Regulatory Decision Summary for Kisqali

This Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for the following expanded indications in males for Kisqali (ribociclib) for the treatment of adult patients, in combination with:

• an aromatase inhibitor for the treatment of pre/perimenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy.

• fulvestrant for the treatment of postmenopausal women or men with HR-positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy or following disease progression on endocrine therapy.

Upon review, the indication for Kisqali in combination with an aromatase inhibitor in men was approved based primarily on evidence from the male patient subpopulation in the pivotal clinical trial (Study A2404). There was no clinical trial or other relevant evidence to support the indication for Kisqali in combination with fulvestrant in men and this indication was not approved.

This SNDS was also filed to update the Clinical Trials section of the Kisqali Product Monograph (PM) to align with the PM Guidance September 2020 Master Template.

One of the proposed expanded indications is for the use of Kisqali plus an aromatase inhibitor (AI) in males with HR-positive HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy, was supported primarily by a pivotal phase IIIb open-label single-arm Study A2404 (Compleement-1). The purpose of this study was to validate the safety and tolerability and clinical efficacy of Kisqali plus letrozole in a large cohort of patients with HR-positive HER2-negative advanced breast cancer who had not received prior hormonal treatment for advanced disease. The primary endpoint was safety and tolerability, the secondary objectives included investigator-assessed efficacy measures of objective response rate (ORR) and clinical benefit rate (CBR) based on investigator assessment per RECIST 1.1, duration of response (DoR) and time to progression (TTP). Patient-reported outcomes were only collected in females given that the FACT-B questionnaire was validated in this population.

The study enrolled 3,246 male and female patients with HR-positive HER2-negative advanced or metastatic breast cancer who had not received prior treatment. A subgroup of 39 males was evaluated. Patients received oral Kisqali 600 mg per day in combination with letrozole (an aromatase inhibitor). Males and premenopausal females also received a luteinizing hormone releasing hormone (LHRH) agonist/gonadotropin releasing hormone analogue (GnRH), such as goserelin. Median age of the male patients was 62.0 years. The majority were Caucasian (71.8%). All had HR-positive breast cancer and were also HER2-negative. Nearly all patients (97.4%) had a baseline ECOG performance status of 0 or 1. Of the total males enrolled, 38.5% were de novo metastatic breast cancer patients. Approximately one-half (43.6%) had ≥ 3 metastatic sites. The majority had bone and/or visceral metastasis (69.2%, each).

In the male subgroup, the ORR was 46.9% based on 15 males with confirmed complete response (CR) or partial response (PR) of 32 males with measurable disease at baseline. The clinical benefit rate (CBR) was 71.9% based on 23 males with confirmed CR or PR or prolonged stable disease of a total of 32 males with measurable disease at baseline. The efficacy findings in the male subgroup are comparable with the magnitude of efficacy in the overall population of 3,246 patients in Study A2404 and with that of the female subgroup in the same study.

In the male population, the median duration of response (DoR) was not reached and 80.0% (12/15 patients) had DoR ≥12 months.

To further assess the benefit of Kisqali plus an AI in males, the efficacy of treatment (ORR and CBR) in the male population in Study A2404 was also compared to that of the female population from the phase 3 Monaleesa studies (A2301, E2301 and F2301) in various breast cancer settings. Study A2301 is a randomized double-blind, placebo-controlled, multicenter, phase III study of ribociclib in combination with letrozole for the treatment of postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease. Study E2301 is a randomized, double-blind, placebo-controlled, multicenter, phase III study of ribociclib or placebo in combination with a nonsteroidal AI and goserelin or tamoxifen and goserelin in pre- or perimenopausal women with HR-positive, HER2-negative, advanced breast cancer who had received no prior hormonal therapy for advanced disease. Study F2301 is a randomized, double-blind, placebo-controlled, multicenter, phase III study of ribociclib or placebo in combination with fulvestrant in post-menopausal women with HR-positive, HER2-negative, advanced breast cancer who received up to one line of endocrine therapy for the advanced disease.

While a retrospective direct comparison of data from open-label Study A2404 to data from phase III double-blind placebo-controlled trials should be interpreted with caution, taken together, the above efficacy findings suggest that the benefit of Kisqali combination therapy with an aromatase inhibitor in male breast cancer patients is clinically meaningful as findings are aligned with that reported in similarly treated female populations.

While Study A2404 supports the proposed expanded indication for Kisqali plus an AI in males, there are some important aspects to consider. Study A2404 was single arm and not designed as a comparative study. The benefit in males is supported by a small sample of 39 males, which is acceptable given the challenges of conducting controlled clinical trials in this very rare population. While PFS and OS are the standard endpoints used to support the benefit of Kisqali plus AI or plus fulvestrant in female breast cancer patients (in the Monaleesa studies), ORR and CBR in male patients which is aligned with that of female patients, together with a durable response, provide a useful estimate of the clinical benefit of Kisqali in male patients.

The safety profile of Kisqali in Study A2404 was based on patients whose enrolment criteria were less restrictive than other studies. Generally, the adverse events reported in this population were consistent with the known safety profile for Kisqali, and adequately managed with dose modification.

A Canadian Addendum to the European Union Risk Management Plan (RMP) Version 6.0 was reviewed. The sponsor will be requested to provide segregated male and female post-market data when assessing new information for the safety concerns.

On the basis of the above presented data, the benefit-harm-uncertainty profile for the use of Kisqali plus an aromatase inhibitor in this male population with HR-positive HER2-negative advanced breast cancer who had not received prior hormonal treatment for advanced disease is considered favorable. This indication offers a valuable treatment option for a rare patient population with limited treatment modalities.

Given that the dossier did not include clinical trial data or any relevant information for use of Kisqali with fulvestrant in male breast cancer patients with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy, this indication could not be supported.

For further details about Kisqali, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.