Regulatory Decision Summary for LENVIMA

In the pivotal Phase 3 trial in radioactive iodine-refractory differentiated thyroid cancer patients, Lenvima extended progression-free survival the primary efficacy endpoint, by 14.7 months compared to placebo (18.3 versus [vs.] 3.6 months, p<0.001; hazard ratio 0.21, 99% Confidence Interval [CI] 0.14 to 0.31). These results are considered clinically relevant and are statistically significant. The median overall survival (OS) was not reached in either group. Progression-free survival data from Phase 2 trials are consistent with the results of the pivotal trial.

The proportion of patients with a treatment-related adverse event (AE) of any grade was higher with Lenvima compared to placebo (97% vs. 60%) as was the incidence of Grade ≥3 (76% vs. 10%) and serious AEs (31% vs. 6%). The most common adverse drug reactions observed in Lenvima-treated patients were hypertension, diarrhea, nausea, vomiting, decreased appetite, weight loss and palmar-plantar erythrodysesthesia, all of which are labelled in the Product Monograph (PM). The PM is also labelled with a Serious Warnings and Precautions box to highlight specific toxicities, some of which were fatal in the pivotal trial. These include hepatotoxicity, arterial thromboembolism, renal failure, and hemorrhage. Other serious adverse reactions that were not fatal in clinical trials are hypertension and posterior reversible encephalopathy syndrome. The PM also provides appropriate recommendations for the monitoring and management of the toxicities associated with Lenvima use.

In the pivotal trial, the Lenvima daily dose (24 mg) was modified in 89.7% of patients (interrupted in 85.3%, reduced in 78.2%) due to treatment emergent adverse events (TEAEs) so that the median daily dose of Lenvima was 16.2 mg. The implemented dose reduction algorithm resulted in decreasing the rate of TEAEs. It is uncertain if the lower staring dose may result in comparable efficacy with less toxicity. This will be investigated in a post-authorization study that the Sponsor has committed to provide to Health Canada. Currently, the PM provides recommendations for dosing and dose adjustments to manage Lenvima-related adverse events.

The overall benefit-harm-uncertainty balance is considered to support the use of Lenvima for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.