Doctors Review Best Practices in Metastatic EGFR–Mutated NSCLC Cases

Metastatic EGFR-Mutated NSCLC Case Review

Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with lung cancer experts coinciding with the 2026 American Society of Clinical Oncology Annual Meeting to discuss two metastatic EGFR–mutated NSCLC cases for the Challenging Cases series. They were joined by Shirish Gadgeel, MBBS, FASCO, of Winship Cancer Institute of Emory University, and Wade Iams, MD, MSCI, of Tennessee Oncology.

Frontline Treatment Options for EGFR–Mutated NSCLC

The first case described a 54-year-old male with active tobacco use who presented with diffusely metastatic NSCLC with EGFR exon 19 deletion and an asymptomatic isolated brain lesion. This case highlighted the nuance in choosing between the three approved frontline treatment options: amivantamab plus lazertinib, osimertinib plus chemotherapy, or osimertinib monotherapy. When selecting a frontline therapy for metastatic EGFR–mutated NSCLC, oncologists must consider age, demographics, burden of disease, commutations, circulating tumor DNA status, and central nervous system involvement. 

For this case, Drs. Gadgeel and Iams felt amivantamab plus lazertinib was an appropriate choice based on the patient’s age and risk features. Ultimately, however, the choice of treatment should be a shared decision with the patient. Amivantamab plus lazertinib has a more challenging side effect profile, and patients may opt for osimertinib plus chemotherapy to avoid toxicities. In general, combination therapy is strongly preferred for higher risk profiles like this patient, although osimertinib monotherapy may still be appropriate for patients with low disease burden or limited metastases.

When using amivantamab plus lazertinib, prophylactic anticoagulation is recommended for the first 4 months of treatment. While infusion-related reactions (IRRs) can occur, the recently approved subcutaneous formulation of amivantamab has significantly lower rates of IRRs. Dermatologic toxicities remain a challenge, and counseling patients to adhere to the COCOON regimen is critical for managing side effects.

Treatment Sequencing in Metastatic EGFR–Mutated NSCLC

The second case discussed by the experts involved a 63-year-old patient with metastatic NSCLC with EGFR exon 21 L858R mutation. This patient was initially started on amivantamab plus lazertinib but experienced lingering grade 1 to 2 rash. The doctors discussed how to approach this scenario, and also what subsequent treatments could be used. 

While prophylactic measures are important, many patients will still develop dermatologic toxicities. Dr. Gadgeel recommended frequent check-ins with patients for the first 2 months after starting treatment to monitor for toxicities. When toxicities develop, oncologists should proactively reduce or hold amivantamab doses to curtail escalating side effects. Current data support that dose holds or dose reductions do not compromise the efficacy of amivantamab plus lazertinib for patients with EGFR–mutated NSCLC. 
If side effects persist despite prophylaxis and dose modifications, it may be necessary to swap to another treatment option. For patients who started with amivantamab plus lazertinib, sequencing to a chemotherapy–based regimen and then datopotamab deruxtecan (Dato-DXd) ensures exposure to available treatments. However, if patients start on osimertinib plus chemotherapy, Dr. Gadgeel typically switches directly to Dato-DXd.