Intracranial and systemic progression on amivantamab in platinum-treated epidermal growth factor receptor exon 20 insertion-mutated advanced non-small cell lung cancer

Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved as monotherapy and as combination therapy for patients with advanced non-small cell lung cancer (NSCLC) harboring various EGFR mutations in first-line and refractory settings. Sites of progressive disease on amivantamab monotherapy are not well understood and could be instructive for treatment management. Methods: CHRYSALIS (NCT02609776) enrolled participants with NSCLC, including those with treated brain metastases. Brain magnetic resonance imaging was required at screening but performed per local practice after enrollment (conducted postbaseline every 6 [±1] weeks after Cycle 1 Day 1). Sites of target, non-target, and new lesion progression were reported. This analysis includes 114 participants with EGFR exon 20 insertion (Ex20ins) NSCLC after disease progression on platinum-based chemotherapy who received amivantamab monotherapy on or before June 4, 2020. Results: As of March 30, 2021, the median follow-up was 12.5 months (range, 0.2–30.5). Among 114 participants, the objective response rate by blinded independent central review was 43 %; median duration of response was 10.8 months, and median progression-free survival was 6.7 months. RECIST-defined progressive disease occurred in 72/114 participants (63 %); 25/72 (35 %) continued amivantamab after progression (4.2 median additional months; range, 1.0–12.5). The most common first sites of progression were the lungs/pleura (29 %), followed by bone (21 %), brain (15 %), and lymph node (12 %). Thirteen participants (11 %) had intracranial-only first progression. Six of these 13 participants underwent stereotactic radiosurgery (SRS) while continuing amivantamab. The median duration of amivantamab treatment post-progression in these 6 participants was 4.0 months (range, 2.3–6.0). SRS was well tolerated, with 2 adverse events reported (nausea and fatigue, n = 1 each). Conclusions: Amivantamab monotherapy in post-platinum Ex20ins NSCLC demonstrated meaningful antitumor activity in participants, and intracranial-only progression was infrequent. Treatment of brain progression with SRS while continuing amivantamab appears feasible and tolerable.