Alpelisib for PIK3CA‐Mutated, Hormone Receptor–Positive Advanced Breast Cancer

By F. André, E. Ciruelos, G. Rubovszky, Mario Campone, S. Loibl, H. Rugo, H. Iwata, P. Conte, Ingrid A. Mayer, B. Kaufman and 10 more. New England Journal of Medicine, 2019

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Background PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The PI3Kα‐specific inhibitor alpelisib has shown antitumor activity in early studies. Methods In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR‐positive, HER2‐negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor‐tissue PIK3CA mutation status. The primary end point was progression‐free survival, as assessed by the investigator, in the cohort with PIK3CA‐mutated cancer; progression‐free survival was also analyzed in the cohort without PIK3CA‐mutated cancer. Secondary end points included overall response and safety. Results A total of 572 patients underwent randomization, including 341 patients with confirmed tumor‐tissue PIK3CA mutations. In the cohort of patients with PIK3CA‐mutated cancer, progression‐free survival at a median follow‐up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib–fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo–fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA‐mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA‐mutated cancer was greater with alpelisib–fulvestrant than with placebo–fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib–fulvestrant group vs. 0.7% in the placebo–fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib–fulvestrant group, as compared with 0.3% of those in the placebo–fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. Conclusions Treatment with alpelisib–fulvestrant prolonged progression‐free survival among patients with PIK3CA‐mutated, HR‐positive, HER2‐negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR‐1 ClinicalTrials.gov number, NCT02437318.)

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

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Citations in the corpus

ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. (2021, background): “…hyperglycaemia, rash, gastrointestinal (GI) toxicity (nausea, vomiting, loss of appetite, mucositis, diarrhoea) and fatigue, which led to dose reductions/ interruptions in w 70% and discontinuations in 25% of patients, 36 although no new safety signals were observed with longer follow-up.”
5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (2020, methodology): “The SOLAR-1 phase III, randomised, placebo-controlled trial evaluated the role of alpelisib, an oral inhibitor of the phosphoinositide 3-kinase alpha (PI3Ka) isoform, in combination with fulvestrant, for postmenopausal women andmenwhohad previously been treated with an AI.(58) In the PIK3CA-mutated ”
Harnessing multimodal data integration to advance precision oncology (2021, background): “Targeted cancer therapies are continually being added to the clinical arena; for example, ongoing clinical trials of KRAS-G12C inhibitors 50,51 and the PI3Kα-specific inhibitor targeting PIK3CA mutations 52 in lung cancer and breast cancer, respectively.”
Targeting PI3K/Akt signal transduction for cancer therapy (2021, methodology): “Based on the antitumor activity of BYL-719 in phase I clinical trials, scientists conducted a phase III clinical trial of BYL-719 combined with fulvestrant in the treatment of advanced breast cancer.(205) The phase III trial showed a significantly prolonged survival rate of patients with advanced br”
Overcoming Endocrine Resistance in Breast Cancer (2020, positive): “Importantly, PIK3CA-mutant cancers that had progressed on CDK4/6i-containing regimens remained sensitive to alpelisib + fulvestrant (Andre et al., 2019).”
Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group. (2020, background): “Alpelisib, an a-selective phosphatidylinositol 3-kinase (PI3K) inhibitor, improves PFS in patients with HRþ/HER2 mBC that harbours PIK3CA hotspot mutations, and is approved in this group of patients.(72) Drugs targeting rare alterations found in different solid tumours, like microsatellite instabili”