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Expert Answers to Frequently Asked Questions About Selective RET Inhibition in RET-Driven Cancers

Joshua Bauml, MD

Assistant Professor of Medicine
Division of Hematology/Oncology
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, Pennsylvania

Joshua Bauml, MD, has disclosed that he has received consulting fees from AstraZeneca, Ayala, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis, Genentech, Guardant Health, Inivata, Janssen, Merck, Novartis, Regeneron, and Takeda and funds for research support from AstraZeneca, Bayer, Carevive Systems, Carisma Therapeutics, Clovis, Janssen, Merck, Novartis, and Takeda.

View ClinicalThoughts from this Author

Released: May 11, 2021

In this commentary, I answer the most common questions on the use of selective RET inhibitors in the management of patients with RET-altered cancers posed by the audience during a series of live CCO webinars presented in early 2021.

How do you choose between the 2 selective RET inhibitors selpercatinib and pralsetinib for treating your patients with advanced RET-driven cancer? Are there any notable differences between these 2 drugs?
In looking at the clinical trial data, there’s not a lot of difference between selpercatinib and pralsetinib in terms of their efficacy or toxicity profiles. In the phase I/II LIBRETTO-001 study, selpercatinib achieved overall response rates of 64% to 85% in RET fusion–positive non-small-cell lung cancer (NSCLC), 79% in RET fusion–positive differentiated thyroid cancer (DTC), and 69% to 73% in RET mutation–positive medullary thyroid cancer (MTC). In the phase I/II ARROW study, pralsetinib achieved overall response rates of 61% to 73% in RET fusion–positive NSCLC, 91% in RET fusion–positive DTC, and 60% to 74% RET mutation–positive MTC. In these trials, both selpercatinib and pralsetinib demonstrated low rates of grade ≥3 treatment-related adverse events.

The critical element here is that selpercatinib and pralsetinib are both very active and well-tolerated drugs, and I would feel comfortable giving either of them to any patient with a RET-positive cancer. In particular for RET fusion–positive NSCLC, these are the most active drugs available and should be used in the first-line setting. There are some logistical differences that could be taken into consideration when deciding between these drugs for a particular patient: Pralsetinib is to be taken once daily on an empty stomach, and selpercatinib is to be taken twice daily with or without food. However, that I’m even talking about logistical differences as a decision point is reflective of how similar these drugs are in terms of their efficacy.

How do you approach treatment of patients who progress through selective RET inhibitor therapy?
The standard of care outside of the confines of a clinical trial for patients with advanced RET fusion–positive NSCLC who progress through first-line selective RET inhibitor therapy is to stop the RET inhibitor and give platinum-doublet chemotherapy. That said, I typically continue the RET inhibitor and graft on chemotherapy, as I think patients benefit from continuation of the tyrosine kinase inhibitor, even though this is off-label use. I withhold the use of immunotherapy for these patients until later lines because data indicate that these patients, many of whom are never or light smokers, do not respond well to immunotherapy.

However, if available, my first choice for patients with RET fusion–positive NSCLC who progress through first-line selective RET inhibitor therapy would always be a clinical trial. The challenge with treating biomarker-positive cancers with selective tyrosine kinase inhibitors is always going to be resistance—how can we prevent it and how can we manage it when it occurs? Although the primary mechanisms of resistance to RET‑directed therapy are yet unknown, there is some early data identifying solvent-front mutations that would prevent binding of pralsetinib or selpercatinib to the RET receptor, and investigational inhibitors are under development against these mutations. For example, TPX-0046, a next-generation RET/SRC inhibitor that is active against a broad range of RET mutations, including solvent-front mutations, is currently being investigated in a phase I/II trial in patients with a solid tumor and a RET fusion or mutation, including advanced/metastatic RET fusion–positive NSCLC and RET mutation–positive MTC (NCT04161391).

For a discussion of how to approach treatment of DTC or MTC following progression on selective RET inhibitor therapy, please click here.

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