A phase 3, international, randomized clinical trial has demonstrated significant improvements in progression-free survival with combination amivantamab plus lazertinib therapy compared to osimertinib alone as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. The study, known as the MARIPOSA trial, was funded by Janssen Research and Development and published on October 24, 2024 in the New England Journal of Medicine.
The trial aimed to assess the efficacy and safety of amivantamab-lazertinib versus osimertinib in previously untreated patients with locally advanced or metastatic NSCLC with common EGFR mutations (exon 19 deletion or L858R). A total of 1074 patients were enrolled and randomized in a 2:2:1 ratio to receive amivantamab-lazertinib (429 patients), osimertinib (429 patients), or lazertinib monotherapy (216 patients). The lazertinib monotherapy arm was included to evaluate the contribution of treatment components in the combination therapy.
Eligible patients were 18 years or older with previously untreated locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutations. Patients with asymptomatic or stable brain metastases were allowed to participate. The study population was generally representative of patients with EGFR-mutated NSCLC, with the majority being female, Asian or White, and never-smokers. However, Black patients were underrepresented in the trial.
The primary endpoint was progression-free survival in the amivantamab-lazertinib group compared to the osimertinib group, as assessed by blinded independent central review. Key secondary endpoints included overall survival, objective response rate, duration of response, and safety.
Results of the trial showed that the median progression-free survival was significantly longer in the amivantamab-lazertinib group at 23.7 months (95% CI, 19.1-27.7) compared to 16.6 months (95% CI, 14.8-18.5) in the osimertinib group. This difference corresponded to a hazard ratio for disease progression or death of 0.70 (95% CI, 0.58-0.85; P<0.001). The progression-free survival curves separated at 6 months and continued to widen over time.
The objective response rate was similar between the amivantamab-lazertinib (86%) and osimertinib (85%) groups. However, among patients with a confirmed response, the median duration of response was notably longer in the combination therapy group at 25.8 months compared to 16.8 months with osimertinib monotherapy.
An interim analysis of overall survival showed a trend favoring amivantamab-lazertinib, with a hazard ratio for death of 0.80 (95% CI, 0.61-1.05). However, the data were not mature enough to draw definitive conclusions about overall survival benefit.
The safety profile of amivantamab-lazertinib was consistent with previous reports from phase 1-2 studies. The combination therapy was associated with a higher incidence of EGFR- and MET-related adverse events compared to osimertinib, except for diarrhea which was more frequent in the osimertinib group. Most adverse events were grade 1 or 2. The rate of discontinuation of all agents due to treatment-related adverse events was 10% in the combination group compared to 3% in the osimertinib group.
A notable finding was the higher incidence of venous thromboembolic events in the amivantamab-lazertinib group (37%) compared to the osimertinib group (9%). The majority of these events occurred during the first 4 months of treatment. The study authors hypothesized that this could be due to a transitory prothrombotic state caused by rapid tumor cell death with the combination therapy.
The authors concluded that amivantamab-lazertinib demonstrated superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. They suggested that the combination therapy could proactively address mechanisms of resistance to osimertinib, potentially leading to improved clinical outcomes.
This study has several strengths, including its large sample size, international scope, and blinded evaluation of two third-generation EGFR-TKIs. The inclusion of a lazertinib monotherapy arm allowed for assessment of the contribution of individual components in the combination treatment.
However, there are limitations to consider. The study population underrepresented Black patients, which may limit generalizability to this group. Additionally, the overall survival data were not mature at the time of this analysis, necessitating longer follow-up to determine if the progression-free survival benefit translates into an overall survival advantage.
The potential clinical impact of this study is significant. If approved, amivantamab-lazertinib could become a new standard first-line treatment option for patients with EGFR-mutated advanced NSCLC. The combination therapy may offer a way to delay or prevent resistance mechanisms that typically emerge with EGFR-TKI monotherapy, potentially extending the duration of disease control.
However, the higher incidence of adverse events, particularly venous thromboembolic events, with the combination therapy will require careful consideration in clinical practice. The authors noted that prophylactic anticoagulation is now recommended for the first 4 months of treatment in ongoing trials of amivantamab-lazertinib.
Furthermore, the study raises important questions about the optimal sequencing of therapies in EGFR-mutated NSCLC. While the combination therapy showed improved progression-free survival, it remains to be seen how this approach impacts subsequent treatment options and long-term outcomes.
In conclusion, the MARIPOSA trial provides compelling evidence for the efficacy of amivantamab-lazertinib as first-line therapy in EGFR-mutated advanced NSCLC. As with any new treatment approach, the benefits will need to be weighed against the potential risks and increased toxicity. Ongoing follow-up from this trial and real-world data will be crucial to fully understand the long-term impact of this combination therapy on patient outcomes.
As the landscape of targeted therapies for NSCLC continues to evolve, this study represents an important step forward in addressing the challenge of treatment resistance in EGFR-mutated disease. It underscores the potential of combination approaches to improve outcomes in this patient population and sets the stage for further research into strategies to optimize the use of targeted therapies in lung cancer.
References
Cho BC, Lu S, Felip E, et al. Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
