Alpelisib Generates Promising Responses in PI3KCA+ Breast Cancer After Progression on CDK Inhibitor


“Preliminary data for the 18 patients who have received belantamab mafodotin 2.5 mg/kg single dosing with bortezomib/dexamethasone suggests that this combination has an acceptable safety profile with no new safety signals identified."

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

More than 50% of patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer who had received a CDK4/6 inhibitor plus an aromatase inhibitor previously remained alive and progression-free at 6 months after the start of alpelisib (Piqray) plus fulvestrant (Faslodex), according to the phase 2 BYLieve study.1

Results presented during the 2020 ASCO Virtual Scientific Program showed that among 121 patients, 50.4% (n = 61) were alive and progression-free at 6 months. The 95% confidence interval was 41.2% to 59.6%, meeting the study’s primary end point with a lower bound of greater than 30%. The median progression-free survival (PFS) was 7.3 months (95% CI, 5.6-8.3).

“The combination of alpelisib and fulvestrant has demonstrated clinically meaningful efficacy in patients with PIK3CA-mutated, HR-positive/HER2-negative advanced disease who progressed on treatment with CDK4/6 inhibitors plus an aromatase inhibitor,” said lead investigator Hope S. Rugo, MD, professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

The FDA previously approved alpelisib for use in combination with fulvestrant as a treatment for postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. The approval was based on the phase 3 SOLAR-1 trial, in which among a subset of patients with PIK3CA mutations, the median PFS was 11.0 months with the alpelisib combination versus 5.7 months in patients who received placebo plus fulvestrant (HR, 0.65; 95% CI, 0.50-0.85; P <.001).2 Among a small group (n = 20) of patients who had prior CDK inhibitor treatment, the median PFS was 5.5 months versus 1.8 months, respectively. In this group, 44.4% of patients were alive without disease progression at 6 months.

Providing background for the data she shared on the ASCO platform, Rugo explained that, “The current standard of care in the first-line setting for patients with HR-positive, HER2-negative advanced breast cancer is endocrine therapy plus a CDK inhibitor; however, in almost all patients, resistance develops over time. For [those patients who have] PI3KCA-mutated [disease] who progress on a CDK inhibitor–based treatment, alpelisib plus fulvestrant is a treatment option, but there is limited clinical data available to inform treatment decisions in this setting.”

The ongoing, open-label, phase 2 noncomparative BYLieve trial (NCT03056755) accrued men or pre-/postmenopausal women with HR-positive, HER2-negative advanced breast cancer with a PIK3CA-mutation whose last line of prior therapy was a CDK inhibitor plus endocrine therapy; systemic chemotherapy; or endocrine therapy. The study included 3 cohorts. Cohort A comprised patients who received a CDK inhibitor plus an aromatase inhibitor as immediate prior therapy; cohort B comprised patients who received a CDK inhibitor plus fulvestrant as immediate prior therapy; and cohort C comprised patients who progressed on/after an aromatase inhibitor and received chemotherapy or endocrine therapy as immediate prior treatment.

On the ASCO virtual platform, Rugo shared findings from Cohort A. The cohort enrolled 127 patients between August 14, 2017, and December 17, 2019. The median follow-up was 11.7 months. The median patient age was 58 years (range, 33-83) and all patients were female. Among patients whose race was known, 63.8% were white, 9.4% were Asian, and 4.7% were black. ECOG performance status included 0 (62.2%), 1 (23.3%), 2 (1.6%), and unknown (3.9%).

Overall, 121 of the 127 patients had centrally confirmed PIK3CAmutations. Of this group, 100 patients had measurable disease at baseline and the remaining 21 did not. Lines of prior therapy in the metastatic setting included 0 (11.8%), 1 (70.1%), 2 (16.5%), and 3 (1.6%). Fifteen patients had received a CDK inhibitor in the adjuvant setting. Lines of prior endocrine therapy in the metastatic setting included 0 (11.8%), 1 (77.2%), and 2 (11%). No patients had fulvestrant as first-line treatment in the metastatic setting, while 6.3% had chemotherapy. Among patients whose endocrine status was known at study entry, 20.5% had primary endocrine resistance, 59.8% had secondary endocrine resistance, and 0.8% had endocrine sensitivity.

Patients in cohort A received oral alpelisib at 300 mg once daily plus 500 mg of fulvestrant through intramuscular injection on days 1 and 15 on cycle, followed by day 1 of each cycle thereafter. The primary end point of the study is the rate of patients who are still alive without progressive disease at 6 months. Secondary end points include PFS, PFS2, overall response rate (ORR), overall survival, and safety.

Among the 121 patients with a centrally confirmed PIK3CA mutation at baseline, the ORR was 17.4% (n = 21), comprising all partial responses (PRs). About half (45.5%; n = 55) of patients had stable disease and 11.6% (n = 14) of patients had progressive disease.

Among the 100 patients with PIK3CA-positive tumors and measurable disease at baseline, the ORR was 21%, comprising all PRs. Across the subgroup, 55.5% of patients had stable disease and 11% patients had progressive disease.

The safety analysis included all 127 patients. The most common (≥15% of patients) adverse events (AEs) across all grades included diarrhea (59.8%), hyperglycemia (58.3%), nausea (45.7%), fatigue (29.1%), decreased appetite (28.3%), rash (28.3%), stomatitis (26.8%), vomiting (23.6%), asthenia (19.7%), headache (18.9%), dry skin (15.7%), pruritus (15.7%), and dyspnea (15.0%).

Overall, grade ≥3 AEs occurred in 66.9% of patients. These included, hyperglycemia (28.3%), rash (9.4%), diarrhea (5.5%), dyspnea (2.4%), stomatitis (1.6%), vomiting (1.6%), and pruritus (1.6%). Additionally, grade ≥3 fatigue, decreased appetite, asthenia, headache, and dry skin occurred in 1 patient each.

Grade ≥3 serious AEs (SAEs) occurred in 24.4% of patients. There was 1 fatal SAE, which was respiratory failure. AE-related discontinuation occurred in 20.5% of patients, and AE-related dose adjustment/interruption occurred in 64.6% of patients.

For a comparison of cohort A to patients receiving other standard therapies, Rugo et al also conducted a weighted/matched analysis between the patients in cohort A of BYLieve and a real-world similar group of 95 patients with HR-positive/HER2-negative, PIK3CA-mutated advanced breast cancer who were treated with standard therapies.

The real-world patient data came from the de-identified US Flatiron Health-Foundation Medicine clinicogenomics database. The 95 patients had received a wide range of regimens, with the most frequent being capecitabine monotherapy (n = 14), fulvestrant monotherapy (n = 14), fulvestrant plus palbociclib (n= 13), everolimus plus exemestane (n = 11), and fulvestrant plus letrozole and palbociclib (n = 5).

Unadjusted results showed a median PFS of 7.3 months in BYLieve cohort A versus 3.6 months in the real-world cohort. Analyses using weighting by odds, propensity score matching, and exact matching also favored the alpelisib combination at 7.3 versus 3.7 months, 8 versus 3.5 months, and 6.5 versus 3.4 months, respectively.

“Matched analysis comparing BYLieve with real-world [data of] standard treatment in post–CDK4/6 inhibitor setting further supports use of alpelisib plus fulvestrant,” concluded Rugo.


  1. Rugo HS, FLerebours F, Ciruelos E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 1006.
  2. André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. Presented at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3.

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