Regulatory Decision Summary for Piqray

Advanced breast cancer is serious, life-threatening, and incurable. Although new treatment options for patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have recently been approved, there remains an unmet need for therapies for postmenopausal women and men with advanced breast cancer with a PIK3CA mutation following disease progression on endocrine-based therapy. Study C2301 was the first trial specifically designed to evaluate a targeted treatment of alpelisib in combination with fulvestrant in patients whose tumors have a PIK3CA mutation.

In the PIK3CA mutation cohort, the primary efficacy endpoint, progression-free survival (PFS) assessed by investigators, was met in the randomized, double blind, placebo-controlled phase III trial, Study C2301. A statistically significant improvement of PFS in favour of alpelisib plus fulvestrant treatment over fulvestrant alone was demonstrated, with an estimated 35% risk reduction in disease progression or death. A clinically meaningful improvement in median PFS of 5.3 months (11.0 months in the alpelisib plus fulvestrant arm vs. 5.7 months in the fulvestrant alone arm) was also observed. The PFS benefit was generally consistent across pre-planned sensitivity and supportive analyses, indicative of the robustness of the primary analysis. PFS analysis of a randomly sampled subset of 50% of the subjects by blinded independent review committee (BIRC) assessment confirmed the primary analysis assessed by the investigators. Treatment with alpelisib plus fulvestrant also showed improvements in PFS across subgroups including different demographics, endocrine-resistant populations, subgroups with baseline bone and/or visceral metastases, and patients with mutations at 3 different axons of PIK3CA gene (e.g. known hotspot mutations).

In the PIK3CA mutation cohort, overall survival (OS) data were not yet mature at the primary analysis. Although statistical significance was not demonstrated, no detriment was observed in patients treated with alpelisib. Treatment with alpelisib plus fulvestrant was associated with marked improvements in objective response rates (ORR) and clinical benefit response (CBR) relative to placebo plus fulvestrant. The differential rates in ORR and CBR between the two treatment arms were consistent with the observed gain in PFS. In addition, no differences were observed between the two treatment arms in time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status in the PIK3CA mutant cohort. Data from a Phase I/II study (Study X2101) provided further supportive evidence of dose selection and efficacy for alpelisib plus fulvestrant in a more heavily pretreated patient population with PIK3CA altered advanced breast cancer.

As a secondary endpoint, PFS per investigator assessment was evaluated for patients in the PIK3CA non-mutation cohort, using Proof of Concept (PoC) criteria. These PoC criteria were not met in the PIK3CA non-mutation cohort, indicating a lack of clinical efficacy. There were no statistically significant differences in ORR and CBR between the two arms. Therefore, Piqray is not recommended for breast cancer patients without a PIK3CA mutation.

Overall, alpelisib in combination with fulvestrant has a manageable safety profile in patients with HR-positive, HER2-negative advanced breast cancer, based primarily on the data from the pivotal study. Alpelisib plus fulvestrant has a well-characterized safety profile with adverse events (AEs) that are associated with PIK3 pathway inhibition such as hyperglycemia, rash, and Gastrointestinal (GI) toxicity. These AEs are well characterized and manageable with dose modifications and/or intervention therapies. A 90-day safety update was largely consistent with the safety profile reported at the primary analysis cutoff and no new safety concerns were identified.

Strong Cytochrome P450 3A4 (CYP3A4) inducers (rifampin) may decrease alpelisib plasma concentration and co-administration of these agents must be avoided. Alpelesib may reduce the plasma concentration of CYP2C9 substrate (Warfarin) and hence Cytochrome P450 2C9 (CYP2C9) substrate plasma concentrations must be monitored. Breast Cancer Resistance Protein (BCRP) inhibitors (cyclosporine) may increase alpelisib plasma concentration and the risk of adverse reactions. Co-administration of these agents must be avoided. Alpelisib pharmacokinetics is not significantly altered when co-administered with fulvesterant or acid reducing agents (ranitidine) in presence of food.

The combination of alpelisib plus fulvestrant at the recommended dose offers a valuable new treatment option for patients with HR-positive, HER2-negative, PIK3CA mutated advanced breast cancer with disease progression on or following an endocrine-based regimen. The safety profile of alpelisib is acceptable for the intended target population that has a serious and life-threatening disease. Adverse events associated with alpelisib were well characterized and considered manageable with clinical monitoring and appropriate supportive therapy or intervention, including dose interruptions, reduction or discontinuation of Piqray. The Serious Warnings and Precautions Box, Warnings and Precautions, and Adverse Reactions sections of the Product Monograph (PM) detail the serious risks associated with alpelisib plus fulvestrant while the Dosage and Administration section provides further guidance for safety management. The reviews of nonclinical and clinical pharmacology support an approval of Piqray for the indicated population. A Risk Management Plan (RMP) was reviewed by Marketed Health Products Directorate (MHPD) and considered acceptable.

In conclusion, the pivotal study met its primary endpoint in the PIK3CA mutant cohort, demonstrating a statistically significant and clinically meaningful improvement in PFS in favor of the alpelisib plus fulvestrant treatment. This combination at the recommended dose offers a valuable new treatment option for patients with HR-positive, HER2-negative advanced breast cancer harboring a PIK3CA mutation, with disease progression on or following an endocrine-based regimen. In the context of the significant clinical benefit observed for this target population with limited therapeutic options, the tolerability of this combination regimen is considered acceptable. The totality of the data supports a favorable benefit-risk profile for alpelisib in combination with fulvestrant for the treatment of postmenopausal women and men with HR-positive, HER2-negative, PIK3CA mutated, advanced breast cancer after disease progression following an endocrine-based regimen.