Evolving Therapy Options in 2L and Beyond in EGFR-mutant NSCLC

At the recent ASCO meeting, there was a mix of encouraging and somewhat disappointing data regarding treatment options for patients with EGFR-mutant non-small cell lung cancer who have developed resistance to tyrosine kinase inhibitors (TKIs). One notable study evaluated a HER3-targeted antibody-drug conjugate (ADC) compared to chemotherapy, showing a progression-free survival benefit, though the magnitude of this benefit was modest. Following this, the FDA withdrew its application for this agent in the resistant population, signaling a need for more effective therapies. Fortunately, the pipeline remains active with promising new HER3 and TROP2 ADCs, as well as bispecific antibodies targeting EGFR and other pathways, offering hope for more effective and targeted options in the near future. Additionally, trials like the Harmony study have explored combining chemotherapy with immunotherapy agents, showing improved progression-free survival but mixed results on overall survival, emphasizing that more data and longer follow-up are needed.

The evolving landscape is marked by the availability of multiple mechanisms of action in the treatment arsenal. Beyond traditional chemotherapy, there are oral targeted agents, bispecific antibodies, and ADCs that may be used sequentially or in combination to overcome resistance. This multifaceted approach allows clinicians to tailor therapy based on tumor biology and resistance mechanisms. For example, if molecular testing reveals MET amplification, agents targeting this pathway may be preferred. The flexibility in sequencing and combining treatments helps prolong disease control and manage resistance, even as overlapping resistance mechanisms complicate the picture. Importantly, emerging therapies such as subcutaneous antibody formulations improve convenience and reduce infusion-related side effects, enhancing patient experience without sacrificing efficacy.

Practically, treatment decisions after frontline osimertinib and chemotherapy also hinge on prior exposure and timing. Patients who have received chemotherapy with radiation may not have had full systemic dosing, which can influence the choice and effectiveness of subsequent regimens. A detailed understanding of the resistance mechanism via biopsy or liquid biopsy remains crucial before selecting the next therapy. In the absence of actionable mutations, agents like docetaxel remain options, though newer targeted or antibody-drug conjugates are increasingly preferred where available. The current era is defined by the availability of diverse and evolving therapies, offering more options than ever before to personalize treatment and improve outcomes in this challenging patient population.