The previously demonstrated progression-free survival benefit from the addition of alpelisib to fulvestrant appeared consistent among subgroups of patients with hormone receptor–positive/HER2-negative advanced breast cancer who have a PIK3CA mutation.
The previously demonstrated progression-free survival (PFS) benefit from the addition of alpelisib (BLY719) to fulvestrant (Faslodex) appeared consistent among subgroups of patients with hormone receptor (HR)—positive/HER2-negative advanced breast cancer who have a PIK3CA mutation, according to results from the phase III SOLAR trial presented at the 2019 Miami Breast Cancer Conference®.1-3
PFS was assessed by line of therapy; it improved with second-line treatment of the combination (10.9 months vs 3.7 months; HR, 0.61; 95% CI, 0.42-0.89). Also, PFS was prolonged with the alpelisib combination in the circulating tumor (ct)-determined PIK3CA-mutant population.1
Similarly, a treatment benefit was observed whether a patient was previously treated with a CDK4/6 inhibitor (HR, 0.48; 95% CI, 0.17-1.36) or without (HR, 0.67; 95% CI, 0.51-0.87); however, the researchers noted the total number of patients enrolled who had received prior CDK4/6 inhibitor therapy was small (n = 20).
“Alpelisib is the first PI3K inhibitor to show clinically meaningful, statistically significant results in breast cancer,” the researchers wrote. “…Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant HR-positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy (with/without a CDK4/6 inhibitor).”2
Previously reported findings from the PIK3CA-mutated subset of patients in SOLAR-1 showed a median PFS by local assessment of 11.0 months (95% CI, 7.5-14.5) for those who received the alpelisib combination compared with 5.7 months (95% CI, 3.7-7.4) for those who received placebo plus fulvestrant—resulting in a 35% reduction in the risk of progression or death, with a hazard ratio of 0.65 in favor of alpelisib (95% CI, 0.50-0.85; P = .00065).1-2
Of note, proof-of-concept criteria were not met and there was no advantage to alpelisib on median PFS in patients without a PIK3CA mutation (median PFS, 7.4 months vs 5.6 months; HR, 0.85; 95% CI, 0.58-1.25).
When PFS was assessed by a blinded independent review committee in the PIK3CA-mutated subgroup, the median PFS was 11.1 months (95% CI, 7.3-16.8) in the alpelisib combination arm versus 3.7 months (95% CI, 2.1-5.6) in the placebo arm, demonstrating a 7.4-month improvement with the addition of alpelisib to fulvestrant (HR, 0.48; 95% CI, 0.32-0.71).
In addition, the overall response rate (ORR) was superior in the alpelisib combination arm (35.7%; 95% CI, 27.4%-44.7%) compared with the placebo group (16.2%; 95% CI, 10.4%-23.5%) in the PIK3CA-mutated subset.
Overall survival (OS) data at the first interim analysis in patients with a PIK3CA mutation were immature (52% of planned events); however, the median OS was not reached in the alpelisib combination arm compared with 26.9 months with placebo.
Regarding safety, the most common adverse events (AEs) in the entire safety population (occurring in >20% of patients) were consistent with previous findings of alpelisib, and included hyperglycemia (63.7% vs 9.8%), diarrhea (57.7% vs 15.7%), nausea (44.7% vs 22.3%), decreased appetite (35.6% vs 10.5%), rash (35.6% vs 5.9%), vomiting (27.1% vs 9.8%), decreased weight (26.8% vs 2.1%), stomatitis (24.6% vs 6.3%), fatigue (24.6% vs 6.3%), and asthenia (20.4% vs 12.9%) compared with placebo.3
In total, 6.3% of patients were reported to have discontinued alpelisib due to hyperglycemia and 3.2% of patients discontinued due to rash; no patients discontinued placebo due to either hyperglycemia or rash.
However, the researchers noted that hyperglycemia was easily identifiable and reversible in the study, adding that, “Screening and monitoring of blood glucose levels are recommended for patients receiving alpelisib (and) hyperglycemia should be managed with dietary measures and early pharmacologic intervention.”
“Awareness, prevention, and early management of common AEs associated with alpelisib are critical to ensure continued therapy and optimal clinical benefit,” they concluded.3
Currently, endocrine therapy, with or without a CDK4/6 inhibitor, serves as the first-line treatment for HR-positive, HER2-negative advanced breast cancer; however, only 39% of patients remain progression-free on treatment 2.2 years after initiating treatment. “There is a need for new effective drugs in HR-positive, HER2-negative advanced breast cancer resistant to endocrine therapy,” the researchers wrote.
In the phase Ib trial of alpelisib in combination with fulvestrant among heavily pretreated patients with estrogen receptor—positive advanced breast cancer and known PIK3CA mutation status, median PFS was longer in patients with PIK3CA-altered tumors (9.1 months) compared with wild-type tumors (4.7 months).4
Therefore, the researchers aimed to determine whether treatment with alpelisib in combination with fulvestrant prolonged PFS compared with fulvestrant and placebo in men and postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received prior treatment with an aromatase inhibitor either as neoadjuvant therapy or for advanced disease.
Locally assessed PFS in the PIK3CA-mutant cohort served as the primary endpoint. Secondary endpoints included OS in the PIK3CA-mutant cohort, PFS in the non-mutant cohort, PFS of those with PIK3CA mutations in ctDNA, OS in the non-mutant cohort, ORR/clinical benefit rate (CBR), and safety.
Exclusion criteria included symptomatic visceral disease; prior treatment with chemotherapy (except for neoadjuvant/adjuvant chemotherapy), fulvestrant, any PI3K, mTOR, or AKT inhibitor; inflammatory breast cancer at screening; diabetes mellitus type I or not controlled type II; history of chronic pancreatitis or acute pancreatitis ≤1 year of screening; an ECOG performance status ≥2; central nervous system involvement, unless at >4 weeks from prior therapy completion to study start and stable; a patient who relapsed with progression >12 months from completion of neoadjuvant endocrine therapy with no treatment for metastatic disease.
Overall, 572 men or postmenopausal women with HR-positive, HER2-negative advanced breast cancer were randomized to oral alpelisib (300 mg/day) or placebo plus intramuscular fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle 1). A total of 341 patients had PIK3CA mutations when tumor tissue was tested, with 169 receiving the alpelisib combination and 172 taking fulvestrant alone; and 231 patients did not have the mutation, with 115 and 116 patients, respectively, given the alpelisib combination or fulvestrant alone.
“In advanced breast cancer, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is frequently activated due to mutations or amplification of PIK3CA, which encodes the catalytic subunit of the α-isoform of class I PI3K (PI3Kα),” the researchers wrote. “Alpelisib is an α-specific PI3K inhibitor and has demonstrated significant clinical activity in combination with endocrine therapy.”