Regulatory Decision Summary for Rybrevant

Conditional authorization was based on the results of a Phase 1, first-in-human, open-label study designed to evaluate the tolerability, safety, pharmacokinetics, and anti-tumour activity of Rybrevant in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Rybrevant was administered, by intravenous infusion, at a dose of 1,050 mg for patient with a baseline body weight <80 kg and 1,400 mg for patient with a baseline body weight ≥80 kg. Administration was once weekly for the first 4 weeks (cycle 1, 28-days/cycle), and then every 2 weeks in subsequent 28-day cycles starting at week 5. The first infusion was administered as a split dose in week 1 on day 1 and day 2.

The primary efficacy endpoint was objective response rate (ORR) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy, treated with Rybrevant monotherapy. Patients had to have undergone at least 3 scheduled post-baseline disease assessments to allow confirmation of a response, at the clinical cut-off date (n = 81). The confirmed ORR, by blinded independent central review (BICR), was 39.5%. This was supported by a median duration of response of 11.14 months. Of the patients who achieved an objective response, 62.5% had a DOR for ≥6 month.

Clinically important adverse reactions (AR) associated, and observed, with Rybrevant included, rash (including dermatitis acneiform), infusion-related reactions (IRR), interstitial lung disease/pneumonitis, and eye disorders. Along with these several other ARs were defined based on the safety profile, which included paronychia, peripheral edema and diarrhea. The most commonly reported Treatment-emergent adverse events (TEAEs) (≥20%) included rash (including dermatitis acneiform), IRRs, paronychia, musculoskeletal pain, dyspnea, nausea, hypoalbuminemia, fatigue, peripheral edema, stomatitis, cough, and constipation. Serious TEAEs occurred in 30.2% of patients with pulmonary embolism, dyspnea, pneumonitis and musculoskeletal pain being the most common events observed. There was also one incidence of Toxic epidermal necrolysis (TEN) reported. Treatment-emergent AEs leading to treatment discontinuation occurred in 10.9% of patients in the target patient population. These were mainly due to pneumonia, pneumonitis, pleural effusion, and IRR. The risks associated with Rybrevant are tolerable and manageable, and have been adequately communicated in the Product Monograph.

The magnitude of the treatment effect demonstrates promising evidence of a positive benefit in the target patient population. The evidence provided shows a promising benefit/risk profile for the proposed patient population. As a condition of authorization, the sponsor will be required to commit to file the results of a well-controlled Phase 3 clinical trial to confirm the efficacy of Rybrevant in patients with advanced NSCLC with EGFR Exon 20 insertion mutations. As a second commitment, the Sponsor will be required to submit further follow-up data for the Phase 1 study, to allow for confirmation of the treatment effect observed, with respect to ORR and DOR.

The recommended dosing regimen of Rybrevant follows a 28-day cycle dosing schedule. The recommended dosing of Rybrevant is 1,050 mg for patient with a baseline body weight <80 kg or 1,400 mg for patient with a baseline body weight ≥80 kg. See the Rybrevant Product Monograph for complete dosing information.

For more information on Health Canadas decision, please view the Summary Basis of Decision.