In a phase III trial, patients with PIK3CA-mutant advanced breast cancer benefited from taking the PI3Kα inhibitor alpelisib in addition to fulvestrant endocrine therapy. The combination extended median progression-free survival, elevated response rates, and proved tolerable compared with fulvestrant plus placebo.

After years of disappointing breast cancer trials in which experimental PI3K inhibitors proved too toxic, ineffective, or both, an agent targeting this aberrant signaling enzyme has demonstrated strong activity in phase III testing.

graphic

Fabrice André, MD, PhD, reported positive results from a phase III trial of alpelisib in HR-positive, HER2-negative advanced breast cancer at the ESMO 2018 Congress.

At the European Society for Medical Oncology (ESMO) 2018 Congress in Munich, Germany, clinicians reported findings from the SOLAR-1 trial, which evaluated the PI3Kα inhibitor alpelisib (Novartis) in men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer that had progressed on or after treatment with an aromatase inhibitor. Researchers showed that alpelisib nearly doubled median progression-free survival (PFS) compared with placebo—from 5.7 months to 11 months—when given with the antiestrogen fulvestrant to patients with PIK3CA-mutant disease.

Overall response rates were also greater in the alpelisib study arm: 36% versus 16%. Plus, toxicity levels proved manageable, with 5% of trial participants in the alpelisib arm discontinuing study treatment due to adverse events, compared with 1% in the control arm.

“We have a tolerable agent with a manageable side-effect profile that results in a pretty remarkable response rate and a clinically meaningful extension of progression-free survival,” says Dejan Juric, MD, director of the Termeer Center for Targeted Therapies at the Massachusetts General Hospital Cancer Center in Boston, who co-led the trial with Fabrice André, MD, PhD, of Institut Gustave Roussy in Villejuif, France.

Approximately 40% of patients with HR-positive breast tumors harbor driver mutations in PIK3CA, which encodes the alpha isoform of PI3K targeted by alpelisib. That's made PI3Kα inhibition an attractive strategy for these patients—although initial drug-discovery efforts were less targeted.

Pan-PI3K inhibitors such as buparlisib (Novartis) and pictilisib (Roche) fared poorly, with problematic safety profiles or lack of efficacy scuttling their clinical advancement. Earlier this year, Roche halted development of its β-sparing PI3K blocker taselisib following disappointing results from the SANDPIPER trial. In that phase III study of women with PIK3CA-mutant disease, taselisib plus fulvestrant offered only a 2-month PFS advantage over placebo plus fulvestrant, and 17% of taselisib recipients discontinued treatment due to side effects.

Part of the difference between the success of alpelisib and taselisib may be attributed to clinical management, says Filip Janku, MD, PhD, of The University of Texas MD Anderson Cancer Center's Department of Investigational Cancer Therapeutics in Houston, who was not involved in either trial. In SOLAR-1, he says, researchers seem to have done “a far better job of proactively managing side effects,” such as hyperglycemia and rash, with quick and early interventions that helped avoid the high rate of withdrawal from SANDPIPER.

Juric, however, thinks the lower discontinuation rate with alpelisib—and thus higher efficacy with more patients staying on the drug—boils down to pharmacology. “The main reason is a much wider therapeutic index with alpelisib,” he says. Taselisib, owing to its action against the gamma and delta isoforms of PI3K, can trigger gastrointestinal side effects such as colitis that can be difficult to manage. Alpelisib, because it hits only the alpha isoform, avoids these problems. It does, however, cause a high rate of hyperglycemia, which can be reversed with metformin.

The only PI3K-targeted agents currently approved—the PI3Kγ inhibitor idelalisib (Zydelig; Gilead) and the pan-PI3K inhibitor copanlisib (Aliqopa; Bayer)—are reserved for hematologic malignancies. Alpelisib could join that list based on SOLAR-1 data, but the “holy grail,” says Juric, would be “an inhibitor that preferentially hits just the mutant PI3Kα and not the wild-type enzyme.” He and others are now clinically evaluating a next-generation inhibitor called GDC-0077 (Genentech) that, based on preclinical data, may do exactly that. –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.