Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib

Patients with NSCLC harboring uncommon EGFR mutations have limited therapeutic options and often poor outcomes, especially following progression on standard EGFR tyrosine kinase inhibitors (TKIs). Amivantamab, an anti-EGFR/MET bispecific antibody, shows efficacy in EGFR-mutated NSCLC, but its role in rare EGFR alterations and CNS involvement, including leptomeningeal disease (LMD), remains insufficiently characterized. We report a 67-year-old male with stage IVB NSCLC harboring EGFR G719A and A289V mutations who developed LMD while on osimertinib. After progression on immunotherapy and chemotherapy, amivantamab monotherapy was initiated. Treatment produced a durable response over 19 months, including a 32.2% reduction in tumor size at six weeks, and complete resolution of brain metastases and LMD by six months. Circulating tumor DNA analyses showed EGFR variant allele fractions decreasing from 25.6% to undetectable. This case challenges current paradigms, demonstrating that amivantamab monotherapy can effectively target rare EGFR mutations, achieve durable extracranial and CNS disease control, and potentially overcome blood-brain barrier limitations. These findings suggest that amivantamab's utility may extend beyond established combination regimens and well-characterized EGFR mutations, offering an effective option for patients with atypical molecular profiles who lack standard therapies. Amivantamab monotherapy may represent a viable strategy for patients with uncommon EGFR mutations and CNS involvement, including LMD. Further research is warranted to elucidate underlying mechanisms, refine treatment strategies, and assess amivantamab's broader applicability in similarly challenging NSCLC scenarios.