Mobocertinib for Platinum-Pretreated Patients With EGFR Exon 20 Insertion–Positive Metastatic NSCLC

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In a phase I/II trial reported in JAMA Oncology, Caicun Zhou, PhD, MD, and colleagues found that mobocertinib, a first-in-class oral kinase inhibitor, produced durable responses in platinum-pretreated patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer (NSCLC). 

The agent is a first-in-class irreversible tyrosine kinase inhibitor designed to selectively target in-frame EGFR exon 20 insertion mutations in NSCLC. The findings in the platinum-pretreated cohort of the trial supported the September 2021 accelerated approval of mobocertinib for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease progressed on or after platinum-based chemotherapy.

Caicun Zhou, PhD, MD

Caicun Zhou, PhD, MD

Study Details

The multicenter study enrolled patients between June 2016 and November 2020. The platinum-pretreated cohort consisted of 114 patients who received 160 mg of mobocertinib once daily, including 6 from a dose-escalation and 22 from a dose-expansion U.S. cohort and 86 from the EXCLAIM single-group extension cohort, which included patients from sites in Asia, Europe, and North America.

The EXCLAIM cohort consisted of a total of 96 patients, of whom 10 were not platinum-pretreated. Asian patients constituted 60% of the platinum-pretreated cohort and 69% of the EXCLAIM cohort.

Mobocertinib treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate on independent review committee (IRC) assessment.


Median follow-up at data cutoff was 14.2 months (range = 0.7–35.8 months) in the platinum-pretreated cohort. Objective responses (all partial) were observed in 32 patients (28%, 95% confidence interval [CI] = 20%–37%) on IRC assessment. An additional 57 patients (50%) had stable disease, yielding a disease control rate of 78%.

The median duration of response was 17.5 months (95% CI = 7.4–20.3 months). Median progression-free survival was 7.3 months (95% CI = 5.5–9.2 months). Median overall survival was 24.0 months (95% CI = 14.6–28.8 months). On investigator assessment in the platinum-pretreated cohort, the objective response rate was 35% (95% CI = 26%–45%), median response duration was 11.2 months (95% CI = 5.6 months–not reached), and median progression-free survival was 7.3 months (95% CI = 5.6–8.8 months).

In the EXCLAIM cohort (including the 86 patients in the platinum-pretreated cohort), with median follow-up of 13.0 months, the objective response rate on IRC assessment was 25% (95% CI = 17%–35%) and median response duration was not reached (95% CI = 5.6 months–not reached). Median progression-free survival was 7.3 months (95% CI = 5.5–9.1 months), and median overall survival was not reached (95% CI = 13.1 months–not reached).


  • Objective response was observed in 28% of platinum-pretreated patients, and disease control was observed in 78%.
  • Median duration of response was 17.5 months.

Adverse Events

Among the 114 patients in the platinum-pretreated cohort, the most common treatment-related adverse events of any grade were diarrhea (91%), rash (45%), and paronychia (38%). Grade ≥ 3 adverse events occurred in 69% of patients and were considered treatment-related in 47%, with the most common treatment-related events being diarrhea, nausea, stomatitis, and increased lipase.

Serious adverse events occurred in 49% of patients. Adverse events led to treatment discontinuation in 17% of patients, most commonly due to diarrhea and nausea (4% each). One death—due to cardiac failure—was considered related to treatment.

The investigators concluded: “In this open-label, phase I/II nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFR exon 20 insertion–positive metastatic NSCLC, with a manageable safety profile.”

Dr. Zhou, of the Department of Oncology, Shanghai Pulmonary Hospital, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. For full disclosures of the study authors, visit

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