Dacomitinib With or Without Dose Titration in Treatment-Naive Advanced <i>EGFR</i>-Mutated NSCLC - Primary Analysis of the ATORG-003 Phase 2 Trial.

Abstract

Dacomitinib is an approved second-generation EGFR tyrosine kinase inhibitor. In the phase 3 ARCHER 1050 trial, both progression-free survival (PFS) and overall survival (OS) were improved with first-line dacomitinib compared with gefitinib. Post hoc analysis revealed that efficacy (PFS, OS) was similar in both dose-reduced patients and the overall study population. ATORG-003 evaluated a dose-titration strategy to improve tolerability while maintaining efficacy. This is also the first prospective study of dacomitinib's intracranial efficacy and resistance (tissue and plasma next-generation sequencing). ATORG-003 (Asian Thoracic Oncology Research Group; five Asian countries) was a single-arm, investigator-initiated phase 2 trial that enrolled patients with treatment-naive stages IIIB to IV <i>EGFR</i>-mutated NSCLC. Patients received dacomitinib 30 mg daily for 4 weeks, with a shared investigator and patient decision for titration to 45 mg in patients with grade less than or equal to 1 toxicity (Common Terminology Criteria for Adverse Events version 5.0). The primary end point was the 12-month PFS rate (in patients without central nervous system metastases only) compared with the historical control. Secondary end points were time to treatment failure (TTF), objective response rate (ORR), OS, intracranial ORR (iORR) and intracranial PFS (iPFS), and safety and tolerability. From September 2019 to October 2022, 118 patients were enrolled. The median age was 65 (range 33-84) years, and 54% were female. <i>EGFR</i> mutation type was exon 19 deletion in 57%, L858R mutation in 42%, and both in 1%. There were 18% of patients who were dose titrated to 45 mg at cycle 2, and 70% tolerated 30 mg (67%) or 45 mg (3%) without dose reduction. The primary end point was met, with a 12-month PFS proportion rate of 59.6% (90% confidence interval [CI]: 50.6%-68.1%) and a 12-month PFS rate of 61.2% (95% CI: 50.5%-70.3%) in the primary analysis cohort. The median PFS was 16.1 months (95% CI: 12.1-19.2), and the median TTF was 19.3 months (95% CI: 16.1-22.1). In the overall study population, the ORR was 77% and the median OS was not reached. In patients with central nervous system metastases (<i>n</i> = 24), the iORR was 54% and the median iPFS was 17.6 months (95% CI: 7.2-23.1). All patients had treatment-related adverse events (TRAEs), with grade 3/4 TRAEs occurring in 25%. The most common grade 3/4 TRAEs were rash (7%), paronychia (4%), and hypokalemia (3%). <i>EGFR</i> T790M resistance was detected in 29 of 96 patients (30%) through plasma next-generation sequencing and in 15 of 29 patients (52%) through tissue next-generation sequencing. ATORG-003 prospectively revealed that dacomitinib with dose titration is a viable strategy in advanced <i>EGFR</i>-mutated NSCLC, maintaining efficacy while improving tolerability. Dacomitinib has substantial intracranial activity and high rates of T790M resistance, making it suitable for sequential treatment approaches.