Alexander Drilon, MD
Discussant of the TATTON study presentation, Alexander Drilon, MD, Chief of Early Drug Development at Memorial Sloan Kettering Cancer Center, New York, finds the idea of combination therapy with a MET inhibitor and an EGFR tyrosine kinase inhibitor attractive for the treatment of EGFR mutation–positive NSCLC. “We would welcome this in the future,” he commented.
That said, he raised several concerns regarding the interpretation of these data. “The presence or acquisition of MET dependence is a liability for patients with NSCLC treated with first-, second-, or third-generation EGFR tyrosine kinase inhibitor; however, this may be subclonal and may not be present in every tumor cell,” he explained.
“MET dependence can be challenging to interrogate. Trials have shown that the MET-positive population is heterogeneous. MET expression and copy number changes are continuous variables with no standardized cutoffs,” Dr. Drilon continued. “Loose definitions of MET dependency make these trial data difficult to interpret, particularly since the degree of MET dependence likely influences outcome," he said.
“Using gene copy number via fluorescence in situ hybridization alone presents problems because this method may not identify patients with true amplification and may not represent true MET dependence. Further, MET dependence may vary. Focal amplification of MET on next-generation sequencing may identify a greater degree of MET dependency, and the degree of MET amplification matters. Tumors with higher levels of MET amplification had higher response rates,” Dr. Drilon explained.
Standardized Testing Needed
To move the field of MET-directed targeted therapy forward, diagnostics with standardized cutoffs are needed and patients with higher levels of MET dependency, or MET amplification, need to be recruited for clinical trials, he continued.
“The assays used to detect MET in TATTON were heterogeneous, whereas the ORCHARD trial is doing better in trying to standardize testing,” Dr. Drilon said.
Regarding the combination of osimertinib and savolitinib, it appears the best activity is seen in patients resistant to first- and second-generation EGFR tyrosine kinase inhibitors who have EGFR T790M–positive disease. The activity is somewhat attenuated in part B2—the same population but EGFR T790M–negative. Patients in the group refractory to osimertinib had less activity, and this group was heterogeneous with regard to MET dependence.
“Taken together, all three cohorts represent reasonable groups to move forward with combination therapy. In all three cohorts, EGFR clearance was associated with longer progression-free survival. The population was sensitive to the combination of osimertinib and savolitinib, despite intratumor heterogeneity. As other patients did not clear EGFR, it is clear that not all MET-positive patients are MET-dependent. Other resistant clones may be present,” he said.
“Serial ctDNA changes can provide information on the likelihood of durable benefit with combination therapy; intratumoral/intertumoral heterogeneity that may affect durability; and primary and acquired mediators of resistance,” Dr. Drilon stated.
DISCLOSURE: Dr. Drilon has received honoraria from Foundation Medicine, Medscape, MORE Health, OncLive, PeerView, PeerVoice, Physicians Education Resources, Research to Practice, and Targeted Oncology; has served in a consulting or advisory role for 14ner/Elevation Oncology, AbbVie, Archer Biosciences, AstraZeneca, Bayer, BeiGene, BerGenBio, Blueprint Medicines, Exelixis, Genentech/Roche, Helsinn Therapeutics, Hengrui Therapeutics, Ignyta, Lilly, Loxo, Monopteros, MORE Health, Pfizer, Remedica, Takeda/Ariad/Millennium, TP Therapeutics, Tyra Biosciences, and Verastem; has received research funding from Foundation Medicine; holds intellectual property in Wolters Kluwer; and has had other relationships with GlaxoSmithKline, Merck, Pfizer, PharmaMar, Puma Biotechnology, Taiho Pharmaceutical, and Teva.
