Potential for Long-Term Disease Control with Alpelisib Plus Fulvestrant Spans Patient Subgroups in HR+ PIK3CA-Mutated Advanced Breast Cancer

Approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) harbor mutations in the PIK3CA gene. The presence of PIK3CA mutations leads to hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway, treatment resistance, and worse prognosis.

Alpelisib is an oral PI3K inhibitor approved for use in combination with fulvestrant for patients with HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer following progression on or after endocrine therapy. The approval of alpelisib was based on findings from the phase III SOLAR-1 trial, which showed that adding alpelisib to fulvestrant improved progression-free survival (PFS) in patients with PIK3CA-mutated disease [1]. Within this subgroup, the median PFS was 11.0 months with alpelisib plus fulvestrant and 5.7 months with fulvestrant alone (HR, 0.65; 95% CI, 0.50–0.85; p = .001).

Findings from the SOLAR-1 trial confirmed earlier results from the phase Ib X2101 trial of alpelisib in patients with HR-positive, PIK3CA-mutated ABC [2].

Given the challenges of treatment resistance associated with PIK3CA mutations, it is critical to better understand predictors of long-term disease control. In the current analysis, Dejan Juric, M.D., of Massachusetts General Hospital, presented results from a new analysis of patients in the SOLAR-1 and X2101 studies who achieved long-term disease control with alpelisib plus fulvestrant [3].

Key Findings: SOLAR-1

The phase III SOLAR-1 trial enrolled 341 patients with HR-positive, HER2-negative, PIK3CA-mutated advanced breast cancer that had progressed on prior aromatase inhibitor therapy. Patients were randomly assigned to alpelisib plus fulvestrant (n = 169) or placebo plus fulvestrant (n = 172). The trial also included a cohort of 231 patients with PIK3CA wild-type advanced breast cancer who were evaluated separately.

Within the alpelisib plus fulvestrant group, 51 patients (30.2%) achieved long-term disease control. Of these, 37 patients (72.5%) also reached very long-term disease control, defined as achieving a median duration of PFS of 24 months or longer.

To identify potential predictors of long-term treatment benefit, researchers evaluated baseline characteristics across patient groups (Table 1). In general, patients who achieved long-term disease control had better Eastern Cooperative Oncology Group performance status (ECOG PS) at baseline, longer time from initial diagnosis to first recurrence, fewer metastatic sites, and a lower occurrence of visceral metastases and primary endocrine resistance than the overall study population.

Key Findings: X2101

In the phase Ib X2101 trial, 52 patients with HR-positive, PIK3CA-mutated ABC that had progressed after antiestrogen therapy were treated with alpelisib plus fulvestrant. Of these, 7 patients (13.5%) reached long-term disease control and 5 patients (9.6%) achieved very long-term disease control.

Compared with the overall study population, those who achieved long-term disease control were more likely to have an ECOG PS of 0 at baseline (42.3% vs. 57.1%), <3 metastatic sites (34.6% vs. 57.1%), and a lower occurrence of liver metastases (53.8% vs. 42.9%). As with the analysis of SOLAR-1; however, the presence of less favorable clinical and disease features did not preclude long-term disease control.

In the safety analysis, the median duration of exposure to alpelisib was 6.6 months for all patients and 29.7 months for those who achieved long-term disease control. The longer exposure to alpelisib in those who achieved long-term disease control had no effect on the median RDI compared with the overall study population (90.7% vs. 90.9%, respectively).

Summary

Findings from this updated analysis of the SOLAR-1 and X2101 trials support the role of alpelisib plus fulvestrant in patients with endocrine-resistant, HR-positive, PIK3CA-mutated ABC. Patients with good performance status, low disease burden, bone-only disease, absence of liver metastases, or endocrine sensitivity at baseline were especially likely to achieve long-term disease control with alpelisib plus fulvestrant.

References

Author notes