MET amplification

After resolution with corticosteroids, treatment was switched to afatinib. This study highlights the heterogeneous approaches to OILI and the potential feasibility of rechallenge in selected patients. Given the expanding osimertinib use for early and advanced stage NSCLC, further research is warranted to refine treatment decisions and optimize patient safety.

The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population.

Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.

Treatment-related adverse events of grade 3 or higher occurred in 2 patients (8.7%) in cohort 1 and 12 patients (57.1%) in cohort 2. Osimertinib plus savolitinib showed promising antitumor activity and manageable safety.

Our study demonstrated that the biological and clinical significance of MET alterations is highly context dependent. In lung cancer, MET serves primarily as a predictive biomarker for targeted therapy, whereas in brain tumors, it functions as a prognostic marker of genomic instability and aggressive disease. These findings advocate for context-specific clinical management strategies.

Despite the exploratory nature of the analysis on a small population, the study underscores the biological and transcriptional heterogeneity of LGGs and highlights the limitations of tumor-only sequencing approaches. Broader genomic profiling and matched normal controls are warranted to refine the interpretation of rare or non-canonical variants.

MET-altered NSCLC is a challenging and heterogeneous molecular subset, and our knowledge is rapidly evolving. Work is ongoing to define the spectrum of actionable mutations, to develop standardized and clinically meaningful biomarker-driven identification of these alterations, and to determine the most effective treatment approaches, with the goal of expanding the treatment landscape and improving outcomes for a subset of patients with limited treatment options.

P2, N=60, Recruiting, Qingdao Central Hospital

The patient eventually developed resistance to both first-line gefitinib and later almonertinib...He received ivonescimab monotherapy, achieving disease control for nearly 5 months before transitioning to ivonescimab plus pemetrexed with continued benefit and a manageable safety profile. This case illustrates the potential benefit of ivonescimab in patients with EGFR-mutant LUAD and baseline MPE who develop complex, non-canonical resistance to EGFR-TKIs. These findings support further clinical evaluation of ivonescimab in this poor-prognosis subgroup and highlight the importance of repeated molecular profiling in guiding treatment strategy.

These data confirm the efficacy and safety of first line D/T in BRAF V600E-mutated pts in the real-world setting consistently with prior studies, suggesting a differential activity among key clinical-molecular subgroups.

For metastatic disease, frontline combination strategies, such as osimertinib plus chemotherapy (FLAURA2) and amivantamab plus lazertinib (MARIPOSA), building on the EGFR-TKI backbone have improved progression-free and overall survival, particularly in higher-risk subgroups. Following progression on third-generation TKIs, potential avenues for overcoming resistance include mechanism-based strategies targeting MET amplification or EGFR C797S, as well as mechanism-agnostic approaches such as bispecific antibodies and antibody-drug conjugates (ADCs). Collectively, these recent advances reflect the dynamic nature of the therapeutic landscape for EGFR-mutant NSCLC, which is becoming increasingly individualized, mechanism-informed, and resistance-adaptive, in efforts to achieve durable systemic and intracranial disease control.