The Oncology Brothers—Rahul Gosain, MD, MBA, and Rohit Gosain, MD—and Susan Scott, MD, of The Johns Hopkins Hospital, discussed first-line treatment for non–small cell lung cancer (NSCLC) with targetable mutations.
In the most common EGFR gene mutations, exon 19 deletion and L858R point mutation in exon 21, the previous standard of osimertinib monotherapy is being challenged by FLAURA2 and MARIPOSA data. FLAURA2 found improvements in progression-free survival by combining osimertinib with chemotherapy, while MARIPOSA projected better overall survival with amivantamab plus lazertinib (ami-laz) compared with osimertinib alone.
When asking Dr. Scott how she selects first-line treatments for NSCLC with these more classical mutations, Dr. Rohit Gosain noted that “about one-third of our patients with EGFR mutations did not even get to the second-line treatment,” highlighting the importance of treatment selection.
Dr. Scott said she considers the FLAURA2 or MARIPOSA regimen in patients with higher-risk features, such as brain metastases, positive circulating tumor DNA, TP53 comutation, or a heavy burden of disease. Notably, this represents the majority of patients with these mutations. Some patients without high-risk disease features could still be considered for osimertinib monotherapy, she added.
The adverse event profiles of these 3 regimens are a major consideration in treatment selection. Osimertinib is fairly well tolerated, and oncologists are already familiar with managing the adverse events of chemotherapy, Dr. Scott suggested. However, ami-laz is associated with distinct cutaneous toxicities such as paronychia, rash, and scalp rash.
Data from the COCOON trial presented at the 2025 European Lung Cancer Conference reported that the adverse events of ami-laz were more effectively managed with an enhanced dermatologic care regimen of 12 weeks of doxycycline, daily chlorhexidine, and a daily ceramide-containing lotion, Dr. Scott said.
When treating patients with S768I, L861Q, and G719X mutations, Dr. Scott stated, she still chooses osimertinib for most patients, especially those with L861Q mutation: “They really behave more like a classical mutation.” Dr. Scott noted that she does consider afatinib for G719X mutations, as well as potential clinical trials for rare patients.
Current treatment options for patients with ALK rearrangements include alectinib, brigatinib, lorlatinib, ceritinib, and crizotinib. Dr. Scott said that based on data from the CROWN trial, she starts more patients with lorlatinib. The primary toxicities Dr. Scott sees with lorlatinib involve neurological effects and metabolic complications.
For patients with ROS1 rearrangements, the approvals for repotrectinib and entrectinib may mean more effective options than the previous standard, crizotinib, given these therapies’ central nervous system (CNS) penetration. Dr. Scott stressed that immunotherapy has not been shown to be effective in ROS1 or RET fusions and is not part of her treatment algorithm.
Conversely, for patients with BRAF-mutated NSCLC, immunotherapy with or without chemotherapy is an effective first-line treatment option. However, Dr. Scott noted her low threshold for halting immunotherapy to preserve the opportunity for BRAF-targeted therapies. Between dabrafenib plus trametinib and encorafenib plus binimetinib, she prefers the latter due to greater tolerability.
As part of the discussion, the doctors emphasized the importance of RNA and DNA sequencing to screen for very rare mutations such as NTRK fusions. Drs. Scott and Rahul Gosain mentioned seeing unique toxicities, including CNS toxicity and widespread pain, while managing these patients with larotrectinib.
For the similarly rare MET exon 14 (METex14) skipping mutation, Dr. Scott views capmatinib and tepotinib as relatively interchangeable. Her primary toxicity concern is edema, which she addresses by pausing treatment and then restarting at a lower dose.
Immunotherapy is also an option for some patients with METex14 skipping mutations, though Dr. Scott stated she typically combines front-line immunotherapy with chemotherapy in case immunotherapy is ineffective.
Finally, among treatments for NSCLC with RET rearrangements, approved targeted therapies include selpercatinib, pralsetinib, and cabozantinib. Despite a lack of data to inform a choice between selpercatinib and pralsetinib, pralsetinib was associated with more cytopenias, according to Dr. Scott. She noted that both agents can involve unique toxicities such as chylous effusions.
Considering the wide range of mutations and approved targeted therapies, the doctors ultimately emphasized the need for next-generation sequencing (NGS), with potential retesting to screen for additional mutations or clones if disease progresses. Beyond informing the choice of targeted therapies, NGS can determine whether patients may benefit from immunotherapy and chemotherapy.
