Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Clinical outcome of treatment of metastatic non-small cell lung cancer in patients harboring uncommon EGFR mutation.

BACKGROUND: Uncommon epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a rare subset of NSCLC. The aim of this study was to investigate the prevalence, characteristics, and clinical outcomes of metastatic NSCLC harboring uncommon EGFR mutation at Thailand's largest national tertiary hospital. The secondary objective was to compare treatment efficacy between EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy. METHODS: This retrospective chart review included patients that were tested for EGFR-mutation NSCLC during 2014-2018. Patient demographic and clinical data, treatment data, and outcome data were collected and analyzed. RESULTS: Of the 681 patients that were evaluated for EGFR mutation, 317 (47.0%) had EGFR-mutant NSCLC, and 28 (8.8%) of those harbored uncommon EGFR mutations. The median follow-up was 19.1 months. History of tobacco use was reported in 50% of patients. The most common single mutation among uncommon EGFR was exon 20 insertion (n = 6), followed by L861Q (n = 5) and G719X (n = 4). Thirteen (46%) patients had compound mutations. One hundred percent of male patients with G719X mutation were smokers. Sixteen of 28 patients were treated with EGFR-TKI. Most received first-generation EGFR-TKI, and 29% were treated with chemotherapy alone. The objective response rate was 37.5% in the EGFR-TKI group. Median progression-free survival (PFS) in the EGFR-TKI group was 10.2 months. Median PFS among the 8 patients in the chemotherapy group that received first-line platinum doublet was 6.5 months. Three-year overall survival (OS) among 28 patients was 34%. Three-year OS was significantly better in patients treated with EGFR-TKI. CONCLUSIONS: Uncommon EGFR mutations was detected in 8.8% of EGFR-mutant NSCLC. Exon 20 insertion was the most common mutation, and 50% of patients had history of tobacco use. First- or second-generation EGFR-TKI demonstrated greater OS benefit than platinum-doublet chemotherapy among patients harboring uncommon EGFR-mutant NSCLC. Survival outcomes were comparable to those reported from previous large cohort studies.