Identifying the Remaining Treatment Gaps and Unanswered Questions

Despite major advances in EGFR-mutated non-small cell lung cancer, several critical gaps remain in the field. One of the most pressing challenges is managing CNS progression, particularly leptomeningeal disease and refractory brain metastases, which continue to significantly impact outcomes. Another major area of need is optimizing treatment sequencing. With multiple effective agents now available—including targeted therapies, immunotherapy-based approaches, and antibody-drug conjugates—it's still unclear how to best deploy these options to maximize both survival and quality of life. A better understanding of resistance mechanisms and improved inclusion of complex patient populations in trials, such as those with CNS involvement or small cell transformation, is urgently needed.

In parallel, there's a growing call to explore more transformative therapies beyond incremental improvements. While current combination regimens have extended survival, they still fall short of offering cures or long-term disease control for most patients. Immune-modulating strategies, including bispecific antibodies and cellular therapies, hold promise, but their benefits remain unproven in this setting. There is strong interest from both clinicians and patients in finding regimens that could provide durable responses, particularly for younger individuals or those with aggressive disease biology who are willing to take on more experimental approaches for the potential of long-term benefit.

Looking ahead, a key takeaway for the clinic is the importance of comprehensive biomarker testing at diagnosis. Ensuring that no patient with a potentially targetable mutation is missed is foundational to delivering effective care. At the same time, clinicians must remain engaged with the evolving data, involve patients in shared decision-making, and advocate for personalized, risk-adaptive approaches. The field is becoming more nuanced, and leveraging both emerging evidence and patient perspectives will be essential to continue advancing care for this population.