Regulatory Decision Summary for Lonsurf

In this Supplemental New Drug Submission (SNDS), a randomized, double blind, Phase 3 study (TAS-102-302 (TAGS)) was submitted in support of Lonsurf in patients with metastatic gastric cancer (mGC) or adenocarcinoma of the gastroesophageal junction (GEJ) who were previously treated with at least two prior regimens for advanced disease. A total of 507 patients were randomized to Lonsurf (N = 337) or placebo (N = 170) arms.

The Lonsurf dose of 35 mg/m²/dose was administered twice daily on Days 1 through 5 and Days 8 through 12 of each 28-day cycle along with best supportive care. Similar dosing was previously approved in patients with metastatic colorectal cancer (mCRC). The primary efficacy outcome measure was overall survival (OS) and an additional outcome measure was progression free survival (PFS).

All patients in the TAGS study received at least 2 prior regimens for advanced disease and these included a fluoropyrimidine, a platinum, and either a taxane or irinotecan as per National Comprehensive Cancer Network (NCCN) as well as Canadian practice guidelines for gastric cancer. Patients with HER2/neu-positive tumours had received prior HER2/neu-targeted therapy.

Results of the TAGS study showed a statistically significant survival benefit in favour of Lonsurf with an median OS of 5.7 months compared to 3.6 months for placebo treated patients (HR:0.69, 95% CI 0.56-0.85; p <0.0006). Similarly, there was an improvement in median PFS in patients receiving Lonsurf as compared to the placebo arm (2 months vs 1.8 months, respectively).

Greater hematological toxicities including ≥Grade 3 adverse reactions (AR), serious ARs, dose delays and dose reductions were reported in patients with moderate renal impairment compared to the patients with normal (creatinine clearance ≥90 mL/min) or mild renal impairment (creatinine clearance 60 to 89 mL/min). This occurred in both the TAGS study (indication: mGC) as well as in the previously submitted RECOURSE study for metastatic colorectal cancer (mCRC) patients. These patients are advised to be monitored closely. Hematological laboratory abnormalities were higher in elderly patients than in younger patients (65 years of age or less); therefore, these patients are advised to be monitored. Lonsurf has not been studied in and is not recommended in children (<18 years of age).

The Safety results seen in patients with mGC, including Grade ≥3 TEAE, were similar to those previously reported in patients with mCRC. No new safety signals were seen in patients with mGC. The most frequent adverse reactions were reported as blood and lymphatic and gastrointestinal disorders. The reported hematologic toxicities were often severe and life threatening. Common Terminology Criteria for Adverse Events (CTCAE) Grades 3 and 4 included neutropenia (23%), leukopenia (7%), anemia (19%), and gastrointestinal disorders [nausea (3%), vomiting (4%), diarrhea (3%)]. One patient (0.2%) died due to neutropenic infection considered related to Lonsurf treatment. Thirteen percent of patients discontinued Lonsurf for a TEAE and 11% of patients receiving Lonsurf required a dose reduction. The safety information and measures to manage serious adverse reactions are adequately present in the Lonsurf Product Monograph.

With the current labelling, Lonsurfs Benefits-Risk profile is deemed to be favourable for the proposed indication of metastatic gastric cancer or adenocarcinoma of gastro esophageal junction in patients who received two prior therapies (as specified in the indication).