Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study.

8504 Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. Lazertinib (laz) is a CNS-penetrant, 3 rd -generation EGFR TKI. In MARIPOSA (NCT04487080), first-line ami+laz provided a statistically significant improvement in progression-free survival (PFS) vs osimertinib (osi) in patients (pts) with EGFR-mutant advanced NSCLC (HR, 0.70; P< 0.001), including in pts with a history of brain metastases (HR, 0.69; Cho Ann Oncol 2023;34:S1306, LBA14). Pts with TP53co-mutations, detectable circulating tumor DNA (ctDNA), and baseline brain or liver metastases have poor prognoses. We evaluated outcomes for pts in these high-risk subgroups from MARIPOSA. Methods: MARIPOSA enrolled pts with treatment-naïve, EGFR-mutant (Ex19del or L858R) advanced NSCLC. This analysis included pts randomized to ami+laz (n = 429) or osi (n = 429). Pathogenic alterations were analyzed by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and Cycle (C) 3 Day (D) 1 with Biodesix droplet digital PCR (ddPCR). Results: Baseline ctDNA for NGS analysis of pathogenic alterations was available for 636 pts (ami+laz, n = 320; osi, n = 316). Among pts with TP53 co-mutation, mPFS was 18.2 months (mo) for ami+laz vs 12.9 mo for osi (HR, 0.65; P= 0.003). Pts with TP53 wild-type had a trend favoring ami+laz for mPFS (HR, 0.75; P =0.11). In pts with ddPCR-detectable ctDNA at baseline, ami+laz significantly prolonged mPFS vs osi (20.3 vs 14.8 mo; HR, 0.68; P= 0.002). Further, ami+laz significantly improved mPFS vs osi in pts with ctDNA clearance at C3D1 (24.0 vs 16.5 mo; HR, 0.64; P= 0.004) and in pts who did not clear ctDNA (16.5 vs 9.1 mo; HR, 0.48; P= 0.014). For pts with liver metastases at baseline, ami+laz significantly prolonged mPFS vs osi (18.2 vs 11.0 mo; HR, 0.58; P= 0.017), which is consistent with the improved PFS for ami+laz vs osi in pts with a history of brain metastases. Conclusions: Ami+laz demonstrated significantly improved mPFS vs osi in pts with biomarkers of high-risk disease. Given these features can occur in up to 85% of pts, ami+laz represents an important new standard of care for treatment-naïve EGFR-mutant advanced NSCLC. Clinical trial information: NCT04487080 . [Table: see text]