Metastatic NSCLC: Recent Developments on ALK, ROS1, and NTRK - Episode 6

Future Directions for ROS1 rearranged mNSCLC


Balazs Halmos, MD: It’s important to remember that we built a paradigm in molecular oncology to look for mechanisms of acquired resistance, to learn from that and try to guide the next line of treatment based on that understanding. I can’t say that that’s fully established for ROS1, but I don’t see any reason why we wouldn’t want to continue to learn. It’s good to retest the patient for the development of secondary mutations. We’ve learned there are some very specific ROS1 mutations that can potentially match patients for potentially active second-line therapy, such as lorlatinib, which is a highly potent next-generation drug for the management of both ALK and ROS1 translocation-positive patients. I tend to use the same paradigm that we use for EGFR- and ALK-positive patients in terms of ctDNA [circulating tumor DNA] with tissue-based retesting and learn from that experience. Fortunately, we have second-line agents to possibly be used. There are others under development, such as repotrectinib, which is a very potent and highly promising agent as well.

Jonathan W. Riess, MD: In terms of mechanisms of resistance to ROS1 inhibition, there have been a lot of exciting developments. As we do for many oncogene-driven lung cancers, I really look at mechanisms of resistance in 2 categories. One is the on-target resistance mechanisms, for example, within ROS1 that eventually cause changes that prevent the drug from binding. Then there are bypass tracks and off-target resistance mechanisms that signal around ROS1, bypassing track signals that allow the tumor to grow despite the inhibition of the target with the drug.

There are a number of secondary on-target resistance mutations and bypass tracks. In terms of on-target mutations, there are mutations such as G2032R, in which response to lorlatinib occurred about over 20% of the time. There are solvent front mutations as well. Some of these mutations looking at structural modeling that causes interference with binding of these ALK and ROS1 TKIs [tyrosine kinase inhibitors]; some of these mutations—lorlatinib, crizotinib, and entrectinib—may be more sensitive to certain ROS1 inhibitors than others.

Like ALK lung cancer, there is some type of a heat map you could use, where you can look at what you would expect the relative inhibitory concentrations to be and then potentially pick a ROS1 inhibitor that may have efficacy. A tougher one to target is G2032R. With that, there is a drug called repotrectinib that’s now being looked at. You could look to potentially match those up in clinical trials. There are also bypass tracks, for example, as a resistance mechanism to lorlatinib; MET amplification has been noted as well.

This has been noted as an EGFR- and ALK-resistance mechanism, and that’s a major bypass track that signals around the drug. I divide it into these on-target mutations, which may differ a bit among crizotinib and then lorlatinib and entrectinib, and off-target mutations. Plus, molecular aberrations such as MET amplification, where going back to crizotinib—crizotinib is also a MET inhibitor—may have some additional activities. We’ve certainly seen that in ALK-rearranged non–small cell lung cancer. That could apply to ROS1 as well.

Transcript Edited for Clarity