Fatima Cardoso, MD

The SOLAR-1 invited discussant, Fatima Cardoso, MD, Director of the Breast Unit at the Champalimaud Clinical Center in Lisbon and Chair of the ABC Global Alliance, commented: “The overall survival results, though numerically different by almost 8 months, unfortunately do not reach statistical significance. I make a plea [to drug developers and regulators] to make overall survival a co-primary endpoint or, at least, to power the trials to evaluate overall survival with statistical significance.”

Currently, the ABC international guidelines state that alpelisib is a treatment option for patients with PIK3CA-mutant tumors previously exposed to an aromatase inhibitor and with appropriate hemoglobin A1c levels. “The decision to give alpelisib should take into consideration the inclusion and exclusion criteria of the study (ie, preexisting diabetes and hemoglobin A1c level), as well as the toxicity profile,” she said.

Concern About Toxicity

Dr. Cardoso did express concern about the potential for toxicity with this drug. “In clinical experience, alpelisib is actually very toxic and difficult to manage. There are a high percentage of dose modifications, interruptions, or reductions (74% in SOLAR-1), so we need to pay much attention to the side effects,” she reminded providers.

The ESMO Magnitude of Clinical Benefit Scale currently ranks alpelisib for PIK3CA-mutant advanced breast cancer a score 3 (out of 5). Based on the lack of a significant overall survival benefit, this score is not likely to increase and, in fact, could be downgraded in the next version, Dr. Cardoso predicted, given “the high percentage of dose adjustments needed.”

Sequencing With CDK4/6 Inhibitors

The main question for the use of alpelisib remains how to sequence it with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors. For the small group of SOLAR-1 patients who had been exposed to CDK4/6 inhibitors (only 6%), 44% of the PIK3CA-mutant cohort were alive without disease progression at 6 months. Similarly, in the BYLieve trial (presented during the ASCO20 Virtual Scientific Program), 50% of patients with prior exposure were progression-free at 6 months.¹ These results demonstrate that -alpelisib seems to retain efficacy when used after CDK4/6 inhibitors, she said.

“With our current knowledge, CDK4/6 inhibitors remain the preferred first-line therapy for hormone receptor–positive, HER2-negative advanced breast cancer, independently of PIK3CA status, in view of their overall survival benefit,” stated Dr. Cardoso. In locations where both the drug and a test for the mutation are accessible, the preferred second-line therapy is endocrine therapy plus alpelisib for PIK3CA-mutant tumors and endocrine therapy plus everolimus for PIK3CA wild-type tumors, she said. Although alpelisib is approved in the United States and Europe only for postmenopausal patients and men, the breast cancer community strongly believes it is also appropriate for premenopausal women with ovarian suppression or ablation.

“Education, prophylaxis (antihistamines, steroid mouthwash), monitoring, and early intervention are crucial to making this a tolerable agent, and it should be used with caution in elderly -patients,” she added. 

DISCLOSURE: Dr. Cardoso has served as a consultant or advisor to Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, -Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck Sharp & Dohme, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seattle Genetics, and Teva.

REFERENCE

1. Rugo HS, Lerebours F, Ciruelos E, et al: Alpelisib + fulvestrant in patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer previously treated with cyclin-dependent kinase 4/6 inhibitor + aromatase inhibitor: BYLieve study results. ASCO20 Virtual Scientific Program. Abstract 1006. Presented May 30, 2020.