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

Pasi A Jänne; Bin-Chao Wang; Byoung Chul Cho; Jun Zhao; Juan Li; Maximilian Hochmair; Solange Peters; Benjamin Besse; Nick Pavlakis; Joel W Neal; Terufumi Kato; Yi-Long Wu; Danny Nguyen; Junjing Lin; Jianchang Lin; Florin Vranceanu; Annette Szumski; Huamao M Lin; Robert J Fram; Tony S K Mok

doi:10.1200/JCO-24-01269

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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

Authors: Pasi A Jänne ; Bin-Chao Wang ; Byoung Chul Cho ; Jun Zhao ; Juan Li ; Maximilian Hochmair ; Solange Peters ; Benjamin Besse ; Nick Pavlakis ; Joel W Neal ; Terufumi Kato ; Yi-Long Wu ; Danny Nguyen ; Junjing Lin ; Jianchang Lin ; Florin Vranceanu ; Annette Szumski ; Huamao M Lin ; Robert J Fram ; Tony S K Mok

Citation: JOURNAL OF CLINICAL ONCOLOGY, Vol.43(13) : 1553-1563, 2025-05

Journal Title: JOURNAL OF CLINICAL ONCOLOGY

ISSN: 0732-183X

Issue Date: 2025-05

MeSH: Adult ; Aged ; Aged, 80 and over ; Aniline Compounds ; Antineoplastic Combined Chemotherapy Protocols* / adverse effects ; Antineoplastic Combined Chemotherapy Protocols* / therapeutic use ; Carboplatin / administration & dosage ; Carboplatin / adverse effects ; Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / enzymology ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Cisplatin / administration & dosage ; Cisplatin / adverse effects ; ErbB Receptors / antagonists & inhibitors ; ErbB Receptors / genetics ; Exons ; Female ; Humans ; Indoles ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / enzymology ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Male ; Middle Aged ; Pemetrexed / administration & dosage ; Pemetrexed / adverse effects ; Progression-Free Survival ; Protein Kinase Inhibitors* / adverse effects ; Protein Kinase Inhibitors* / therapeutic use ; Pyrimidines

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 > 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.