NEJM Volume 394, Issue 9: February 26, 2026 – Medical Research

A novel combination therapy—amivantamab–lazertinib—shows promising results in treating advanced non-small cell lung cancer (NSCLC) with specific EGFR mutations. Published in the New England Journal of Medicine on February 26, 2026, a Phase 1 study details the efficacy and safety of this approach for patients whose cancer has become resistant to other treatments. This development offers a potential new avenue for those with limited options, though further research is needed to fully understand its long-term benefits and risks.

Understanding EGFR-Mutated NSCLC and Treatment Resistance

Non-small cell lung cancer is the most common type of lung cancer, accounting for 80-85% of all cases. Within NSCLC, mutations in the epidermal growth factor receptor (EGFR) gene are frequently found, particularly in never-smokers. These mutations drive cancer growth, and drugs specifically targeting EGFR, like osimertinib, have become standard first-line treatments. However, resistance to these therapies almost inevitably develops, leading to disease progression. The most common mechanism of resistance is the L858R mutation combined with an insertion in exon 20 of the EGFR gene. This is where amivantamab–lazertinib comes into play.

Amivantamab is a bispecific antibody that targets EGFR exon 20 insertion mutations. It works by binding to the mutated EGFR protein, blocking its signaling and triggering the immune system to destroy the cancer cells. Lazertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) designed to overcome resistance mutations. Combining these two agents aims to provide a more comprehensive attack on the cancer cells.

Phase 1 Study: Details and Findings

The Phase 1 study, detailed in the February 26th issue of the New England Journal of Medicine, involved patients with advanced NSCLC harboring EGFR exon 20 insertion mutations who had previously been treated with platinum-based chemotherapy and at least one EGFR TKI. The study assessed the safety and efficacy of amivantamab–lazertinib at various dose levels.

The study included a relatively small sample size, and the primary endpoints were safety and tolerability. However, the researchers similarly evaluated anti-tumor activity, measured by objective response rate (ORR) – the percentage of patients whose tumors shrank significantly – and progression-free survival (PFS) – the length of time patients lived without their cancer worsening. Preliminary results showed an ORR of 38% and a median PFS of 6.3 months. While these results are encouraging, it’s important to note that this is a Phase 1 study, primarily designed to assess safety, and the observed efficacy needs to be confirmed in larger, randomized Phase 2 and 3 trials.

Safety Profile and Adverse Events

As with most cancer therapies, amivantamab–lazertinib was associated with side effects. Common adverse events included rash, diarrhea, and fatigue. More serious adverse events, such as interstitial lung disease (inflammation of the lungs) and cardiac issues, were also reported, requiring careful monitoring and management. The study authors emphasize the need for vigilant monitoring of patients receiving this combination therapy to mitigate potential risks.

What So for Patients

For patients with EGFR exon 20 insertion-mutated NSCLC who have exhausted other treatment options, amivantamab–lazertinib represents a potential new hope. The observed response rates and progression-free survival in the Phase 1 study are promising, suggesting that this combination therapy can provide clinical benefit. However, it’s crucial to understand that this is not a cure, and the therapy is associated with potential side effects. Patients should discuss the risks and benefits of this treatment with their oncologist to determine if it’s the right option for them.

It’s also important to remember that this therapy is specifically designed for patients with EGFR exon 20 insertion mutations. Genetic testing is essential to identify these mutations and determine if a patient is eligible for this treatment. The National Cancer Institute provides comprehensive information about genetic testing for cancer.

Context within the Broader Landscape of Lung Cancer Treatment

Lung cancer remains a leading cause of cancer death worldwide. While advancements in treatment, including targeted therapies and immunotherapy, have improved outcomes for some patients, many still face a poor prognosis. The development of new therapies, like amivantamab–lazertinib, is crucial to address the unmet needs of patients with advanced NSCLC. The ongoing success of Medicare drug-price negotiation, as discussed in a recent NEJM article, may also play a role in increasing access to these innovative treatments.

Next Steps: Ongoing and Future Research

The Phase 1 study of amivantamab–lazertinib is an important first step, but further research is needed to confirm its efficacy and safety. Larger, randomized Phase 2 and 3 trials are currently underway to compare this combination therapy to standard-of-care treatments. These trials will provide more definitive evidence about the benefits and risks of amivantamab–lazertinib and help determine its optimal role in the treatment of EGFR exon 20 insertion-mutated NSCLC. Researchers will also continue to investigate ways to manage the side effects associated with this therapy and identify biomarkers that can predict which patients are most likely to respond.

The results of these ongoing trials will inform clinical guidelines and ultimately shape the future of lung cancer treatment. Patients and their healthcare providers should stay informed about the latest research findings and discuss the most appropriate treatment options based on individual circumstances.