First-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With <i>EGFR</i> Exon 20 Insertion–Positive Metastatic Non–Small Cell Lung Cancer in the Phase III EXCLAIM-2 Trial

Abstract

PURPOSE Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets EGFR exon 20 insertion (ex20ins) mutations in non–small cell lung cancer (NSCLC). This open-label, phase III trial (EXCLAIM-2, ClinicalTrials.gov identifier: NCT04129502 ) compared mobocertinib versus platinum-based chemotherapy as first-line treatment of EGFR ex20ins+ advanced/metastatic NSCLC. METHODS Patients with treatment-naive EGFR ex20ins+ locally advanced/metastatic NSCLC were randomly assigned 1:1 to mobocertinib 160 mg once daily or pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by maintenance pemetrexed. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR), with planned interim analysis (IA) after approximately 70% of 227 expected PFS events. RESULTS A total of 354 patients were randomly assigned (mobocertinib: n = 179; chemotherapy: n = 175). Baseline characteristics were balanced between arms. At IA (cutoff: April 4, 2023), the median PFS per BICR was 9.6 months in each treatment arm (hazard ratio [HR], 1.04 [95% CI, 0.77 to 1.39]; P = .803). The primary end point crossed the prespecified futility boundary (HR &gt; 1). The confirmed objective response rate (95% CI) per BICR was 32% (26 to 40) with mobocertinib versus 30% (24 to 38) with chemotherapy; the median duration of response was 12.0 versus 8.4 months. Quality-of-life assessments indicated clinically meaningful delays in time to deterioration of lung cancer symptoms, cognitive function, and constipation with mobocertinib versus chemotherapy. Grade ≥3 adverse events in &gt;5% of patients (mobocertinib, chemotherapy) were diarrhea (20%, 1%), anemia (6%, 10%), increased lipase (6%, 0%), and decreased neutrophil count (1%, 7%). CONCLUSION The EXCLAIM-2 trial did not meet its primary end point. The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC.