Improving Outcomes for Patients With NSCLC and RET Alterations


Nathan A. Pennell, MD, PhD, discusses the importance of developing new RET inhibitors for patients with non–small cell lung cancer.

Nathan A. Pennell, MD, PhD, medical oncologist at the Taussig Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine, discusses the importance of developing new RET inhibitors for patients with non–small cell lung cancer (NSCLC).

According to Pennell, RET alterations have been recognized as a biomarker in lung cancer, but older targeted therapies were less selective and had poor efficacy. The introduction of the selective RET inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto) made RET a more significant biomarker in NSCLC, as well as in medullary thyroid cancer (MTC). While these therapies can sometimes offer years of clinical benefit, many patients develop resistance to RET inhibition.

Pennell says the major unmet need is a treatment option for patients who are resistant to selpercatinib and pralsetinib. There are no next-line options for these patients besides standard chemotherapy regimens for advanced NSCLC, which have limited efficacy in later lines of therapy.

He is currently investigating the novel RET inhibitor LOXO-260 in the ongoing phase 1 trial (NCT05241834) for patients with NSCLC and MTC.


0:08 | They have been recognized as a subtype of lung cancer and MTC for many years. However, the older drugs—the first-generation drugs—just did not work very well. They had a lot of toxicities, and they weren't specific for RET. Specifically, they covered a lot of other types of tyrosine kinases in addition.

In the last few years, with the approval of selpercatinib and pralsetinib, the other selective RET inhibitor—it’s really revolutionized treatment of these patients. Now, with very minimal adverse events, it is able to get durable responses that can sometimes last years. I've seen patients’ lives transformed by being able to access these drugs. The downside, of course, is that it is still not a cure, and unfortunately, these patients go on to develop resistance at some point, so they definitely need more options.

1:14 | The major unmet need is for another option when patients develop resistance to the initial drugs like selpercatinib and pralsetinib. Right now, if [patients] are treated with those drugs and then develop resistance, we are left with very old options like chemotherapy, which don't last very long. We really are understanding more about how [patients] develop resistance and how tumors develop resistance to the first-generation drugs or the selective RET inhibitors, so we need to continue to find better options for those patients.

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