Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. Eligible patients were aged ≥ 20 years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240 mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9 months; estimated survival rates at 12, 24, and 36 months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240 mg/day was consistent with previous findings. Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. ClinicalTrials.gov identifier NCT03046992.

Han JY ，Ahn MJ ，Lee KH ，Lee YG ，Kim DW ，Min YJ ，Kim SW ，Cho EK ，Kim JH ，Lee GW ，Lee SS ，Lee NM ，Jang HW ，Han H ，Park H ，Lee J ，Cho BC ... -  《BMC Medicine》

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.

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. 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). 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]. 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.

Felip E ，Cho BC ，Gutiérrez V ，Alip A ，Besse B ，Lu S ，Spira AI ，Girard N ，Califano R ，Gadgeel SM ，Yang JC ，Yamamoto S ，Azuma K ，Kim YJ ，Lee KH ，Danchaivijitr P ，Ferreira CG ，Cheng Y ，Sendur MAN ，Chang GC ，Wang CC ，Prabhash K ，Shinno Y ，Stroyakovskiy D ，Paz-Ares L ，Rodriguez-Cid JR ，Martin C ，Campelo MRG ，Hayashi H ，Nguyen D ，Tomasini P ，Gottfried M ，Dooms C ，Passaro A ，Schuler M ，Gelatti ACZ ，Owen S ，Perdrizet K ，Ou SI ，Curtin JC ，Zhang J ，Gormley M ，Sun T ，Panchal A ，Ennis M ，Fennema E ，Daksh M ，Sethi S ，Bauml JM ，Lee SH ... -  《-》

Sunvozertinib monotherapy in EGFR tyrosine kinase inhibitor-resistant non-small cell lung cancer with EGFR mutations.

Multiple agents can be used to treat patients with EGFR mutated non-small cell lung cancer (NSCLC) who develop resistance to EGFR tyrosine kinase inhibitors (TKIs), but the clinical outcome was not satisfactory, especially in patients with multiple lines of prior therapies. Therefore, there is an unmet medical need for these patients. Sunvozertinib is an oral, potent, irreversible, and mutant-selective EGFR TKI targeting EGFR mutations with weak activity against wild-type EGFR. We investigated the efficacy and safety of sunvozertinib monotherapy in treating EGFR TKI-resistant patients with NSCLC harboring EGFR mutations. This was a pooled analysis of phase 1 and 2 studies (WU-KONG1, WU-KONG2 and WU-KONG15). Eligible patients received sunvozertinib at doses ranging from 50 mg to 400 mg once daily. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS). Safety endpoints included adverse events and serious adverse events. In addition, plasma specimens were collected at baseline to assess EGFR mutation types and genetic alterations in EGFR downstream signaling pathway. Forty patients were enrolled. Ninety percent received ≥ 3 prior lines of therapies. The best ORR was 27.5 %, and DCR was 60 %. The median DoR and PFS were 6.5 months and 6 months, respectively. Higher ORR was seen in patients whose last line of treatment was chemotherapy rather than EGFR TKI (31.6 % vs. 14.3 %). Greater responses were seen in patients with EGFR sensitizing and T790M double mutations (ORR: 55.6 %). The safety profile of sunvozertinib was consistent with previous reports. Sunvozertinib has promising activity implying future investigations in the patients with EGFR mutated NSCLC who developed resistance to prior EGFR TKI.

Wang M ，Xu Y ，Huang WT ，Su WC ，Gao B ，Lee CK ，Fang J ，Zhu X ，Yang Z ，Jänne PA ，Yang JC ... -  《-》

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

Dong S ，Wang Z ，Zhang JT ，Yan B ，Zhang C ，Gao X ，Sun H ，Li YS ，Yan HH ，Tu HY ，Liu SM ，Gong Y ，Gao W ，Huang J ，Liao RQ ，Lin JT ，Ke EE ，Xu Z ，Zhang X ，Xia X ，Li AN ，Liu SY ，Pan Y ，Yang JJ ，Zhong WZ ，Yi X ，Zhou Q ，Yang XN ，Wu YL ... -  《-》

A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor-Naïve EGFR-Mutant Metastatic Non-Small Cell Lung Cancer (RAMOSE trial).

Le X ，Patel JD ，Shum E ，Baik C ，Sanborn RE ，Shu CA ，Kim C ，Fidler MJ ，Hall R ，Elamin YY ，Tu J ，Blumenschein G ，Zhang J ，Gibbons D ，Gay C ，Mohindra NA ，Chae Y ，Boumber Y ，Sabari J ，Santana-Davila R ，Rogosin S ，Herzberg B ，Creelan B ，Pellini B ，Tanvetyanon T ，Heeke S ，Hernandez M ，Gray JE ，Saltos A ，Heymach JV ... -  《-》