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Updated: May 30, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
First-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With EGFR Exon 20 Insertion-Positive
Pasi A Jänne1, Bin-Chao Wang2, Byoung Chul Cho3
1Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
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 > 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 >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.
Insights
Mobocertinib did not show superior efficacy compared to chemotherapy for first-line treatment in advanced non-small cell lung cancer with EGFR exon 20 insertion mutations. The EXCLAIM-2 trial did not meet its primary endpoint of improved progression-free survival.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations presents a therapeutic challenge.
- Mobocertinib is an oral tyrosine kinase inhibitor targeting these specific EGFR mutations.
Purpose of the Study:
- To compare the efficacy of first-line mobocertinib versus platinum-based chemotherapy in patients with advanced NSCLC harboring EGFR ex20ins mutations.
- To evaluate progression-free survival (PFS) as the primary endpoint in the phase III EXCLAIM-2 trial (NCT04129502).
Main Methods:
- Randomized, open-label, phase III trial involving 354 treatment-naive patients with EGFR ex20ins+ advanced/metastatic NSCLC.
- Patients were assigned 1:1 to receive mobocertinib (160 mg once daily) or pemetrexed plus platinum-based chemotherapy.
- Primary endpoint: PFS assessed by blinded independent central review (BICR).
Main Results:
- Median PFS was 9.6 months for both mobocertinib and chemotherapy arms (HR, 1.04; P = .803), failing to meet the primary endpoint.
- Objective response rates were similar (32% vs 30%), but median duration of response favored mobocertinib (12.0 vs 8.4 months).
- Mobocertinib demonstrated benefits in quality-of-life measures and a distinct safety profile, notably higher rates of diarrhea.
Conclusions:
- The EXCLAIM-2 trial did not demonstrate superior efficacy of mobocertinib over platinum-based chemotherapy as a first-line treatment for EGFR ex20ins+ NSCLC.
- Mobocertinib's efficacy was not superior to standard chemotherapy in this patient population, despite some quality-of-life benefits.
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