The combination of alpelisib and letrozole sustained efficacy and did not result in any new safety signals in patients with PIK3CA-mutant hormone receptor–positive, HER2-negative advanced breast cancer who received prior treatment with the combination of a CDK4/6 inhibitor and fulvestrant.
The combination of alpelisib (Piqray) and letrozole (Femara) sustained efficacy and did not result in any new safety signals in patients with PIK3CA-mutant hormone receptor (HR)–positive, HER2-negative advanced breast cancer who received prior treatment with the combination of a CDK4/6 inhibitor and fulvestrant (Faslodex), according to findings from cohort B of the ongoing phase 2 BYLieve trial (NCT03056755) that were presented virtually during the 2020 San Antonio Breast Cancer Symposium.
At a median follow-up of 15 months, the combination of alpelisib and letrozole led to a median progression-free survival (PFS) of 5.7 months (n = 126; 95% CI, 4.5-7.2). A total of 46.1% of patients were alive without disease progression at 6 months per local investigator assessment (n = 53; 95% CI, 36.8%-55.6%), meeting the primary end point of the study.
“Data from these patients, many of whom progressed on a prior AI [aromatase inhibitor], as well as CDK4/6 inhibitors and fulvestrant, suggest that the combination of alpelisib and letrozole maintains efficacy with manageable adverse effects [AEs]. Thus, it may be an effective treatment option for patients with PIK3CA-mutated, HR-positive advanced breast cancer who progress on prior treatment with a CDK4/6 inhibitor and fulvestrant,” Hope S. Rugo, MD, a professor in the Department of Medicine, Hematology/Oncology, and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, said in a virtual presentation of the data.
The combination of a CDK4/6 inhibitor and endocrine therapy is the current standard frontline therapy for patients with HR-positive, HER2-negative advanced breast cancer. However, when resistance to endocrine therapy occurs, patients experience disease progression. In up to 40% of patients, endocrine therapy resistance is a result of an acquired mutation in PIK3CA.
In May 2019, the FDA approved the PI3K inhibitor alpelisib for use in combination with fulvestrant as a treatment for postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutant, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.
The multicenter, open-label, 3-cohort noncomparative BYLieve study is evaluating the combination of alpelisib and endocrine therapy in patients with PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer who progressed on or after prior therapy with a CDK4/6 inhibitor plus endocrine therapy, systemic chemotherapy, or endocrine therapy alone.
In cohorts A (n = 112), B (n = 112), and C (n = 112), patients will receive 300 mg of oral alpelisib daily plus 500 mg of fulvestrant, alpelisib plus 2.5 mg of letrozole, or alpelisib plus 500 mg of fulvestrant, respectively.
In cohorts A and B, patients had to have progressed on a CDK4/6 inhibitor as their last treatment. In cohort C, patients had to have progressed on or after an AI and received chemotherapy or endocrine therapy as their last prior treatment before enrollment.
The percentage of patients with a centrally confirmed PIK3CA tumor mutation who were alive without disease progression at 6 months by local investigator assessment per RECIST v1.1 criteria within each cohort served as the primary end point of the study. The primary end point was met and clinically meaningful if the lower bound of the 95% CI was greater than 30%.
Prior findings from cohort A demonstrated that the combination of alpelisib and fulvestrant led to a median PFS of 7.3 months in patients who received the combination of a CDK4/6 inhibitor and an AI as their last therapy (n = 72; 95% CI, 5.6-8.3), meeting the primary end point of the study. At a median follow-up of 11.7 months, 50.4% of patients were alive without disease progression at 6 months per local investigator assessment (n = 61; 95% CI, 41.2%-59.6%).
In cohort B, the majority of patients had received 1 line of prior therapy in the metastatic setting (57.9%), had secondary endocrine resistance (57.9%), and had progression on a prior AI (81.7%).
At the time of data cutoff, 92.9% of patients in cohort B had discontinued treatment (n = 117) because of progressive disease (64.3%; n = 81), an AE (11.1%; n = 14), physician decision (9.5%; n = 12), death (1.6%; n = 2), patient or guardian decision (4.8%; n = 6), protocol deviation (0.8%; n = 1), and lost follow-up (0.8%; n = 1).
Additional findings from cohort B demonstrated that the overall response rate, which consisted of all partial responses, was 15.7% (n = 18; 95% CI, 9.5%-23.6%). The clinical benefit rate was 32.2% (n = 37; 95% CI, 23.8%-41.5%).
Cohort B also showed a similar reduction in tumor size compared with that of cohort A. Specifically, the decrease in best percentage change from baseline was 66.3% in cohort B and 70.1% in cohort A. The increase or zero change in best percentage change from baseline was 24.4% and 26.4%, respectively.
Regarding treatment exposure and dose adjustments, the median duration of exposure to alpelisib and letrozole was 4.0 months and 4.2 months, respectively (n = 126). The median relative dose intensity (RDI) for alpelisib was 87.6%. Moreover, the RDI was greater than 90% for 48.4% of patients and between 75% and 90% for 25.4% of patients.
In terms of safety, serious grade 3 or greater AEs (SAEs) occurred in 30.2% of patients (n = 38); 13.5% were treatment related (n = 17). Fatal SAEs occurred in 1.6% of patients (n = 2). Grade 3 or greater AEs leading to discontinuation or dose adjustment or interruption occurred in 8.7% (n = 11) and 54.8% (n = 69) of patients, respectively.
The most common AEs included diarrhea (all-grade, 67.5%; grade ≥3, 4.0%), hyperglycemia (all-grade, 63.5%; grade ≥3, 25.4%), nausea (all-grade, 54.8%; grade ≥3, 2.4%), rash (all-grade, 31.0%; grade ≥3, 9.5%), rash maculopapularc (all-grade, 16.7%; grade ≥3, 7.9%), fatigue (all-grade, 31.0%; grade ≥3, 4.0%), decreased appetite (all-grade, 44.4%; grade ≥3, 0.8%), stomatitis (all-grade, 34.1%; grade ≥3, 0.8%), vomiting (all-grade, 24.6%; grade ≥3, 0.8%), and asthenia (all-grade, 21.4%; grade ≥3, 4.0%).
Other grade 3 or greater AEs reported in at least 2 patients included hypertension (5.6%), abdominal pain (4.8%), gamma-glutamyl transferase increase (3.2%), and aspartate aminotransferase increase, dyspnea, headache, and weight decrease (1.6% each).
Hyperglycemia was the most common reason for dose interruption or adjustment, occurring in 36 patients (28.6%), followed by diarrhea and rash (10.3% each).
AEs leading to treatment discontinuation included rash (3.2%; including rash maculopapular), fatigue and diarrhea (2.4% each), and hyperglycemia, urticaria, increased aspartate aminotransferase, nausea, pneumonia, stomatitis, lower abdominal pain, acute kidney injury, decreased appetite, general physical health deterioration, hypersensitivity, increased lipase, peripheral edema, syncope, and thirst (0.8% each).
Rash, which was an AE of special interest, occurred in 49.2% of patients (n = 62). Among patients who received antihistamines before rash onset (n = 30), 33.3% of patients had a grade 1/2 rash, 20.0% of patients had a grade 3/4 rash, and 46.7% of patients had no rash. Among patients who received antihistamines after rash or who did not receive antihistamines before rash (n = 96), 29.2% of patients had a grade 1/2 rash, 18.8% of patients had a grade 3/4 rash, and 52.1% of patients had no rash.