Regulatory Decision Summary for Rybrevant

This Priority Review Supplement to a New Drug Submission (SNDS) was submitted to seek market authorization for Rybrevant (amivantamab) in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations.

After evaluation of the submitted data package, Health Canada authorized Rybrevant for the following indication: Rybrevant (amivantamab for injection) in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations.

The submission was classified as a Project Orbis Type B submission and Health Canada collaborated with United States Food and Drugs Administration (FDA), Brazil’s National Health Surveillance Agency (ANVISA), Singapore’s Health Science Authority (HSA).

The submission was filed, and approved, under the Priority Review Policy.

Market authorization for the use of Rybrevant (amivantamab) in combination with carboplatin and pemetrexed, was based on the results of an open-label, placebo controlled, randomized, multicenter trial designed to assess the use of Rybrevant in combination with carboplatin and pemetrexed versus (vs.) placebo in combination with carboplatin and pemetrexed in the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours harboured activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations.

A total of 308 patients were randomized 1:1 to receive Rybrevant plus carboplatin and pemetrexed (n = 153; ACP arm) or placebo plus carboplatin and pemetrexed (n = 155; CP arm). The primary efficacy analysis was a prespecified event-driven analysis which compared progression-free survival (PFS) assessed by blinded independent central review (BICR) in the intent to treat population. At the time of this analysis, the study met the primary objective of demonstrating both a statistically significant and clinically meaningful improvement in BICR assessed PFS for patients treated with Rybrevant in combination with carboplatin and pemetrexed over patients treated with placebo in combination with carboplatin and pemetrexed. The median PFS was estimated as 11.4 months for patients treated with Rybrevant in combination with carboplatin and pemetrexed and 6.7 months for patients treated with placebo in combination with carboplatin and pemetrexed. The estimated hazard ratio (HR) was 0.40, representing a 60% reduction in the risk of disease progression or death with the addition of Rybrevant to carboplatin and pemetrexed. The primary efficacy outcome was supported by the key secondary endpoints of objective response rate and overall survival (OS).

At the prespecified first interim analysis for OS, statistical significance was not been achieved (HR = 0.72), however, the OS data were immature. An imbalance in the initiation of subsequent systemic therapies received by patients in the study, where more patients treated with placebo in combination with carboplatin and pemetrexed received subsequent systemic therapy which can impact OS results. Moreover, the Papillon study design allowed for patients randomized to receive placebo in combination carboplatin and pemetrexed to crossover and receive Rybrevant monotherapy following confirmed disease progression. As such, 42% of patients randomized to receive placebo in combination with carboplatin and pemetrexed crossed over to receive subsequent Rybrevant monotherapy. Additional OS analyses were performed to assess the impact of subsequent therapies received and patient crossover to Rybrevant monotherapy. The results of these analyses supported that subsequent therapies received and patient crossover may have impacted the OS analysis and outcomes observed by improving the OS outcome in these patients. Based on these analyses, the OS appears to have been improved due to the effect of these variables. The OS result be communicated in the Product Monograph, along with the proportion of patients that crossed over from the CP arm to receive subsequent Rybrevant monotherapy.

The safety profile observed in patients with locally advanced or metastatic NSCLC treated with Rybrevant in combination with carboplatin and pemetrexed was consistent with the known profiles for Rybrevant and the platinum-based chemotherapy. No new safety signals were identified. The most commonly reported adverse reactions (incidence ≥20%) in patients treated with Rybrevant in combination with carboplatin and pemetrexed were neutropenia, paronychia, rash, anaemia, infusion-related reactions, hypoalbuminaemia, constipation, leukopenia, nausea, thrombocytopenia, decreased appetite, ALT increased, dermatitis acneiform, AST increased, peripheral oedema, stomatitis, covid-19, vomiting, hypokalaemia, and diarrhea. Skin toxicity (grouped adverse reaction term), infusion-related reactions, and interstitial lung disease/pneumonitis have been identified as clinically important adverse reactions associated with Rybrevant. In addition, EGFR and MET inhibition associated adverse events were examined. These include paronychia, rash, dermatitis acneiform, stomatitis, diarrhea, hypoalbuminaemia, and peripheral oedema. An assessment of these reactions in the Papillon study showed higher incidences in the patients who received Rybrevant in combination with carboplatin and pemetrexed compared to patients treated with placebo plus carboplatin and pemetrexed. The majority of these events were low Grade in intensity (Grades 1-2), and no reactions reported were greater than Grade 3. The safety profile observed with Rybrevant in combination with carboplatin and pemetrexed, given the life-threatening nature of advanced or metastatic NSCLC, is considered tolerable and manageable based on the assessed information. Overall, the risks with this combination regimen, and appropriate risk management strategies, have been adequately addressed and communicated in the Product Monograph.

The recommended dose of Rybrevant when used in combination with carboplatin and pemetrexed is 1,400 mg for patients <80 kg or 1,750 mg for patients ≥80kg, administered as an intravenous (IV) infusion once weekly for the first 4 weeks inclusive. The first dose of Rybrevant, at week 1, is administered as a split doses on days 1 and 2, where the patients <80 kg receive 350 mg and 1,050 mg respectively and patients ≥80 kg receive 350 mg and 1,400 mg respectively. Patients do not receive Rybrevant treatment in weeks 5 or 6. On Day 1 of week 7, patients are administered Rybrevant IV at a dose of 1,750 mg for patients <80 kg or 2,100 mg for patients ≥80 kg. Treatment is continued at this dose continues every 3 weeks until disease progression or unacceptable toxicity. The administration of these agents is to be performed in the following order: Pemetrexed infusion first, carboplatin infusion second, and the Rybrevant infusion last. See the Product Monograph for Rybrevant for complete details on the dosage and administration for Rybrevant when used in combination with carboplatin and pemetrexed.

Health Canada granted this application priority review.

An updated core risk management plan (RMP) version 3.0 and Canadian Addendum version 5 was reviewed by Health Canada and considered acceptable. No further RMP-related follow-up is warranted.

Revisions made to the Rybrevant package inserts met all applicable regulations and guidance.

A Notice of Compliance (NOC) was recommended. 

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