Discussion
NSCLC, tumor
TUMOR, NSCLC, CNS METASTASES
EGFR 20ins has long been an unadopted orphan in NSCLC. Challenges in developing effective 20ins-targeted therapies lie in the structural heterogeneity of 20ins TKDs and their resemblance to EGFR wildtypeIn the phase 1b trial, JMT101 6 mg/kg every 2 weeks plus osimertinib 160 mg daily yielded an IRC-assessed confirmed ORR of 36.4%, DCR of 95.0% and a median PFS of 8.2 months in the efficacy population (Osimertinib is an ATP-competitive covalent TKI designed against EGFR TKDs. Similar to other EGFR/pan-HER TKIs, its activity in 20ins is limitedUnlike classic EGFR mutations, there are few studies investigating tumor genomic features and their clinical implications for EGFR 20ins. Concurrent alterations in TP53, CDK4/6 and cell cycle-regulating genes have been identified as inferior prognostic factors for patients with classic EGFR mutationsAcquired resistance to EGFR targeted therapies in NSCLC predominantly fall into two categories, on-target (EGFR-dependent) resistance and off-target (EGFR-independent) resistanceThis study has several limitations. First, although we accrued a relatively large population of 150 patients, interpretation of the study outcome is limited by its early phase nature and a lack of control arm. Second, we used a targeted NGS panel, instead of whole-exosome sequencing, in cfDNA analysis. This may limit our identification of other potential resistance drivers. Additionally, no patient in this study had been treated with amivantamab or mobocertinib. It remains unclear whether this combination will be effective in patients progressing on the above two therapies.Despite the above limitations, this study demonstrates that dual targeting EGFR 20ins with JMT101 and osimertinib has the potential to become a new treatment option for EGFR 20ins-positive NSCLC, especially for those with untreated baseline CNS metastases. Mechanistically, the combination led to a thorough and sustained EGFR blockade in distinct 20ins variants. Acquired resistance was predominantly driven by EGFR-independent mechanisms that partly overlapped with those observed in classic EGFR mutations. The ongoing pivotal phase 2 trial (NCT05132777) will further establish the activity and feasibility of JMT101 plus osimertinib in patients with EGFR 20ins-positive advanced NSCLC.