Regulatory Decision Summary for Qinlock

Gastrointestinal stromal tumors represent the most common form of soft tissue sarcoma, a relatively rare subset of cancers arising from mesenchymal cells in the body. GISTs occur primarily in older patients of either sex, with an annual incidence between 11 and 19.6 per million population worldwide. Approximately 500 cases of GIST are diagnosed per year in Canada.

Currently, there are 3 approved tyrosine kinase inhibitors that are indicated to treat patients with this disease: imatinib mesylate, sunitinib malate, and regorafenib. Once patients have received imatinib, sunitinib, and regorafenib, there are no other approved treatment options for patients with advanced or unresectable GIST. There are limited data to support that re-challenge with prior failed treatment options may offer minor benefit.

The efficacy and safety data are derived from the pivotal study (INVICTUS), a randomised, double-blinded, placebo-controlled study in patients with advanced GIST who have received prior treatment with imatinib, sunitinib and regorafenib. The primary endpoint was progression-free survival (PFS); key secondary endpoints included objective response rate (ORR) and overall survival (OS).

A total of 129 patients were enrolled in INVICTUS; 85 patients were randomized to ripretinib and 44 patients to placebo. Treatment with Qinlock led to a statistically and clinically meaningful improvement in PFS. The median PFS was 6 months in the treatment arm as compared to 1 month for the placebo arm. This represented an into a 85% decrease in the risk of progression or death favouring QUINLOCK arm over the placebo arm. ORRs also favoured Qinlock (9%) as compared to placebo (0%) but failed to reach the predetermined threshold for statistical significance. As a result a formal statistical  analysis of OS could not be performed. Nevertheless, the analysis of OS demonstrated a clinically meaningful improvement in survival favouring the treatment arm. The median OS was 15 months in the Qinlock arm as compared to 7 months in the placebo, representing a 64% decreased risk in death.

The safety data were derived from the pivotal study described above, as well as from as a phase I study. The pooled safety population included 351 patients who received at least one dose of Qinlock. In general, Qinlock was well tolerated; and the majority of the adverse events observed can be managed clinically. In the pivotal study, the most common adverse events (≥20%) observed in patients treated with Qinlock were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysaesthesia syndrome, and vomiting. Serious adverse events occurred in 31% of patients who received Qinlock; serious adverse events that occurred in >2% of patients were abdominal pain, anemia, nausea, and vomiting. The serious risks of Qinlock observed across the drug development program include: cardiac dysfunction (left ventricular systolic dysfunction), hypertension, new primary cutaneous malignancies including squamous cell carcinoma and melanoma, cardiac ischemia, hypersensitivity, impaired wound healing, embryofetal toxicity, palmar-plantar erythrodysaesthesia syndrome, and photosensitivity. All of these significant safety risks are now clearly highlighted in the Adverse Reactions table and/or the Warnings and Precautions section and generally manageable, as demonstrated in the pivotal trial, by dose interruption, dose reduction, dose discontinuation and/or standard medical practice. These mitigation strategies are clearly outlined in the Product Monograph.

A Risk Management Plan (RMP) for Qinlock was submitted to Health Canada and considered to be acceptable upon review.

In summary, the pivotal study met its primary endpoint demonstrating a superior PFS benefit favouring Qinlock as compared to placebo. Additionally, the efficacy was coupled with a tolerable and manageable safety profile. As such, Health Canada concluded that the benefits of Qinlock outweigh the risks under the proposed conditions of use.