Identifying High-risk Patient Populations Benefitting From Combination Therapy in the Frontline

The panelists explored the relevance of patient subgroups in determining the most appropriate frontline treatment approach for EGFR-mutated metastatic lung cancer. Recent analyses have identified several potential high-risk features, including specific mutation subtypes like L858R, co-mutations such as TP53, and the presence of brain metastases. While these data help frame the conversation, the group acknowledged that such features are so prevalent that nearly all patients might be labeled “high risk,” which challenges the practicality of using them as strict criteria for escalating to combination therapy.

With the release of definitive overall survival data from the FLAURA2 study, some clinicians are shifting their mindset. Where monotherapy was once a default with escalation only for high-risk cases, combination therapy is now being considered as a baseline option for all eligible patients. The panelists emphasized that willingness and ability to tolerate chemotherapy are becoming more important than the presence of specific risk factors alone. They also acknowledged that some patients still prefer monotherapy, and that shared decision-making is essential, especially in the absence of predictive biomarkers that might guide more personalized choices between escalation strategies.

Real-world applicability was another key concern. Clinical trial populations often differ from the patients seen in everyday practice—older individuals, those with poor performance status, or significant comorbidities may not be candidates for combination therapy. Therefore, while the data support a shift toward combination regimens as a standard approach, treatment must still be individualized. Patient preference, logistical considerations, and overall health status play critical roles in treatment decisions. Ultimately, the panel underscored that clinical judgment, along with an open and thorough dialogue with each patient, remains central to delivering optimal care in this increasingly complex therapeutic landscape.