Abstract Background: In MARIPOSA, 1L amivantamab plus lazertinib (ami-laz) showed a statistically significant and clinically meaningful OS benefit vs osimertinib (osi; HR, 0. 75; P=0. 005). Ami-laz significantly reduced acquired MET amp (P=0. 002) and EGFR resistance mutations (P=0. 01) vs osi, with no significant increase in other resistance pathways (e. g. , RTK signaling, cell cycle), suggesting ami-laz changes the biology of disease. PFS after first subsequent therapy, often used to assess 2L outcomes, may be biased due to significantly longer 1L PFS seen for ami-laz vs osi (HR, 0. 70; P0. 001) in MARIPOSA. Here, we evaluated 2L PFS in participants (pts) in MARIPOSA, measured from time of first subsequent therapy initiation. Methods: To evaluate the effects of starting with ami-laz vs osi on long-term outcomes, we assessed 2L PFS, defined as time from initiation of first subsequent therapy to second objective progressive disease (PD) by investigator, or death. Analyses are post-hoc/exploratory with nominal P values. Acquired resistance was assessed from paired baseline and end of treatment (EOT) plasma samples as previously characterized (Besse ESMO 2024). ctDNA was assessed by NGS. Known resistance mechanisms included EGFR/MET-dependent (e. g. , C797S, MET amp) and/or EGFR/MET-independent resistance (e. g. , PIK3CA, RAS/RAF, cell cycle, TP53/Rb1 LOF) ; absence of these alterations constituted ‘unknown’ resistance. Results: As of the 4 Dec 2024 final analysis data cutoff, median follow-up for pts who received a subsequent therapy (post-ami-laz, 154; post-osi, 209) was 37. 9 mo, which was consistent with the randomized population. Demographics and baseline disease characteristics at the start of 1L tx were balanced. In both arms, the majority of pts started a subsequent regimen that most commonly included platinum chemotherapy and/or an EGFR-targeting agent. In total, EOT acquired resistance data were available for 226 pts. Among all pts who started a first subsequent therapy after 1L ami-laz vs osi, median 2L PFS was 8. 4 vs 5. 3 mo (HR, 0. 72; 95% CI, 0. 54-0. 95; P=0. 02). Harboring unknown resistance was associated with longer PFS, regardless of arm. Median 2L PFS was 4. 6 months for pts with known resistance vs 7. 4 months for pts with unknown resistance (HR, 0. 63; 95% CI, 0. 45-0. 90; P=0. 01), illustrating that outcomes remain worse for pts with common, tractable acquired resistance mutations (e. g. , C797S, MET amp) compared to those harboring unknown resistance mutations. Conclusion: Starting with 1L ami-laz provides long-term durable survival, as demonstrated by improved 1L and 2L PFS vs osi. Development of known resistance at end of 1L tx results in poor prognosis, while unknown resistance mechanisms may not. Ami-laz is the only combination regimen that reduces the most common resistance mechanisms (e. g. , EGFR/MET). Changing the biology of disease may be an important factor for long-term survival. Citation Format: David R. Spigel, Danny Nguyen, Hidetoshi Hayashi, Byoung Chul Cho, Sanjay Popat, James Chih-Hsin Yang, Scott Owen, Antonio Passaro, Clarissa Baldotto, Julian Kam, Seema Sethi, Sujay Shah, Jiarui Zhang, Joshua C. Curtin, Nicolas Girard, William N. William Jr. Impact of first-line (1L) amivantamab-lazertinib vs osimertinib on second-line (2L) progression-free survival (PFS) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB474.
Spigel et al. (Fri,) studied this question.
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