The treatment of EGFR-mutant NSCLC has greatly evolved with targeted therapies, but post-EGFR TKI options remain challenging. RYBREVANT (amivantamab-vmjw), a bispecific antibody targeting EGFR and MET, is approved globally for NSCLC patients with EGFR exon 20 insertion mutations after platinum-based chemotherapy. Johnson & Johnson's oncology portfolio continues to expand with the recent FDA approval of RYBREVANT combined with chemotherapy for newly diagnosed patients with these mutations. The NCCN now endorses this regimen as a preferred first-line option.

In December 2023, Johnson & Johnson submitted a sBLA and NDA for RYBREVANT with lazertinib for advanced NSCLC patients with EGFR exon 19 deletions or L858R mutations. This was based on the Phase III MARIPOSA study, which received a Priority Review in February 2024. A similar application was submitted to the EMA.

Data unveiled at ASCO 2024 showcased the analysis of baseline ctDNA for NGS assessment of pathogenic alterations in 636 patients (amivantamab + lazertinib, n = 320; osimertinib, n = 316). Among patients with TP53 co-mutations, the median progression-free survival (mPFS) was 18.2 months with amivantamab + lazertinib compared to 12.9 months with osimertinib. Notably, even among those with TP53 wild-type, there was a trend favoring the combination therapy.

For patients with detectable ctDNA at baseline, amivantamab + lazertinib significantly prolonged mPFS to 20.3 months versus 14.8 months with osimertinib. The combination therapy also exhibited improved mPFS in patients with ctDNA clearance at Cycle 3 Day 1 (24.0 vs. 16.5 months) and in those who did not clear ctDNA (16.5 vs. 9.1 months). Additionally, among patients with liver metastases at baseline, mPFS was notably longer with amivantamab + lazertinib (18.2 vs. 11.0 months), mirroring the enhanced PFS observed in patients with a history of brain metastases. These findings underscore the efficacy of the amivantamab + lazertinib combination in improving outcomes for high-risk NSCLC patients.

KOL insights

“The combination of the antibody amivantamab and lazertinib, a drug targeting EGFR, shows better clinical benefits compared to standard treatment in patients with advanced or metastatic non-small cell lung cancer with EGFR gene mutations who also present one of these poor prognosis markers: brain and liver metastases, p53 gene co-mutations, or the presence of circulating tumor DNA.” –Expert Opinion.

“In the MARIPOSA trial, which included treatment-naive patients with locally advanced or metastatic NSCLC with either EGFR mutation, median PFS was longer in those patients who received amivantamab plus lazertinib than for those who received osimertinib; however, with no reported differences in overall survival (OS) and a differing toxicity profile, the Expert Panel recommended that most patients should receive osimertinib and that frontline treatment be tailored based on discussion with each patient ”–Expert Opinion.

Conclusion-

As per DelveInsight’s estimates, the total market size for EGFR NSCLC in the US was approximately USD 2 billion in 2023. Johnson & Johnson's RYBREVANT strategy revolves around amivantamab and lazertinib. RYBREVANT primarily targets first-line NSCLC with common exon 19 or exon 21 mutations, an area currently dominated by AstraZeneca's TAGRISSO.

Recently, Johnson & Johnson received an FDA priority review for RYBREVANT plus lazertinib, following a significant victory over TAGRISSO in the Phase III MARIPOSA trial. If approved, this combination would need to surpass both TAGRISSO monotherapy and TAGRISSO with chemotherapy. Notably, the MARIPOSA trial (NCT04487080) demonstrated that first-line amivantamab plus lazertinib significantly improved progression-free survival (PFS) compared to osimertinib in EGFR-mutant advanced NSCLC, even in patients with a history of brain metastases. Furthermore, Johnson & Johnson evaluated outcomes in high-risk subgroups, including those with TP53 co-mutations, detectable ctDNA, and baseline brain or liver metastases.