Approximately 40% of patients with hormone receptor (HR)-positive, HER2-negative breast cancer have mutations in the PIK3CA gene. Although endocrine-based therapy is the standard treatment, acquired resistance remains a challenge.
The recently approved alpelisib (Piqray), a PI3Kα-specific inhibitor, has demonstrated antitumor activity in early studies. Based on the phase 3 SOLAR-1 clinical trial, in May 2019, the FDA approved alpelisib in combination with fulvestrant (Faslodex) for the treatment of patients with HR-positive, HER2-negative advanced breast cancer and PIK3CA mutation. The results of the study were published just before the FDA approval of this new drug (André F, et al. N Engl J Med. 2019;380:1929-1940).
SOLAR-1 was an international, randomized, double-blind, placebo-controlled, phase 3 trial of 572 patients with HR-positive, HER2-negative advanced breast cancer who had undergone endocrine therapy. A total of 341 patients were randomized based on the presence or absence of a PIK3CA mutation. The patients were randomized in a 1:1 ratio to alpelisib 300 mg daily plus fulvestrant 500 mg every 28 days and once on day 15, or to placebo plus fulvestrant. The primary end point was progression-free survival (PFS). The secondary end points included overall response and safety.
At a median follow-up of 20 months, among patients with PIK3CA mutation–positive disease, the PFS was 11.0 months in the group that received alpelisib plus fulvestrant versus 5.7 months in the group that received placebo plus fulvestrant (hazard ratio [HR] for disease progression or death, 0.65; P <.001). In the cohort without a PIK3CA mutation, the HR was 0.85 (posterior probability of HR <1; 79.4%). The overall response rate in patients with PIK3CA mutation was greater in the alpelisib arm than in the placebo arm (26.6% vs 12.8%, respectively), as was the clinical benefit (61.5% vs 45.3%, respectively).
The proof-of-concept criteria, however, were not met in the cohort that did not have a PIK3CA mutation. The median PFS rate was 7.4 months in the alpelisib plus fulvestrant cohort and 5.6 months in the placebo plus fulvestrant cohort. At 12 months, the PFS rate was 28.4% in the alpelisib plus fulvestrant group compared with 22.2% in the placebo plus fulvestrant group.
The safety profile in this trial was similar to previous trials of alpelisib plus fulvestrant. A higher incidence of grade 3 or 4 adverse events was seen in the alpelisib cohort than in the placebo group, including hyperglycemia (36.6% vs 0.7%, respectively), rash (9.9% vs 0.3%, respectively), maculopapular rash (8.8% vs 0.3%, respectively), and diarrhea (6.7% vs 0.3%, respectively). Discontinuation rates of alpelisib and placebo because of adverse events were 25% versus 4.2%, respectively.
“These results show improvements in patients’ outcomes with the addition of an α-specific PI3K inhibitor to standard treatment for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, findings that validate PIK3CA as an important treatment target in this population,” the researchers observed.