FDA Approves Osimertinib with Chemotherapy for EGFR-mutated Non-small Cell Lung Cancer
On February 16, the US Food and Drug Administration approved osimertinib with platinum-based chemotherapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. The drug has been approved in the US for other indications for several years.
The review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and Switzerland’s Swissmedic. Application reviews are ongoing at the other regulatory agencies.
Efficacy was evaluated in FLAURA 2, an open-label, randomized trial of 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive locally advanced or metastatic NSCLC and no prior systemic therapy for advanced disease. Patients were randomized 1:1 to receive either osimertinib with platinum-based chemotherapy or osimertinib monotherapy.
The major efficacy outcome was progression free survival (PFS), with overall survival (OS) as a key secondary outcome measure. Osimertinib plus platinum-based chemotherapy demonstrated a statistically significant improvement in PFS compared to osimertinib monotherapy with a hazard ratio of 0.62 (95% Confidence Interval [CI]: 0.49, 0.79; two-sided p-value<0.0001). The median PFS was 25.5 months (95% CI: 24.7, not estimable [NE]) and 16.7 months (95% CI: 14.1, 21.3) in the respective arms.
While OS results were immature at the current analysis, with 45% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed.
FDA Approves Tepotinib for Metastatic Non-Small Cell Lung Cancer
On February 15, the FDA granted traditional approval to tepotinib for patients with metastatic NSCLC harboring MET exon 14 skipping alterations. Tepotinib was previously granted accelerated approval for this indication on February 3, 2021, based on initial overall response rate (ORR) and duration of response (DOR) in the VISION trial, a multicenter, non-randomized, open-label, multicohort study. The conversion to traditional approval was based on an additional 161 patients and an added 28 months of follow-up time to assess DOR.
Efficacy was demonstrated in a total of 313 patients with metastatic NSCLC harboring MET exon 14 skipping alterations. The primary efficacy measures were ORR and DOR, determined by a blinded independent review committee. Among 164 treatment-naïve patients, ORR was 57% (95% CI: 49, 65), with 40% of responders having a DOR ≥12 months. Among 149 previously treated patients, ORR was 45% (95% CI: 37, 53), with 36% of responders having a DOR ≥12 months.
MARIPOSA Trial Leads to Applications for Amivantamab-Lazertinib Combination in Europe, US
Also this month, Janssen Pharmaceutical Companies submitted applications to the European Medicines Agency and the US FDA regarding the use of amivantamab in combination with lazertinib for the first-line treatment of patients with advanced NSCLC with EGFR exon 19 deletions (ex19del) or exon 21 L858R (L858R) substitution mutations. The EMA accepted Janssen’s Type II extension-of-indication application for the combo. In the US, the FDA will consider a supplemental Biologics License Application and a New Drug Application seeking the approval of the amivantamab-lazertinib combination.
These applications come after results of the MARIPOSA study were announced in 2023. MARIPOSA is a randomized, Phase 3 study evaluating amivantamab in combination with lazertinib compared to osimertinib as first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations. The MARIPOSA study met its primary endpoint, resulting in a statistically significant and clinically meaningful improvement in PFS for the combination of amivantamab and lazertinib versus osimertinib, as assessed by blinded independent central review.
