Although the SOLAR-1 trial did not cross the prespecified O’Brien-Fleming efficacy boundary in postmenopausal patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer, alpelisib and fulvestrant nevertheless prolonged the median OS.
Fabrice André, MD, PhD
Although data from the final overall survival (OS) analysis of the SOLAR-1 trial did not cross the prespecified O’Brien-Fleming efficacy boundary (P ≤ .0161) in postmenopausal patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer, alpelisib (Piqray) and fulvestrant nevertheless prolonged the median OS by 7.9 months versus fulvestrant alone (HR, 0.86; 95% CI, 0.64-1.15; P = .15) and additionally suggested a survival benefit in various patient subgroups with no new safety signals.1
Results from the concluding OS assessment of the phase 3 trial (NCT02437318), presented by Fabrice André, MD, PhD, lead author of the SOLAR-1 study, at the 2020 ESMO Virtual Congress showed that at a median follow-up of 30.8 months, the median OS was 39.3 months (95% CI, 34.1-44.9) with alpelisib and fulvestrant and 31.4 months (95% CI, 26.8-41.3) with fulvestrant. In total, 169 and 172 patients were randomized to the alpelisib and fulvestrant arms, respectively, each of whom had not received prior chemotherapy and experienced disease progression on or after treatment with an aromatase inhibitor.1
“OS in the PIK3CA-mutant cohort was a key secondary end point [for which] statistical testing was planned to be conducted if the primary progression-free survival [PFS] analysis was positive,” said André, director of research at Gustave Roussy Cancer Center in Villejuif, France.
Positive PFS data from the SOLAR-1 study, published in 2019, which led not only to the subsequent OS analysis, but also to the May 24, 2019, approval of alpelisib in combination with fulvestrant for postmenopausal women and men with hormone receptor–positive, HER2-negative, PIK3CA-mutant advanced or metastatic breast cancer as detected by an FDA approved test following progression on or after an endocrine-based regimen.2
Investigators used a 3-look group sequential design to support the OS evaluation, which was based on 181 deaths at the April 23, 2020, cut-off date. At that time, 12.4% of patients receiving alpelisib (n = 169) remained on treatment versus 4.1% of fulvestrant-treated patients (n = 172).
In addition to the nearly 8-month increase in median OS seen in the PIK3CA-mutant cohort, André and fellow researchers also saw survival improvements with the doublet therapy in patients with lung and/or liver metastases and individuals with mutated PIK3CA in circulating tumor DNA (ctDNA). The median OS in this subpopulation was prolonged by 14.4 months with alpelisib and fulvestrant (n = 84) versus fulvestrant alone (n = 86). Specifically, the median OS was 37.2 months (95% CI, 28.7-43.6) with the combination and 22.8 months (95% CI, 19.0-26.8) with the chemotherapy (HR, 0.68; 95% CI, 0.46-1.00).1
Among patients with mutated PIK3CA in ctDNA, the median OS continued to favor alpelisib and fulvestrant. The median OS was 34.4 months 95% CI, 28.7-44.9 in 92 patients and 25.2 months (95% CI, 20.7-29.6) in 94 patients, respectively (HR, 0.74; 95% CI, 0.51-1.08).1 “The median overall survival was approximately 9 months longer for the alpelisib arm. Data suggest that patients with a PIK3CA mutation detected by ctDNA may have greater disease burden or more aggressive disease that might respond better to alpelisib,” André said.
Beyond the superior median OS seen in the PIK3CA-mutant cohort and 2 patient subgroups, investigators also witnessed an improvement in the median time to chemotherapy (mTTC) with the dual-drug regimen (HR, 0.72; 95% CI, 0.54-0.95) in a post-hoc exploratory analysis of the PIK3CA-mutant cohort. Treatment with the alpelisib-fulvestrant combination led to a mTTC of 23.3 months (95% CI, 15.2-28.4) compared with 14.8 months (95% CI, 10.5-22.6) in the placebo arm. “The median time to chemotherapy was about 8.5 months longer for the alpelisib arm, suggesting that alpelisib alone delayed time to first chemotherapy,” André noted.
PFS2 was also evaluated as an exploratory end point in the PIK3CA-mutant cohort and was measured from the time of randomization to the first documented instance of disease progression on the first new systemic antineoplastic therapy initiated after discontinuation of study treatment or death from any cause. The median PFS2 was 22.8 months (95% CI, 18.5-26.3) with alpelisib and 18.2 months (95% CI, 12.8-22.2) with fulvestrant (HR, 0.80; 95% CI, 0.62-1.03).1
At a median follow-up of 42.4 months, “adverse events [AEs] were consistent with those in prior reports and no new safety signals were observed,” André said. Notably, the incidence of hyperglycemia “did not increase with longer time on treatment,” he added.
The 3 most common grade 3 AEs in the alpelisib arm were hyperglycemia (33.1%), diarrhea (7.0%), and decreased weight (5.3%). No grade 4 AEs were seen aside from grade 4 hyperglycemia, which affected 11 of the 284 patients included in the alpelisib safety analysis.
Grade 3 AEs also occurred at a low frequency in the fulvestrant arm. The most prevalent grade 3 events were fatigue (1.0%), hyperglycemia (0.7%), and diarrhea (0.7%). The only grade 4 AE was hyperglycemia, which affected just 1 of the 287 patients evaluated for safety.1
One AE of special interest, rash, was observed in 153 (53.9%) and 27 (9.4%) of patients who received alpelisib-fulvestrant versus fulvestrant, respectively. The majority of these events were grade 1 or 2, André said.
The phase 3 SOLAR-1 (NCT02437318) study enrolled 572 patients with hormone receptor-positive, HER2-negative advanced breast cancer who received prior endocrine therapy. Patients were enrolled into 2 cohorts based on PIK3CA mutation status (mutated vs non-mutated) and randomly assigned in a 1:1 ratio to receive 300 mg of alpelisib plus 500 mg of fulvestrant or fulvestrant alone. In each cohort, randomization was stratified by the presence or absence of lung or liver metastases and prior receipt of a CDK4/6 inhibitor. Of the 572 patients enrolled, 341 had confirmed tumor-tissue PIK3CA mutations. The primary end point was progression-free survival in the PIK3CA-mutant cohort. Secondary end points included overall response and safety.
The statistically significant prolongation of PFS initially observed in the SOLAR-1 study is now supported by a numeric increase in OS. Previously announced PFS data from SOLAR-1 showed that alpelisib and fulvestrant nearly doubled PFS in the PIK3CA-mutant cohort compared with fulvestrant alone. At a median follow-up of 20 months, the PFS was 11.0 months (95% CI, 7.5-14.5) with the doublet therapy and 5.7 months (95% CI, 3.7-7.4) with fulvestrant (HR, 0.65; 95% CI, 0.50-0.85; P < .001). At 12 months, PFS, the primary end point of the study, remained superior in the combination arm (46.3% vs 32.9%).3
Although not statistically significant, the increase in OS seen in alpelisib-treated patients is clinically relevant, and when coupled with the statistically significant and clinically relevant PFS data, the improvements in OS and mTTC “further support” the use of alpelisib and fulvestrant in this poor prognostic population, the authors concluded.1