Year in Review 2024: Updates in the Management of Advanced EGFR-Mutant NSCLC - Episode 6
Panelists discuss how second-line treatment selection depends heavily on frontline therapy choice, emphasizing the importance of repeat biopsies to identify resistance mechanisms and considering continuation of TKI with added chemotherapy for patients with controlled CNS disease.
This video segment addresses the complex treatment landscape for advanced EGFR-mutated non–small cell lung cancer (NSCLC) in the second-line setting, emphasizing how frontline treatment choices significantly impact subsequent therapeutic options. The discussion highlights that treatment selection has become increasingly complicated as more combination regimens become available in the frontline setting, with each initial choice creating different downstream possibilities for managing acquired resistance.
The oncologists outline the key effective therapies available in the EGFR-mutated NSCLC treatment arsenal, including third-generation EGFR tyrosine kinase inhibitors (TKIs) that prevent T790M resistance, chemotherapy combinations like carboplatin and pemetrexed, and amivantamab either alone or in combination. Treatment sequencing depends heavily on frontline therapy selection: patients who received osimertinib monotherapy in the front line typically move to combination approaches like MARIPOSA2 (amivantamab plus chemotherapy), while those who received frontline combinations require different strategies. The importance of repeat tissue and liquid biopsies at progression is emphasized, as these can reveal histologic transformation to small cell or squamous lung cancer, which dramatically alters treatment recommendations and chemotherapy selection.
A particularly nuanced scenario involves patients with baseline brain metastases who experience systemic progression while maintaining central nervous system (CNS) control on their TKI. In these cases, clinicians often prefer adding chemotherapy to the existing TKI rather than switching regimens entirely, to preserve the CNS benefit. The segment concludes with recognition that resistance mechanisms like HER3 upregulation are being studied as potential therapeutic targets, though these remain primarily in the research realm. The overarching message emphasizes that patients should be exposed to multiple effective therapies throughout their treatment course, as predicting which specific approach will work best remains challenging despite molecular profiling efforts.