Amivantamab Plus Lazertinib Demonstrates Superior Overall Survival Over Osimertinib in First-Line EGFR-Mutated Advanced NSCLC

▎Traceability

At WCLC2024, Johnson & Johnson disclosed longer follow-up OS data from the MARIPOSA study:

Amivantamab, as an EGFR-MET bispecific antibody, utilizes low fucose expression to enhance ADCC effects. Lazertinib, as a 3rd-generation EGFR TKI, is capable of penetrating the central nervous system. In the primary analysis of the Phase 3 MARIPOSA study (NCT04487080), with a median follow-up of 22.0 months, Amivantamab + Lazertinib significantly improved progression-free survival (PFS) compared to Osimertinib in treatment-naïve patients with advanced NSCLC harboring EGFR mutations, as assessed by blinded independent central review. An interim overall survival (OS) analysis preliminarily indicated a favorable trend in the Amivantamab + Lazertinib group compared to the Osimertinib group.

Method: MARIPOSA randomly assigned 1,074 treatment-naïve patients with EGFR-mutated (exon 19 deletion or exon 21 L858R substitution) locally advanced or metastatic NSCLC in a 2:2:1 ratio to receive open-label Amivantamab + Lazertinib (n=429), blinded Osimertinib (n=429), or blinded Lazertinib (n=216).

Results: As of May 13, 2024 (median follow-up of 31.1 months), 44% (185/421) of patients in the Amivantamab-lazertinib group and 34% (145/428) in the osimertinib group were still receiving treatment. A total of 155 patients in the Amivantamab-lazertinib group and 233 patients in the osimertinib group experienced investigator-assessed disease progression and discontinued treatment. Among these patients, 72% (111/155) and 74% (173/233), respectively, initiated subsequent therapy, with carboplatin-pemetrexed being the most common first subsequent treatment in both groups (Amivantamab-lazertinib, 26% [29/111]; osimertinib, 28% [48/173]). Progression-free survival after the first subsequent therapy (i.e., PFS2) favored the Amivantamab-lazertinib combination group (HR, 0.73; 95% CI, 0.59-0.91; nominal P=0.004). Compared to osimertinib, patients treated with Amivantamab-lazertinib had significantly longer median time to treatment discontinuation and time to subsequent therapy. The intracranial PFS showed a trend favoring the Amivantamab-lazertinib group over the osimertinib group.Although there was no formal significance test, the median OS in the Amivantamab-lazertinib group has not been reached, while it was 37.3 months in the osimertinib group (HR, 0.77; 95% CI, 0.61-0.96; nominal P=0.019).At 24 months, 75% and 70% of patients in the Amivantamab-lazertinib group and osimertinib group were alive, respectively. The corresponding values at 36 months were 61% and 53%.

Conclusion: Compared with Osimertinib, Amivantamab-lazertinib continued to show a trend of improving OS, while also improving outcomes after disease progression, which again confirmedAmivantamab-Lazertinib can be used as a first-line standard treatment for EGFR-mutated advanced NSCLC.

Based on this result, the landscape of first-line treatment for EGFR-mutated advanced NSCLC patients will change in the future. However, it should be noted that IV injection...Amivantamab can cause severe injection reactions and thrombosis, necessitating more refined clinical management strategies. This may also impact the promotion of this therapy to a certain extent. However, the subcutaneous formulation developed by Johnson & Johnson can significantly reduce thrombosis and injection reactions.

In the frontline treatment of EGFR-mutated advanced NSCLC, AstraZeneca has always been a major player. Under such circumstances, AstraZeneca has launched multiple combination clinical trials with osimertinib, and the combination with chemotherapy is currently at the forefront.On April 5, 2024, AstraZeneca registered the Phase III clinical trial TROPION-Lung14 on the Clinicaltrials.gov website, evaluating Osimertinib in combination with or without the Trop2 ADC novel drug Dato-DXd as a first-line treatment for EGFR mutation-positive non-small cell lung cancer. At the same time, AstraZeneca is also conducting clinical trials of Osimertinib in combination with EGFRxcMET ADC (AZD9592). Recently, they also introducedA preclinical EGFR degrader, also for combination use with Osimertinib.

FLAURA2 Study: A Phase III Randomized Clinical Trial of Osimertinib Combined with Chemotherapy as First-Line Treatment for EGFR-Mutated Advanced NSCLC – Results Show PFS Extended by Approximately 9 Months. According to BICR assessment, the median PFS was 29.4 months vs 19.9 months (HR=0.62; P=0.0002), and according to investigator assessment, it was 25.5 months vs 16.7 months (HR=0.62; P<0.0001), reducing the risk of disease progression or death by 38%. Preliminary OS data already shows an advantage.

This therapy, as a combination regimen with chemotherapy, may significantly reduce the preference of both patients and doctors, unless individual patients require a faster tumor reduction effect. However, it might be rejected by patients due to the side effects of chemotherapy.

Therefore, as a chemotherapy-free combination therapyThe combination of Amivantamab and Lazertinib will have a more competitive edge, emerging as a new option for first-line treatment of EGFR-mutated advanced NSCLC patients.