Crizotinib active against NSCLC with MET exon 14 alterations
medwireNews: The multikinase inhibitor crizotinib elicits responses and is well tolerated in people with non-small-cell lung cancer (NSCLC) positive for MET exon 14 mutations, shows the PROFILE 1001 trial.
These data establish “a clinical paradigm for the treatment of MET-exon-14-altered lung cancers with MET-directed targeted therapy, paving the way for additional research to move forward in this space with the goal of regulatory approval of one or more MET inhibitors for this genomic indication,” say the investigators.
As reported in Nature Medicine, an objective response was achieved by 32% of the 65 evaluable participants who received crizotinib 250 mg twice a day, with three complete and 18 partial responses. The median duration of response was 9.1 months, and 20 participants remained on-treatment at data cutoff.
There was no difference in objective response rates (ORRs) by the type of MET alteration, either by the splice-site region (32% for splice donor site, 31% for splice acceptor site) or by mutation type (36% for base substitution, 25% for indel).
Median progression-free survival (PFS) was 7.3 months and 54% of participants were progression-free at 6 months. Median overall survival was estimated at 20.5 months, with 6 and 12 month rates of 87% and 70%, respectively, but the data were not mature at the time of analysis.
Lead author Alexander Drilon (Memorial Sloan Kettering Cancer Center, New York, USA) and collaborators report that the safety profile “was similar to that reported previously for patients with ALK- and ROS1-rearranged NSCLCs,” which are the indications that crizotinib is currently approved for.
Elevated transaminase levels and dyspnea were the most frequent treatment-related adverse events of grade 3, each observed in 4% of participants. There was one case each of grade 4 hypophosphatemia, lymphopenia, and pulmonary embolism, and one fatal case of treatment-related interstitial lung disease.
Discussing the results, Drilon and colleagues note that “[t]hese outcomes clearly exceed those observed with second-line chemotherapy (ORR, 7–23%; median PFS, 2.4–4.5 months) and are comparable with that of first-line platinum doublet-chemotherapy (ORR, 31–35%; median time to progression, 4.8–6.2 months).”
However, “the ORR of crizotinib in MET-exon-14-altered NSCLCs was lower compared with the ORRs of ~60–80% achieved with targeted therapy for other NSCLC drivers,” they add, noting that this did not appear to be due to the molecular heterogeneity of MET exon 14-altered tumors.
The team continues: “Ultimately, beyond these analyses, the type of MET inhibitor used to treat MET-exon-14-altered cancers may affect clinical outcomes.”
Although crizotinib was the first MET tyrosine kinase inhibitor to be evaluated in this patient group, promising data have since been reported for the more selective agents capmatinib, tepotinib, and savolitinib, say the researchers.
They believe that longer-term efficacy data and “a careful analysis of relative toxicity” are needed to determine “whether these agents are markedly different” to crizotinib.
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