Phase 1/2 trial of brigatinib plus panitumumab in patients with osimertinib-resistant EGFR-mutated non-small cell lung cancer harboring EGFR C797S mutation

• EGFR C797S mutation is the most common on-target acquired resistance mechanism to Osimertinib for advanced EGFR-mutated non-small cell lung cancer. • Brigatinib in combination with anti-EGFR antibody was reported to be effective for EGFR-mutated non-small cell lung cancer harboring EGFR C797S mutation in preclinical model and case reports. • Phase 1/2 study of brigatinib in combination with panitumumab for EGFR-mutated non-small cell lung cancer harboring EGFR C797S mutation was conducted, but this study was early terminated due to high incidence of early-onset pulmonary events by brigatinib. Osimertinib is a standard treatment for advanced EGFR -mutated non-small cell lung cancer (NSCLC). The EGFR C797S mutation is one of the most common resistant mechanisms to osimertinib. Based on our preclinical data, the safety and efficacy of brigatinib combined with panitumumab was evaluated in phase 1/2 study. This open-label phase 1/2 study enrolled patients with osimertinib-resistant EGFR -mutated NSCLC, with phase 1 dose escalation part, followed by phase 2 dose expansion part. The primary endpoint was the incidence of dose-limiting toxicities for phase 1 part, and objective response rate for phase 2 part. A total of 5 patients were enrolled between Dec 2020 and Jun 2021. Patients had received a median of 4 (range, 1-7) prior lines of treatment, no patient received prior immune checkpoint inhibitors. Median washout period from last dose of osimertinib was 10 days (range, 2-393). Three (60%) patients experienced early onset pulmonary event (EOPE) (grade [Gr] 2, n=1; Gr 3, n=2), all of which occurred during brigatinib monotherapy period. All cases with EOPE improved with brigatinib interruption for Gr 2, and systemic corticosteroid treatment for Gr 3. The efficacy to study treatment were PD in all 5 patients, with median progression-free survival of 1.7 months (95% CI, 1.2 to 3.4). Exploratory ctDNA analysis showed the decrease in relative allele frequency (C797S/exon19 deletion) between pre- and post-treatment (n=3). The clinical development of this combination strategy was discontinued, as brigatinib treatment was not feasible in patients with advanced EGFR -mutated NSCLC resistant to osimertinib.