EGFR-mutated mNSCLC: Sharing Clinical Insights and Best Practices - Episode 15
The Future of Tumor Agnostic Therapies in EGFRm m NSCLC
Experts discuss the expanding treatment landscape for EGFR-mutated non–small cell lung cancer (NSCLC), highlighting emerging strategies beyond tyrosine kinase inhibitors (TKIs)—including novel immunotherapy combinations and antibody-drug conjugates (ADCs)—with particular interest in bispecific antibodies and TROP2-directed ADCs that may offer new options for patients progressing on targeted therapy, despite ongoing challenges in translating immune-based approaches into consistent survival gains.
Recent developments in the treatment of EGFR-mutated NSCLC have focused not only on refining targeted therapies, but also on exploring novel immune-based and ADC) approaches. One example is the bispecific antibody targeting both PD-1/PD-L1 and VEGF, evaluated in the Harmony trial. While the study showed an improvement in progression-free survival when combined with chemotherapy in the second-line setting, it did not meet the co-primary end point of overall survival. This underscores the ongoing challenge of harnessing immunotherapy in EGFR-mutant lung cancer, where response to checkpoint blockade has historically been limited. Although the trial adds to the conversation, the field is still searching for more transformative immune-modulating approaches, potentially through cellular therapies or other novel combinations.
Another area of active interest is the integration of ADCs into the treatment landscape. The recent FDA approval of a TROP2-directed ADC offers an alternative mechanism of action for patients progressing on targeted therapies. Early results, including pooled data from clinical trials, suggest promising survival outcomes and activity in the central nervous system, a frequent site of progression in EGFR-mutant disease. While this therapy is currently used in later lines, its activity and manageable toxicity profile have raised interest in moving it earlier in the treatment algorithm, with ongoing trials assessing combinations with EGFR TKIs and head-to-head comparisons against chemotherapy.
Together, these developments reflect a broadening of therapeutic strategies beyond traditional TKIs. While EGFR-targeted treatments remain foundational, the addition of immune-modulating agents and ADCs introduces more tools that may work through complementary mechanisms. These new options are especially relevant for patients with atypical EGFR mutations or those with limited responses to prior therapies. As data mature, thoughtful sequencing and combination strategies will be essential to maximizing benefit while managing toxicity.
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