As reported inThe New England Journal of Medicine by Jürgen Wolf, MD, of the Center for Integrated Oncology, University Hospital Cologne and University of Cologne, and colleagues, the phase II GEOMETRY mono-1 trial has shown durable responses with the selective MET inhibitor capmatinib in patients with advanced non–small cell lung cancer (NSCLC) with MET exon 14 skipping mutations.¹

Jürgen Wolf, MD

The trial supported the May 2020 accelerated approval of capmatinib for treatment of adult patients with metastatic NSCLC with tumors that have a mutation that leads to MET exon 14 skipping.

Study Details

The international trial enrolled a total of 364 patients with MET-dysregulated advanced disease, with assignment to cohorts based on previous lines of therapy and MET status of MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue. Patients received oral capmatinib at 400 mg twice daily. All previously treated patients had received one or two lines of prior therapy. The primary endpoint was an objective response based on Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by an independent review committee blinded to cohort assignments.

In cohorts of previously treated patients, capmatinib was considered to have clinically relevant efficacy if the objective response rate was at least 35%, with a lower boundary of the 95% confidence interval (CI) greater than 25%. In cohort of treatment-naive patients, the threshold for clinically relevant efficacy was a response rate of at least 55%, with a 95% CI lower boundary greater than 35%.

Responses

Across cohorts, a total of 97 patients had a MET exon 14 skipping mutation, and 210 had MET amplification.

Among 97 patients with a MET exon 14 skipping mutation, an objective response was observed in 28 (41%, 95% CI = 29%–-53%) of 69 patients who had received one or two lines of prior therapy and in 19 (68%, 95% CI = 48%–84%) of 28 patients who had received no prior treatment. Median durations of response were 9.7 months (95% CI = 5.6–13.0 months) and 12.6 months (95% CI = 5.6 months to not estimable), respectively. Tumor response was observed at first evaluation after the start of treatment in 82% of previously treated responders and in 68% of responders without prior treatment. Median progression-free survival was 5.42 months (95% CI = 4.17–6.97 months) among previously treated patients and 12.42 months (95% CI = 8.21 months to not estimable) among treatment-naive patients. Among 13 evaluable patients with brain metastases at baseline, 12 had intracranial disease control, including 7 with an objective response (4 with a complete response). Intracranial responses were observed at first assessment.

Limited efficacy was observed among patients with MET amplification with a gene copy number of less than 10, all of whom had received previous treatment. An objective response was observed in 5 (12%) of 42 patients with a gene copy number of 6 to 9, in 5 (9%) of 54 with a gene copy number of 4 or 5, and in 2 (7%) of 30 with a gene copy number of less than 4. Median progression-free survival was 2.7 months, 2.7 months, and 3.6 months, respectively, in these cohorts. These cohorts were closed for futility at interim analysis.

Among patients with MET amplification with a gene copy number greater than 10, an objective response was observed in 20 (29%, 95% CI = 18.7%–41.2%) of 69 with previous treatment and in 6 (40%, 95% CI = 16.3%–67.7%) of 15 with no previous treatment. The overall response rate among these patients did not meet the prespecified threshold for clinically relevant efficacy. Median durations of response were 8.3 months and 7.5 months in the two groups. Median progression-free survival was 4.1 months and 4.2 months.

Adverse Events

Among all 364 patients enrolled in the trial, the most common adverse events of any grade irrespective of causality attribution were peripheral edema (51%), nausea (45%), vomiting (28%), and increased creatinine (24%). Grade 3 or 4 adverse events regardless of causality were reported in 67% of patients, the most common being peripheral edema (9%), dyspnea (7%), increased alanine transaminase (6%), and pneumonia (5%).

Treatment-related serious adverse events occurred in 13% of patients. Treatment-related adverse events led to discontinuation of treatment in 11%, with causes including peripheral edema (2%). Overall, 23% of patients experienced an adverse event regardless of causality that led to dose reduction. Death due to causes other than NSCLC occurred during treatment in 13 patients; causes consisted of cardiac arrest in 2 patients and atrial fibrillation, hepatitis, pneumonia, organizing pneumonia, bacterial pneumonia, pneumonitis, respiratory distress, sepsis, septic shock, sudden death, and assisted suicide in 1 patient each. One death, due to pneumonitis, was considered related to treatment.

The investigators concluded: “Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects.” 

DISCLOSURE: The study was funded by Novartis Pharmaceuticals. Dr. Wolf has received honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, and Roche; has served in a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Ignyta, Janssen/Johnson & Johnson, Lilly, Loxo/Lilly, MSD Oncology, Novartis, Pfizer, Roche, and Takeda; and has received research funding from Bristol-Myers Squibb, Janssen/Johnson & Johnson, Novartis, and Pfizer.

REFERENCE

1. Wolf J, Seto T, Han J-Y, et al: Capmatinib in MET exon 14–mutated or MET-amplified non–small-cell lung cancer. N Engl J Med 383:944-957, 2020.