MET amplification a predictor of response to crizotinib
12 Oct 2021
byNatalia Reoutova
A subanalysis of the ongoing phase II PROFILE 1001 study
suggests that MET amplification may serve as one of the predictive biomarkers
for response to crizotinib among patients with non-small-cell lung cancer
(NSCLC).
“MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC,” wrote PROFILE 1001 investigators. [Front Oncol 2020;10:54] “Crizotinib is an approved tyrosine kinase inhibitor [TKI] for the treatment of ALK- or ROS1-positive advanced NSCLC that is also active against MET. Although there have been case reports of patients with NSCLC with high levels of MET amplification responding to crizotinib, the exact testing methodology for using MET amplification as a predictive biomarker has remained uncertain.” [Drug Des Devel Ther 2011;5:471-485; Lung Cancer 2016;98:59-61; J Thorac Oncol 2017;12:141-144]
To examine the influence of MET amplification on the clinical activity of crizotinib, a total of 38 patients with MET amplification were divided into low (≥1.8 to ≤2.2 mean ratio of the MET gene to the centromere on chromosome 7, on which the MET gene sits [MET-to-CEP7 ratio]), medium (>2.2 to <4 MET-to-CEP7 ratio) or high (≥4 MET-to-CEP7 ratio) amplification categories, as tested by local fluorescence in situ hybridization (FISH), and given crizotinib 250 mg twice daily. [J Thorac Oncol 2021;16:1017-1029]
The median age across the amplification groups was 66.5 years, with 84.2 percent of patients being former smokers, making MET an unusual driver oncogene, which could be of particular value in older patients with a history of smoking and no other detected actionable mutations. While the overall response rate (ORR) was 28.9 percent in the 38 patients, it differed considerably between the MET-amplification groups. “The ORR in the high, medium, and low amplification groups was 38.1 percent [8 of 21 patients], 14.3 percent [2 of 14 patients], and 33.3 percent [1 of 3 patients], respectively. There were two complete responses observed, both of which occurred in the high group,” reported the researchers.
Median progression-free survival was higher in the high MET-amplification group than in the medium and low groups (6.7 months, 1.9 months, and 1.8 months, respectively). The probability of being progression-free at 6 months in the high, medium, and low MET-amplification groups was 55.8 percent, 18.5 percent, and 33.3 percent, respectively, while the probability of survival at 12 months was 46.8 percent, 28.6 percent, and 33.3 percent, respectively.
Durable responses of ≥1 year were observed across all three amplification groups, with three patients in the high MET-amplification group having a duration of response (DoR) of >3 years. In the high group, median DoR was 5.2 months, while it was 3.8 months and 12.2 months in the medium and low groups, respectively. The researchers noted the relatively small sample size as one of the study’s limitations, yet added that crizotinib’s results for the high MET-amplification group were consistent with those reported for the selective MET TKI capmatinib among patients with MET-amplified NSCLC using differing methods of MET amplification detection. [Ann Oncol 2020;31:789-797; N Engl J Med 2020;383:944-957]
“The current analysis also enabled comparisons of MET amplification detection methods and their clinical correlates,” wrote the researchers. “Tissue from two patients who did not have MET amplification detected by next-generation sequencing both had low MET amplification [MET-to-CEP7 ratio, 1.98 and 2.07] detected by FISH.” This suggests FISH as the more sensitive MET amplification detection method.
“MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC,” wrote PROFILE 1001 investigators. [Front Oncol 2020;10:54] “Crizotinib is an approved tyrosine kinase inhibitor [TKI] for the treatment of ALK- or ROS1-positive advanced NSCLC that is also active against MET. Although there have been case reports of patients with NSCLC with high levels of MET amplification responding to crizotinib, the exact testing methodology for using MET amplification as a predictive biomarker has remained uncertain.” [Drug Des Devel Ther 2011;5:471-485; Lung Cancer 2016;98:59-61; J Thorac Oncol 2017;12:141-144]
To examine the influence of MET amplification on the clinical activity of crizotinib, a total of 38 patients with MET amplification were divided into low (≥1.8 to ≤2.2 mean ratio of the MET gene to the centromere on chromosome 7, on which the MET gene sits [MET-to-CEP7 ratio]), medium (>2.2 to <4 MET-to-CEP7 ratio) or high (≥4 MET-to-CEP7 ratio) amplification categories, as tested by local fluorescence in situ hybridization (FISH), and given crizotinib 250 mg twice daily. [J Thorac Oncol 2021;16:1017-1029]
The median age across the amplification groups was 66.5 years, with 84.2 percent of patients being former smokers, making MET an unusual driver oncogene, which could be of particular value in older patients with a history of smoking and no other detected actionable mutations. While the overall response rate (ORR) was 28.9 percent in the 38 patients, it differed considerably between the MET-amplification groups. “The ORR in the high, medium, and low amplification groups was 38.1 percent [8 of 21 patients], 14.3 percent [2 of 14 patients], and 33.3 percent [1 of 3 patients], respectively. There were two complete responses observed, both of which occurred in the high group,” reported the researchers.
Median progression-free survival was higher in the high MET-amplification group than in the medium and low groups (6.7 months, 1.9 months, and 1.8 months, respectively). The probability of being progression-free at 6 months in the high, medium, and low MET-amplification groups was 55.8 percent, 18.5 percent, and 33.3 percent, respectively, while the probability of survival at 12 months was 46.8 percent, 28.6 percent, and 33.3 percent, respectively.
Durable responses of ≥1 year were observed across all three amplification groups, with three patients in the high MET-amplification group having a duration of response (DoR) of >3 years. In the high group, median DoR was 5.2 months, while it was 3.8 months and 12.2 months in the medium and low groups, respectively. The researchers noted the relatively small sample size as one of the study’s limitations, yet added that crizotinib’s results for the high MET-amplification group were consistent with those reported for the selective MET TKI capmatinib among patients with MET-amplified NSCLC using differing methods of MET amplification detection. [Ann Oncol 2020;31:789-797; N Engl J Med 2020;383:944-957]
“The current analysis also enabled comparisons of MET amplification detection methods and their clinical correlates,” wrote the researchers. “Tissue from two patients who did not have MET amplification detected by next-generation sequencing both had low MET amplification [MET-to-CEP7 ratio, 1.98 and 2.07] detected by FISH.” This suggests FISH as the more sensitive MET amplification detection method.