Regulatory Decision Summary for GIOTRIF

Squamous non-small cell lung cancer (NSCLC) is a serious life threatening condition that has a poor prognosis following first line platinum based therapy. Despite the recent approval of nivolumab, pembrolizumab and the common use of docetaxel and erlotinib in the second line setting, drugs with improved efficacy are still required in this setting. This submission provided final results from a phase 3, multicentre, randomized, open label study in the metastatic squamous cell lung cancer second line setting of Giotrif versus erlotinib (LUX-Lung 8). Patients (n = 343) were randomized to receive either Giotrif (40 milligrams [mg]) or erlotinib (150 mg) once daily. The primary endpoint was to demonstrate superiority of Giotrif compared to erlotinib in Progression-Free Survival (PFS) as determined by Central Independent Review (CIR) using RECIST v1.1 criteria. Secondary endpoints included Objective Response Rate (ORR) as assessed by CIR, Overall Survival (OS) and quality of life (QoL).

Based on CIR assessment, treatment with Giotrif resulted in statistically significant superior median PFS (2.4 months versus [vs.] 1.9 months; HR 0.82 [95% CI: 0.68-1.00]; 2-sided p-value <0.0427) as compared to erlotinib. This difference is considered clinically relevant in the advanced and metastatic squamous cell lung cancer population.

Furthermore, treatment with Giotrif resulted in a statistically significant and clinically relevant improvement in OS as compared to erlotinib (HR 0.81; 95% CI 0.69-0.95; p = 0.0077). Median OS was 1.1 months greater with Giotrif treatment (Giotrif 7.9 months vs. erlotinib 6.8 months).

The safety profile of Giotrif in lung cancer patients has been well characterized based on clinical trials involving more than 450 patients. The key toxicities are gastrointestinal and dermatological toxicity. Other important toxicities include interstitial lung disease (ILD)/pneumonitis and hepatotoxicity. These toxicities, although significant, were:

1. consistent with the known toxicity profile of Giotrif observed in other trials;
2. clearly highlighted in the Adverse Drug Reactions table and the Warnings and Precautions section of the Product Monograph; and
3. manageable as demonstrated in the pivotal trial by dose interruption, dose reduction and/or standard medical practice (for example, proactive management of diarrhea).

These mitigation strategies are clearly outlined in the Product Monograph. Additionally, a Serious Warnings and Precautions Box is included in the Product Monograph to highlight more serious safety risks including pneumonitis/interstitial lung disease, hepatotoxicity, severe skin reactions and diarrhea. Finally, no new safety signals have appeared based on the data in the submission relative to the safety profile identified at time of initial market authorization in 2013 for the lung adenocarcinoma indication.

In summary, the submission demonstrated that Giotrif is efficacious as a second line therapy in the advanced and metastatic squamous lung cancer patient population based on the endpoints of Progression Free Survival and Overall Survival. Giotrif is noted to have a tolerable and manageable safety profile in this patient population. No new safety issues were identified during the submission review.

Based on the data provided in this submission, the benefit/harm profile for Giotrif when used under the proposed conditions of use is positive. The Product Monograph has been updated to reflect the safety and efficacy data from the pivotal trial.