Regulatory Decision Summary for Keytruda

The purpose of this new drug submission was to seek market authorization for Keytruda, to be used in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the treatment of adult patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma, whose tumors express PD-L1.

After evaluation of the submitted data package, Health Canada authorized Keytruda for the following indication:

Keytruda, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1) as determined by a validated test.

The market authorization of Keytruda was based on the results of a pivotal Phase 3, randomized, placebo-controlled, double-blind study in adult patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma, who had not received previous treatment for their metastatic disease. Patients were randomized (1:1) to receive either Keytruda in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy or placebo plus trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy.

At the second interim analysis (IA2), a statistically significant improvement in progression-free survival (PFS) was demonstrated for patients randomized to the Keytruda-containing arm compared to the placebo-containing arm with a hazard ratio (HR) (95% confidence interval [CI]) of 0.72 (0.60, 0.87). The result of the analysis of overall survival (OS) at IA2 appears to be favourable for the Keytruda-containing arm but was not statistically significant (HR [95% CI] = 0.87 [0.72, 1.06]). A higher percentage of patients in the Keytruda-containing arm (72.6%) compared with the placebo-containing arm (59.8%) achieved an objective response at IA2. Pre-defined subgroup analysis determined the observed efficacy benefit to be restricted to patients whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥1). In patients with PD-L1 CPS ≥1, the PFS hazard ratio was 0.70 (95% CI: 0.58, 0.85) and the OS HR was 0.79 (95% CI: 0.64, 0.98) with a 4.9-month improvement in median OS, in favour of the Keytruda-containing arm. Conversely, in patients with PD-L1 CPS <1, the PFS HR was 1.17 (95% CI: 0.73, 1.89) and the OS HR was 1.61 (95% CI: 0.98, 2.64). Thus, the addition of Keytruda to the standard of care treatment of trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy demonstrated a clinical benefit for patients with PD-L1 CPS ≥1, over the standard of care treatment alone.

The safety profile of Keytruda in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy is consistent with the known safety profile of Keytruda and the safety profiles of the other components of the treatment regimen. Immune-mediated adverse reactions were observed, consistent with the safety profile of Keytruda. These adverse reactions can be managed in most cases and the Keytruda Product Monograph adequately captures these and other risks of treatment and includes strategies for the management of immune-mediated adverse reactions.

Overall, Keytruda in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy provides an effective first-line treatment option for adult patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma, whose tumors express PD-L1 (CPS ≥1). When administered at the authorized dosage, the Keytruda-containing regimen is expected to provide a clinical benefit with a manageable safety profile. The risks associated with Keytruda can be effectively managed in the post-market setting. The benefit/risk profile of Keytruda in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy is considered favourable for the authorized indication.

The risk management plan for Keytruda was reviewed and considered acceptable.

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