In an estimated 40% of patients with HR-positive/HER2-negative advanced breast cancer, mutations in PIK3CA contribute to lower survival rates and development of resistance to certain cancer therapies. Long-term maintenance of advanced disease with these characteristics has proved difficult, but recent development of novel drug regimens has shown promise. PIK3CA mutations have shown to be predictive of prolonged progression-free survival (PFS) in patients treated with alpelisib.
The phase 3 randomized, double-blind SOLAR-1 trial evaluated alpelisib (ALP) or placebo plus fulvestrant (FUL) in patients with HR-positive/HER2-negative advanced breast cancer that progressed on/after treatment with an aromatase inhibitor. X2101 is a phase 1, open-label, dose-escalation study of ALP ± FUL in advanced solid tumors that progressed on/after antiestrogen therapy or relapsed after adjuvant antiestrogen therapy. ALP + FUL demonstrated efficacy in HR-positive/HER2-negative patient populations in clinical trials, but the predictors of long-term control have not been fully studied. In patients with endocrine-resistant disease, long-term disease control of ≥18 months is clinically relevant. The current study provides data on the impact of ALP in combination with FUL in maintaining HR-positive, PIK3CA-mutated disease control, defined as ≥18 months of PFS in SOLAR-1 or time on treatment in X2101.
In X2101 (N = 52), 7 (13.5%) HR-positive, PIK3CA-mutated patients with advanced disease who received ALP + FUL achieved long-term disease control up to a median of 51.5 months. Among patients who reached long-term disease control, 1 patient achieved complete response; overall response and disease control were 100%. Time on ALP treatment in X2101 patients achieving long-term disease control ranged from 642 to 1457 days. All 7 X2101 disease-controlled patients suffered adverse events such as nausea (100%), hyperglycemia (85.7%), diarrhea (71.4%), fatigue (71.4%), and alopecia (57.1%). In SOLAR-1 (N = 169), 30.2% of HR-positive/HER2-negative PIK3CA-mutated patients receiving ALP + FUL achieved long-term control (median PFS, 33.5 months). Of these patients, 72.5% achieved very long-term disease control with a PFS of 24 months up to 49.7 months. Three SOLAR-1 patients achieved complete response, overall response was 35.3%, and clinical benefit rate was 100%. Median treatment time with ALP was 24.8 months in patients who achieved long-term disease control and 5.5 months overall. All 51 patients achieving long-term disease control experienced adverse events, including diarrhea (78.4%), hyperglycemia (76.5%), nausea (62.7%), reduced appetite (41.2%), and rash (39.2%). In patients with long-term disease control, median ALP relative dose intensity was 79.9% compared with 82.1% in the overall SOLAR-1 study population.
In both the SOLAR-1 and X2101 trials, long-term disease control was observed in HR-positive, PIK3CA-mutated advanced breast cancer patients with ALP + FUL treatment. Characteristics of patients who might achieve the most long-term benefit include those with low disease burden, low number of metastatic sites and no metastasis to the liver, low endocrine resistance, and good Eastern Cooperative Oncology Group performance status. Those with heavy pretreatment, poor prognosis, and diabetes or prediabetes at baseline did not impede long-term disease control. Reports of adverse events were consistent with previous data and had no effect on duration of disease control. In conclusion, this analysis provides support of ALP + FUL as an effective treatment option for achieving long-term disease control in patients with HR-positive, PIK3CA-mutated breast cancer.
Source: Juric D, Andre F, Panwar U, et al. Long-term (LT) disease control in patients (pts) with hormone receptor-positive (HR+), PIK3CA-altered advanced breast cancer (ABC) treated with alpelisib (ALP) + fulvestrant (FUL). American Society of Clinical Oncology Virtual Meeting; June 4-8, 2021. Abstract 1054.