The phase 3 EXCLAIM-2 trial investigating mobocertinib (Exkivity) as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations has failed to meet its primary endpoint, marking a significant setback in the development of targeted therapies for this patient population.
Efficacy Findings
The trial data, published in the Journal of Clinical Oncology, showed identical median progression-free survival (PFS) of 9.6 months for both mobocertinib and platinum-based chemotherapy arms (HR, 1.04; 95% CI, 0.77-1.39; P = .803). The objective response rates were similarly matched, with mobocertinib achieving 32% (95% CI, 26%-40%) compared to chemotherapy's 30% (95% CI, 24%-38%).
While mobocertinib demonstrated a longer duration of response at 12.0 months versus 8.4 months for chemotherapy, overall survival data showed no significant advantage. The two-year survival rates were comparable at 61% for mobocertinib and 62% for chemotherapy.
Trial Design and Patient Population
The open-label study enrolled 354 patients, randomizing them to receive either mobocertinib at 160 mg daily (n = 179) or standard platinum-based chemotherapy (n = 175). The patient population was predominantly female and Asian, with most participants having adenocarcinoma histology and an ECOG performance status of 1.
Safety and Tolerability Profile
Treatment-emergent adverse effects were observed in nearly all patients across both arms, though grade 3 or higher events were more frequent with mobocertinib (62%) compared to chemotherapy (53%). The most notable difference in side effects was the incidence of diarrhea, affecting 96% of mobocertinib patients versus 18% in the chemotherapy group.
Clinical Implications
"The efficacy of mobocertinib was not superior to platinum-based chemotherapy as first-line treatment of EGFR [exon 20 insertion–positive] NSCLC," stated Dr. Pasi A. Jänne from Dana-Farber Cancer Institute. The trial's premature discontinuation after crossing the prespecified futility boundary underscores the continuing challenge in developing effective targeted therapies for this specific NSCLC subtype.
Quality of Life Measures
Despite the primary endpoint failure, mobocertinib showed some advantage in quality of life metrics, with a median time to deterioration of 9.4 months compared to 5.0 months with chemotherapy. However, this benefit must be weighed against the higher incidence of certain adverse events, particularly gastrointestinal toxicities.
