First-Line Mobocertinib Fails to Improve Efficacy for EGFR-Mutated Advanced Non-Small Cell Lung Cancer

According to results from the phase 3 EXCLAIM-2 trial, first-line mobocertinib failed to significantly improve efficacy compared to platinum-based chemotherapy among patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

“Mobocertinib is a first-in-class, oral EGFR TKI that targets in-frame EGFR ex20ins mutations…[approved for patients] whose disease has progressed on or after platinum-based chemotherapy,” stated Pasi Janne, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, and coauthors. “In this trial, we compared the efficacy and safety of first-line mobocertinib with platinum-based chemotherapy.”

In this open-label study, 354 patients were randomized on a 1-to-1 basis to receive either 160 mg of once daily mobocertinib (n = 179) or pemetrexed plus cisplatin or carboplatin once every 3 weeks for 4 cycles followed by maintenance pemetrexed (n = 175) until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS), assessed via blinded independent central review. Key secondary end points included confirmed objective response rate (ORR), duration of response, and safety. 

At analysis, the median PFS was 9.6 months in both treatment arms (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.77 to 1.39; P = .803). The confirmed ORR was 32% in the mobocertinib arm and 30% in the chemotherapy arm. The median duration of response was 12 months and 8.4 months, respectively. The most common grade ≥3 adverse events occurring in > 5% of patients included diarrhea, anemia, increased lipase, and decreased neutrophil count. 

“The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC,” concluded Dr Janne et al. 

“The next generation of EGFR tyrosine kinase inhibitors targeting EGFR ex20ins mutations will need to have greater efficacy and better tolerability,” added Journal of Clinical Oncology associate editor Thomas Stinchcombe, MD, Duke Cancer Institute, Durham, North Carolina.

In an editorial, Zofia Piotrowska, MD, Massachusetts General Hospital, Boston, Massachusetts, noted the EXCLAIM-2 results “led to the withdrawal of mobocertinib from global patients.” As mobocertinib was “the only approved TKI to date for this disease,” these results and the withdrawal emphasize “the need for more active and better tolerated EGFR inhibitors and sets a benchmark for future drug development."

Sources: 

Janne PA, Wang BC, Cho BC, et al. First-line mobocertinib versus platinum-based chemotherapy in patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer in the phase III EXCLAIM-2 trial. J Clin Oncol. Published online: January 29, 2025. doi: 10.1200/JCO-24-01269

Piotrowska Z. Making progress along the challenging road of drug development for patients with EGFR exon 20 insertion-positive non-small cell lung cancer. J Clin Oncol. Published online: February 5, 2025. doi: 10.1200/JCO-24-02656