer, then genomic testing to find patients with PIK3CA mutations will need to be implemented. André told Medscape Medical News that this is easy to do, using polymerase chain reaction testing on archival or fresh tumor tissue.  

In the future, it may be possible to use so called "liquid biopsies" and test for the mutation in plasma samples, which has the considerable advantage of being a noninvasive procedure, commented Di Leo.

The study was funded by Novartis, manufacturer of alpelisib. André has reported receiving grants from Novartis during the conduct of the study, and grants from AstraZeneca, Pfizer, Eli Lilly, and Roche outside the submitted work. Other authors also have disclosures, as listed in the abstract. Dent has reported relationships with AstraZeneca, Lilly, Merck, and Pfizer.

European Society for Medical Oncology (ESMO) 2018 Congress. Presented October 20, 2018. Abstract LBA3.

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