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Alpelisib Combo Promising in PIK3CA-Altered, Heavily Pretreated Breast Cancer

Silas Inman @silasinman
Published: Saturday, Mar 12, 2016

 Dejan Juric, MD

Dejan Juric, MD

The combination of the alpha-specific PI3K inhibitor alpelisib (BYL719) and fulvestrant (Faslodex) demonstrated promising early efficacy and mild toxicity in heavily pretreated postmenopausal women with ER-positive metastatic breast cancer, according to an open-label study presented at the 2016 Miami Breast Cancer Conference.

In evaluable patients with PIK3CA-altered tumors (n = 49), the objective response rate was 27% and the stable disease rate was 53%. The median progression-free survival (PFS) with alpelisib plus fulvestrant was 9 months. Based on these findings, the phase III SOLAR-1 trial is currently enrolling patients with PIK3CA-altered metastatic breast cancer.

“Preliminary efficacy results are extremely promising. Alpelisib with fulvestrant is clearly a very synergistic combination, particularly in PIK3CA-altered tumors,” lead investigator Dejan Juric, MD, from Massachusetts General Hospital, told OncLive. “SOLAR-1 is now actively recruiting patients and is aimed to redefine the second-line ER-positive treatment landscape, particularly in PIK3CA-mutant tumors.”

The study enrolled 87 postmenopausal women with ER-positive, HER2-negative locally advanced or metastatic breast cancer. Alpelisib was administered orally at a starting dose of 300 mg in a continuous daily schedule. A Bayesian logistic regression model guided dose escalation, to avoid overdose. Fulvestrant was administered at a fixed dose of 500 mg every 28 days, with a one-time 500 mg dose administered on day 14 during the first cycle.

The median age of patients was 58 years, the majority were Caucasians (86%), and most had an ECOG performance status of 0 (45%) or 1 (53%). The most common stage at initial diagnosis was stage II (37%), and 26% of patients had stage IV disease. Sixty percent of tumors had PIK3CA alterations and 38% were PIK3CA wild-type. The median number of prior therapies was 5 (range, 1-16), including fulvestrant (45%), everolimus (24%), and chemotherapy (91%).

In the PIK3CA-altered population, the disease control rate (ORR plus stable disease) was 80%. The clinical benefit rate (ORR plus stable disease >24 weeks) was 45%. In the PIK3CA wild-type arm (n = 32), no patients experienced a response. The disease control rate was 47% and the clinical benefit rate was 13%. Median PFS was 5 months in the wild-type group.

“Despite enrolling a heavily pretreated patient population, we have observed a median PFS of 9 months in the PIK3CA-altered group and 5 months in the PIK3CA wild-type group,” Juric noted.

At the February 2015 data cutoff, 13% of patients continued to receive treatment. The primary causes for discontinuation were disease progression (67%), adverse events (AEs; 10%), patient decision (7%), and other reasons (3%). All patients who discontinued for AEs received the largest dose (400 mg), which was identified as the maximum tolerated dose. The most common AEs that led to discontinuation were rash (3%), hyperglycemia (2%), and pruritus (2%).

Across all doses administered in the study, the most frequently reported all-grade AEs were diarrhea (56%), hyperglycemia (48%), rash (48%), nausea (43%), decreased appetite (38%), fatigue (30%), stomatitis (28%), and vomiting (25%). The most common grade 3/4 AEs were diarrhea (47%), rash (26%), and hyperglycemia (18%).

The 300 mg dose was selected for future clinical trials. At this dose, there were no grade 3/4 AEs. The most common all-grade AEs were diarrhea, hyperglycemia, rash, nausea, fatigue, stomatitis, vomiting, and dysgeusia.

“Of note, alpelisib is a new generation, PI3K alpha-specific inhibitor designed to have an improved safety profile and a wider therapeutic window compared to pan-PI3K inhibitors,” said Juric. “At 300mg of alpelisib, the dose selected for subsequent development, we have observed low rates of grade 3/4 treatment-related adverse events and overall very manageable on-target toxicities.”

The phase III SOLAR-1 study is currently assessing alpelisib in combination with fulvestrant as a treatment for postmenopausal women with endocrine-resistant advanced breast cancer. PIK3CA mutation status by ctDNA will be assessed as a secondary endpoint. The study plans to enroll 820 patients, with an estimated study completion date of July 2019 (NCT02437318).


Juric D, André F, Rugo H, et al. Combined alpelisib (BYL719) and Fulvestrant in PIK3CA-altered or wild-type estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Presented at: Miami Breast Cancer Conference; March 10-13, 2016; Miami, FL. Abstract 334.

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