Capmatinib–gefitinib combination has antitumor activity in MET-dysregulated NSCLC
medwireNews: Non-small-cell lung cancer (NSCLC) patients with acquired resistance to epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR–TKI) therapy and MET dysregulation could benefit from the addition of the MET inhibitor capmatinib to gefitinib, early results suggest.
The investigators of the phase Ib/II trial explain that MET dysregulation has been implicated as one of the underlying mechanisms imparting resistance to EGFR–TKIs in patients with EGFR-mutated disease, with MET amplification reported in 5–26% of cases.
They add that capmatinib – a highly selective and potent MET inhibitor – has shown promise in preclinical studies, both when given alone or alongside first- or third-generation EGFR–TKIs.
In the phase Ib part of the current study, 61 participants received the EGFR inhibitor gefitinib at 250 mg/day in combination with capmatinib capsules at doses ranging from 100–800 mg daily or capmatinib capsules or tablets at 200–600 mg twice-daily doses.
Among patients who could be evaluated for dose-limiting toxicities, there was one case of grade 3 dizziness in a patient given the 800 mg/day dose, while another patient given the drug at 600 mg twice daily experienced grade 4 cough and grade 4 dyspnea. No dose-limiting toxicities occurred in any of the patients who received capmatinib tablets at the 400 mg twice-daily dose, and this was set as the phase II recommended dose.
Of the 100 patients enrolled in the phase II part, 29% achieved an overall response following treatment with capmatinib 400 mg twice daily plus gefitinib 250 mg/day, while in the total phase Ib and II population, the overall response rate (ORR) was 27%. The corresponding disease control rates were 73% and 67%.
Interestingly, the ORR was highest for patients with high levels of MET amplification as indicated by six or more MET gene copies, at 47%, compared with a rate of 22% for those who had four or five copies and 12% for those with less than four copies of the gene.
By contrast, MET overexpression as assessed by immunohistochemistry (IHC) appeared to be a less accurate identifier of patients likely to respond to the combination, say lead author Yi-Long Wu (Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China) and team. For instance, the ORR was 25% for participants who had tumors with an IHC score of 0 and 32% for those that had a score of at least 3. The team points out, however, that the groups with lower IHC scores had small sample sizes.
With regard to the safety profile, treatment-related adverse events of grade 3 or 4 occurred in 29% of the total 161 patients, most frequently elevations in amylase (6%) and lipase (6%) levels. Adverse events led to dose reductions or interruptions in 44% of participants and discontinuation in 17%, while one death due to dyspnea was attributed to the study treatment.
On the whole, “[i]n contrast to a number of other combination studies, capmatinib in combination with gefitinib is tolerable,” say Wu et al.
And they conclude in the Journal of Clinical Oncology that capmatinib–gefitinib “may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and particularly for patients with MET-amplified tumors.”
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