Ardaman Shergill, MD
Tumor mutational burden (TMB), NTRK
, and RET
are all molecular markers at the forefront of current research in non–small cell lung cancer (NSCLC), and investigators are in the early phases of learning how they can be used to clinically to benefit patients, said Ardaman Shergill, MD.
“Biomarkers are extremely important for identifying patients,” Shergill explained. “They help us determine or personalize therapy for patients and predict a response to what we are giving them. That is really important, especially in lung cancer, where mortality is so high.”
For example, with TMB, data from the phase III CheckMate-227 trial showed that the 1-year progression-free survival (PFS) rate was 43% for patients with high TMB (≥10 mut/Mb) assigned to receive the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) versus 13% for those assigned to platinum-doublet chemotherapy. The FDA is currently reviewing a supplemental biologics license application for the combination based on these data, with an action date of May 20, 2019.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Shergill, an assistant professor of Medicine at the University of Illinois, highlighted the impact of TMB, as well as RET
fusions, in the NSCLC paradigm.
OncLive: Could you highlight the research exploring TMB as a biomarker for NSCLC?
For TMB, I discussed 2 trials—although there are a lot more data available. One of the 2 trials that I talked about was CheckMate-227, which was a very complex trial designed to test nivolumab plus ipilimumab or nivolumab compared with chemotherapy based on PD-L1 expression. One of the co-primary endpoints of the trial was to look at TMB.
Once they enrolled patients and treated them, investigators looked at TMB. They defined TMB cutoff as 10 mut/Mb in that trial, and based on that, they looked at the responses of the patients as well as PFS. We don’t have any overall survival (OS) data reported at this point, but that showed that high TMB correlated with improved PFS as well as responses to immunotherapy versus chemotherapy.
They further looked at patients who had low PD-L1 expression and high TMB, and those patients also responded to immunotherapy. Therefore, in essence, this helped to select a group of patients who could respond to immunotherapy even when their PD-L1 status—which is a currently used biomarker—is not high.
What trials are looking at RET fusions as an emerging biomarker for NSCLC?
there were 2 drugs that I talked about in my presentation that were tested in rapid phase I studies. For these studies, there were only 1 or 2 patients enrolled, and the doses were rapidly escalated to treat those patients. Investigators showed significant intracranial and extracranial responses for a patient who progressed on multiple lines of therapy, and that was quite significant in that field. This was a patient who progressed through chemotherapy, immunotherapy, and targeted therapy, and then responded to the RET inhibitor, LOXO-292[KR1]
, at that time.
What is the prevalence of RET abnormalities?
It depends on the institution or where the person is being treated and how they perform molecular testing for patients. At most places, testing for mutations such as EGFR
are becoming standard. Therefore, we test these mutations, but not everybody is getting comprehensive panel testing for the mutations the tumors might have.