The potent MET inhibitor capmatinib showed durable responses and a manageable safety profile in patients with non–small-cell lung cancer (NSCLC) and a MET exon 14 skipping mutation, according to researchers.
MET exon 14 skipping mutations are present in 3% to 4% of NSCLC patients, and the mutation “is associated with both poor prognosis and poor responses to standard therapies, and this includes immunotherapy,” said Juergen Wolf, MD, of the University of Cologne in Germany. Capmatinib is a highly selective MET inhibitor, and is more potent than other available inhibitors. Wolf presented results of the GEOMETRY mono-1 phase II trial at the American Society of Clinical Oncology (ASCO) Annual Meeting (abstract 9004).
Sixty-nine pretreated patients were included in cohort 4 of the trial, and 28 treatment-naive patients were in cohort 5b. All patients had stage IIIB/IV NSCLC and a MET exon 14 skipping mutation. The median age in both cohorts was 71 years, and most patients were white. Just under two-thirds of each cohort were never smokers. The most common metastatic sites were bone, brain, liver, and adrenal gland.
In the prior therapy cohort, 88.4% of patients had received platinum-based chemotherapy; 26.1% had received immunotherapy, 13.0% had received single-agent chemotherapy, and 4.3% had received targeted therapy. In these patients, the overall response rate was 40.6% according to a blinded independent review committee (BIRC), and 42.0% by investigator assessment. The disease control rate was 78.3% by BIRC assessment and 76.8% according to investigators.
In the treatment-naive cohort, the response rate was 47.6% by BIRC assessment and 60.7% by investigator assessment. The disease control rate was 96.4% according to both assessments.
Wolf said there were deep responses with substantial tumor shrinkage seen across both cohorts. The median duration of response was 9.72 months in the pretreated cohort, and 11.14 months in the treatment-naive cohort. Responses generally were rapid in onset, with most responding within the first 7 weeks of treatment.
By BIRC assessment, the median progression-free survival was 5.42 months in the pretreated cohort, and 9.69 months in the treatment-naive cohort. Notably, of 13 evaluable patients with brain metastases at baseline, 54% had an intracranial response, and intracranial disease control was achieved in 12 of 13 patients.
The safety of the agent was determined in a total of 334 MET-dysregulated NSCLC patients with a median treatment exposure of 14.9 weeks. Grade 3/4 adverse events occurred in 35.6% of patients, with peripheral edema, fatigue, and nausea and vomiting among the most common. Only 4.5% of patients had grade 4 adverse events. Dose adjustment due to a treatment-related adverse event was required in 21.9% of patients, and 11.1% of patients discontinued therapy as a result.
“Capmatinib is a potent and selective MET inhibitor that represents a new potential treatment option in this rare but challenging patient population of advanced NSCLC harboring MET exon 14 skipping mutations,” Wolf concluded. The agent has been granted Orphan Drug and Breakthrough Therapy designations by the US Food and Drug Administration.
Karen L. Reckamp, MD, MS, of the City of Hope Comprehensive Cancer Center in Duarte, California, was the discussant for the abstract, and she noted the lower response rates in the second- and third-line setting with capmatinib. “This may be due to the higher age of these patients and comorbidities, so that we really only have one chance in getting the right therapy to these patients,” she said.
The responses seen in patients with brain metastases are also promising, she said. “Very small numbers at this point, but these reports and these numbers do indicate that we’re getting crossing [of] the blood-brain barrier and responses in the central nervous system,” Reckamp said. “I think that we are moving in the right direction.”