RET Inhibition Holds Tumor-Agnostic Potential

The development of novel therapies aimed at tumors with RET alterations in non-small cell lung cancer (NSCLC) and thyroid cancers sets the stage for a future tumor-agnostic role for this molecularly targeted approach, according to Razelle Kurzrock, MD.

In 2020, the FDA approved the first 2 selective RET inhibitors, selpercatinib (Retevmo) and pralsetinib (Gavreto), for patients with NSCLC and radioactive iodinerefractory thyroid cancer harboring RET fusions and for RET-mutant medullary thyroid cancer (MTC).

In an interview with OncologyLive^®, Kurzrock, an expert in molecularly targeted therapies, discussed the implications of these agents. She is the Murray Professor of Medicine, an associate director of clinical science, and director of the Center for Personalized Cancer Therapy at Moores Cancer Center at University of California, San Diego.

Please put the recent RET-specific drug approvals into context.

I think the impact is really important, both for lung cancer and for thyroid cancer, because it continues to drive the idea of how important genomic abnormalities are in cancer and that if we can target them, we can get much better responses than just giving drugs blindly. When we look at these responses, they’re really quite incredible. For both drugs, the responses are in the range of 70% [in treatment-naïve NSCLC and MTC], and many of the response are durable. We don’t even know the median duration of response, and many of the responses are ongoing at half a year and longer. These are very high response rates for drugs that are well tolerated.

When it comes to lung cancer, one argument is that RET fusions are found in only 1% or 2% of tumors, so why is this a big deal? But that’s exactly what people have to come to understand. We once had a dream that we were going to have a drug that would treat all lung cancers; we went through decades of looking for that miracle drug, and we couldn’t find it. The reason we didn’t f ind it is not because we didn’t look hard enough or didn’t have enough good drugs but because biologically it’s unlikely that any such drug exists. Even though we call lung cancer 1 disease, it’s made up of many subsets of disease, and the only way we can treat cancer is by identifying those subsets and treating them properly.

Even though this is a drug for only the 1% or 2%, we’re beginning to get a lot of those, and when you add them together, they make up a substantial fraction of the lung cancer population. We have 2% for RET, 4% for ALK, 10% for EGFR, 0.5% for NTRK—I could go on. We’re going to get to the point where we can identify what’s wrong with each patient’s lung cancer and give them the proper drug. We’re not there yet, but for probably 30% of lung cancers, we can identify something that is driving the cancer, and we have an FDA-approved drug for those patients. So these approvals are tremendously important.

Do you foresee a potential “tumor- agnostic” role for RET inhibitors?

This is a really important question, and the answer is absolutely yes. There’s every reason to believe that RET alterations, when they occur, drive a wide variety of cancers. We know that they occur not just in lung and thyroid cancers but also in other cancers. We already have templates to follow with NTRK fusions, which occur in just 0.3% of patients [all cancer types], but that didn’t stop us from developing 2 great drugs to treat those fusions. Even though RET alterations are rare, for patients who have them, the response to therapy could be incredible and durable.

What are the hurdles relating to RET targeting in cancer?

I think the most pressing challenge is that it is a rare alteration and many doctors do not yet do genomic testing. RET as an individual mutation is rare, and that discourages from testing, but we have to look at the whole of what genomic sequencing can tell us now that we’re able to affect a substantial group of patients.

Reference

1. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. Stateof-the-art strategies for targeting RET-dependent cancers. J Clin Oncol. 2020;38(11):1209-1221. doi:10.1200/JCO.19.02551