MET Inhibitors May Prolong Survival in MET Exon 14 Mutated NSCLC

June 27, 2017
Wayne Kuznar

A retrospective analysis suggests that treatment with a MET tyrosine kinase inhibitor can prolong survival in patients with advanced non&ndash;small cell lung cancer with a <em>MET</em>&nbsp;exon 14 mutation.

Mark M. Awad, MD, PhD

A retrospective analysis suggests that treatment with a MET tyrosine kinase inhibitor (TKI) can prolong survival in patients with advanced non—small cell lung cancer (NSCLC) with aMETexon 14 mutation. The analysis found that median overall survival (OS) from the time of stage IV diagnosis was 3 times as long in such patients treated with a MET TKI compared with those not treated with a MET TKI (24.6 vs 8.1 months).

Based on this finding and the poor prognosis of patients with stage IVMETexon 14 mutant NSCLC who are not treated with a MET TKI, “we feel that this justifies strongly that testing forMETexon 14 mutations should be performed upfront in all patients with stage IV NSCLC, in particular among patients whose cancers have already tested negative for genomic alterations in other oncogenic drivers such asKRAS,EGFR,ALK,ROS1,BRAF, and others,” said Mark M. Awad, MD, PhD, at the 2017 ASCO Annual Meeting.

“Prompt initiation with a MET inhibitor should really be considered in all patients withMETexon 14 mutant NSCLC.”

MET exon 14 mutations occur in about 3% of cases of NSCLC. They have proved to be a fairly robust biomarker to predict response to MET TKIs, said Awad, instructor in medicine at Harvard Medical School and physician at the Dana-Farber Cancer Institute in Boston.

Demonstrating a survival benefit with MET TKIs in this population through a randomized prospective trial is challenging, however, because theMETTKI crizotinib (Xalkori) is widely available for the treatment of patients withALK- andROS1-rearranged NSCLC, the built-in patient crossover often incorporated into a prospective trial, and due to post-progression treatment with a MET inhibitor. Therefore, his group conducted a multi-institutional retrospective survival analysis of NSCLC patients withMETexon 14 mutation who did or did not receive treatment with aMETTKI. Twelve academic institutions provided clinical data for the study.

Data from 148 patients withMETexon 14 mutated NSCC were collected. Of these patients, 61 patients either had or developed stage IV disease, 34 of whom did not receive treatment with a MET TKI and 27 who did. In the treated group, 20 received crizotinib off label, 4 received crizotinib as part of a clinical trial, 4 received glesatinib, and 3 received capmatinib (4 patients received >1 TKI).

Of the 148 patients in total, the median patient age was 72 years (range, 43-88) and 61% were smokers. The most common histologies were adenocarcinoma (77%) and pulmonary sarcomatoid (pleomorphic) carcinoma (13.5%). Overlap with oncogenic driver mutations in other genes was rare. At the time of diagnosis, 70% of patients had stage I to III disease and 30% had stage IV disease. Twenty-one percent of 100 patients in whomMETamplification was checked had concurrentMETamplification.

Among the subset of patients treated with crizotinib as their only TKI, median progression-free survival was 7.4 months and median OS was 20.5 months.

OS of the patients with stage IV NSCLC was especially poor at 5.2 months in those with concurrentMETamplification who were never treated with a MET TKI. There was a trend toward worse survival in patients with nonadenocarcinoma histologies compared with adenocarcinoma (2.9 vs 10.3 months;P= .69).

In comparing the treatment histories of patients treated withMETTKIs and those not treated with MET TKIs, Awad noted a few differences between the groups. Patients who received a MET inhibitor more often received multiple lines of systemic therapy; 63% received at least 2 lines of therapy compared with only 15% who never received a MET TKI. Further, 27% of those never receiving a MET TKI received no lines of systemic therapy.

Also, those who received a MET TKI were more likely to also receive treatment with a PD-1 inhibitor than those who never received a MET inhibitor (37% vs 9%). The best overall response to a PD-1 inhibitor was progressive disease in 8 of 10 patients treated with a MET TKI and in 2 of 3 not treated with a MET inhibitor. Therefore, the investigators believed that the difference in receipt of PD-1 inhibitor therapy did not make a significant contribution to the survival difference observed between the 2 groups.

In a survival analysis that adjusted for differences in receipt of a MET inhibitor as first- or second-line therapy, histology, andMETamplification, a significant OS benefit was demonstrated from treatment with a MET inhibitor (HR, 0.11; 95% CI, 0.01-0.92;P= .04).


Awad MM, Leonardi GC, Kravets S, et al. Impact of MET inhibitors on survival among patients (pts) withMETexon 14 mutant (METdel14) non-small cell lung cancer (NSCLC).J Clin Oncol. 2017;35 (suppl; abstract 8511).