Metastatic NSCLC: Recent Developments on ALK, ROS1, and NTRK - Episode 4

Current Management of ROS1 rearranged NSCLC


Balazs Halmos, MD: The subset of ROS1-mutated translocated lung cancers is very important. It’s a small percentage of our patients, maybe 0.5% to 1%. This particular subset derives tremendous benefit from targeted therapy. We have different generations of agents to offer, so identifying these patients is absolutely critical. To integrate ROS1 testing into your platform is an absolute must and cannot be forgotten.

What is the proper test? Well, there are different tests we can perform. The most commonly used platforms are either FISH (fluorescence in situ hybridization), looking for very specific translocations, or next-generation sequencing (NGS) technology. The latter allows us to do more…testing, allowing complete molecular testing. IHC (immunohistochemistry) testing is also under development. It’s not as good for ROS1 as for ALK. For ALK, IHC is very reliable. For ROS1, we’re not so confident yet. Usually, it’s FISH or NGS testing that we want to integrate into the molecular testing paradigms, with NGS providing a one-stop shop for molecular testing with 1 single test integrating all the molecular needs.

You can have translocations that do not yield a functional protein, but that’s unusual. When you see a ROS1 translocation, you have to think this might be an actionable alteration, and the largest majority of those are. Testing companies will do their best to make sure that the information is relayed in an appropriate fashion in regard to the reliability of detection. Was the translocation detected in both directions? Most of the time, when we see a ROS1 fusion detected, that’s an actionable abnormality. It’s most commonly seen in lung cancers but can be seen rarely in other cancers and cholangiocarcinomas, as well as certain CNS (central nervous system) malignancies.

Just like with eGFR and ALK, there are certain subsets of patients where these abnormalities are enriched, usually younger patients, nonsmokers. With eGFR mutations, there’s a gender predilection for females. That’s not the case for ROS1 or ALK. The gender balance seems to be about 50/50. At the same time, it tends to be younger patients with adenocarcinoma histology. That being said, there’s always a certain percentage of patients who are smokers, who are elderly, sometimes with nonadenocarcinoma histology. The best is not to use the phenotype to drive testing, but to make sure that all of our patients with advanced non–small cell lung cancer get appropriate testing at the end of the day.

Jonathan W. Riess, MD: In terms of the standard of care for ROS1 non–small cell lung cancer, my first-line treatment is an ROS1 TKI (tyrosine kinase inhibitor). That could either be crizotinib, which has a median progression-free survival of over 19 months and a response rate of about 70% in the pivotal trial, or entrectinib, which was recently approved for ROS1 non–small cell lung cancer and has additional CNS activity. That's a consideration, particularly in patients with ROS1 rearranged non–small cell lung cancer who have CNS disease. Its duration of response was in excess of 20 months in the pooled clinical trials with entrectinib, looking specifically at ROS1 rearranged non–small cell lung cancer. Those are the preferred agents. Ceritinib has also been looked at and has some activity, but it’s unclear if it's any better than crizotinib or entrectinib. I don't think it's been studied as extensively in ROS1.

Lorlatinib in subsequent lines of therapy appear to have some activity, and there are clinical trials with additional agents, such as repotrectinib, that are particularly of interest. I would also like to mention that beyond ROS1 TKIs, pemetrexed-based therapy, like in ALK non–small cell lung cancer and ROS1 non–small-cell lung cancer, does appear preferentially sensitive to pemetrexed-based therapy in terms of chemotherapy combinations in the future. My initial approach is a ROS1 TKI first, based upon the extraordinary PFS (progression-free survival) benefit observed with crizotinib and entrectinib.

Lyudmila A. Bazhenova, MD: As I mentioned, it is best to hold your treatment until you know that your patient has ROS1 rearranged non–small cell lung cancer. There are several agents available. The data behind efficacy of immunotherapy in that population are quite limited. The only thing we have is a retrospective registry, which is called IMMUNOTARGET. In that registry, patients with ROS1 rearranged lung cancer were given immunotherapy, and the response rate was only 16%.

Eighty-three percent of the patients with ROS1 rearranged lung cancer progressed on immunotherapy. We also know that PD-L1 expression in patients with oncogenic-driven tumors can be falsely elevated and does not necessarily predict efficacy of immunotherapy in that population. That's why I would wait for the molecular testing results. I would like to treat patients with ROS1 rearranged lung cancer with oncogenic-driven therapies and use target therapy instead of immunotherapy.

Transcript Edited for Clarity