Clinical Management of RET+ Advanced NSCLC

Mark Socinski and Stephen Liu describe the current treatment options for patients with RET+ NSCLC. They also summarize recent clinical data for agents that target RET.

Mark A. Socinski, MD: In the past year, we’ve had 2 new drugs indicated for RET fusions in nonsmall–cell lung cancer. Selpercatinib first, followed by pralsetinib shortly thereafter. These are both highly selective RET inhibitors. They do have some activity against the VEGF receptors, so hypertension is an issue with these drugs, but highly selective for RET. They have both been incorporated into the NCCN [National Comprehensive Cancer Network] guidelines for treatment of RET fusion-positive patients in the first-line setting. I will emphasize that RET should be part of your comprehensive genomic testing at the time of initial diagnosis. If you find it, this should be your first-line treatment, but remember that it is also active in the refractory setting, or second- and third-line setting. In your practices, many of you may have patients with lung cancer who you’ve managed for 2, 3, sometimes even 4 years or so. You should go back and look at their initial molecular testing and make sure that RET was tested for. You may have some of these patients that you may not know about because they weren’t included in the testing that was done 2 or 3 years ago when we didn’t have effective RET drugs at the time.

Stephen Liu, MD: When we identify a RET fusion in nonsmall–cell lung cancer, it does impact our decision making. We know from the immuno target study, led by Dr Julian Masieris, that immunotherapy is largely inactive, but we have other RET targeted agents. Our historic agents repurposed multikinase inhibitors, like cabozantinib and vandetanib, had response rates around 30% and 40%. A lot of toxicity from interacting at that VEGF from a lot of off-target toxicity. We now have selective inhibitors and these are the drugs that I would reach for first.

Mark A. Socinski, MD: We recently had an update of the selpercatinib data at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting. [The data] showed a response rate of about 64% in patients who had been previously treated. Most importantly, in the cohort of patients that were treatment-naïve, the overall response rate was approximately 85% with nice durability of these sorts of responses. Often these responses can be deep, durable, and meaningful to patients in this setting. In the setting of CNS [central nervous system] involvement, which is common in these driver populations, there’s not robust data sets yet. However, in the data sets that we do have, there’s clear activity with durability of response in CNS lesions. That should be part of your thinking as you approach these patients who are known to have brain [metastases].

Stephen Liu, MD: Pralsetinib, formerly BLU-667 agent, was studied in the registrational ARROW phase 1, 2 trial. This included patients with medullary thyroid cancer, with RET fusions, solid tumors, and a cohort specifically for RET fusion-positive nonsmall–cell lung cancer. At the ASCO 2021 Annual Meeting, we saw an update on RET-positive nonsmall–cell lung cancer—a large size of over 200 patients. With this rare molecular finding, we saw the response rate around 70% with median duration of response of almost 2 years. If we look at patients who had prior chemotherapy, which was 125 patients, the response rate was 62%—very robust—and the disease control rate was 91%. Responses were fast, the median timer response was at 1.8 months, medium progression-free survival there, almost a year and a half. In the front-line setting, the outcomes were even better. Initially, ARROW was designed to allow front-line use of pralsetinib for people that were not candidates for chemotherapy or chemoimmunotherapy. In that cohort, with that caveat, the response rate was 79% and the disease control rate was 93%. When they started seeing these amazing responses, they amended that study. As of 2019, it was updated to allow anyone in the frontline setting. If we look at that true treatment-naïve population, we saw a response rate of 88%—the highest response rate I’ve seen—and a disease control rate of 96%, median progression of survival not yet reached. These are very effective drugs that are durable, have quick responses, and are well tolerated. There is some myelosuppression with pralsetinib. These are primarily paper toxicities. We see neutropenia, for example, but less than 1% of patients stop treatment for neutropenia—just a dose reduction. It comes as 100-mg pills and you start at 40 mg, low counts, drop to 3 pills, 2 pills, and so forth. In my experience, I’ve seen very durable responses, even at lower doses when needed to dose for dropping. When we look at pralsetinib, what is important about it in this subtype of lung cancer is it’s very CNS penetrant and very CNS active. And I do have a patient who has a CNS response that’s been ongoing for years, even with a dose reduction.

Mark A. Socinski, MD: Shortly after the approval of selpercatinib, we saw pralsetinib come to market with similar data. This is an agent with similar response rates and similar tolerability populations. The activity is seen both in treatment-naïve patients with overall response rates far north of 50%, as well as in patients who have been previously treated. The use of this agent in the second- and third-line setting is appropriate for those patients. In those patients that have been hanging around your practice with metastatic lung cancer for a while, you should review their molecular testing from a couple of years ago to make sure that it included RET, because we now have a couple of good options. I would say either pralsetinib or selpercatinib are excellent options for patients with RET fusions.

Transcript edited for clarity.

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