Emergence of Resistant Clones in Medullary Thyroid Cancer May Not Be Rescued by Subsequent Salvage Highly Selective Rearranged During Transfection-Inhibitor Therapy

Dear Editor:

Selective rearranged during transfection (RET) inhibitors such as LOXO-292 (selpercatinib) and BLU-667 (pralsetinib) are novel highly selective RET inhibitors currently being investigated for therapy of RET-altered solid tumors. They have demonstrated efficacy with durable responses, including tumors in the central nervous system. Selpercatinib is now approved by the Food and Drug Administration (FDA), and is a therapeutic option for RET-altered cancers, including medullary thyroid cancer (MTC) (1). Currently FDA-approved multikinase inhibitors (MKI) such as cabozantinib or vandetanib for therapy of recurrent/metastatic MTC are also frontline options not restricted by RET alteration, and can be used in succession. However, it is not known whether a selective RET inhibitor could be used as salvage therapy once a patient with MTC demonstrates disease progression on another selective RET inhibitor.

In this study, we present a case of a patient with metastatic MTC with somatic testing demonstrating RET M918T mutation by commercial assay. The variant allele frequency (VAF) was 38%. The patient was previously treated with vandetanib (2 months, discontinued for progressive disease), cabozantinib (8 months, discontinued for progressive disease and intolerance) and later treated with selpercatinib on a clinical study. Selpercatinib therapy resulted in partial response and was continued for 12 months, well tolerated, and ultimately discontinued for progressive disease.

He was counseled on further therapy, including cytotoxic chemotherapy versus salvage therapy with another selective RET inhibitor. He agreed to the latter and signed an informed consent form and successfully underwent screening and enrollment on a phase 1/1b study of pralsetinib. Initially, a clinical response was noted with improvement in both the patient's symptoms and liver metastases on physical examination. However, six weeks after initiating therapy he showed sudden and rapid deterioration in his symptoms with worsening liver metastases on imaging consistent with progressive disease (Fig. 1A). The tumors markers showed mixed changes (Fig. 1B). Next-generation sequencing from a tumor biopsy obtained at enrollment (post-selpercatinib and pre-pralsetinib) demonstrated RET M918T (VAF 28%), RET V804M (22%), RET G810S (11.9%), and CDKN2A loss of heterozygosity in addition to this original RET mutation (RET M918T; VAF 38%). Both RET V804M and RET G810S have been shown to be resistant clones that emerge during selpercatinib or other MKI therapy (2 –4). Both selpercatinib and pralsetinib have inhibitory activity against RET V804M; therefore, the observed clinical resistance could be mediated by the newly emergent RET G810S mutation (2).

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FIG. 1.

(A) Cross-sectional imaging showing progression on selpercatinib. The white arrows delineate the extent of the target lesion. (B) Both calcitonin and CEA were measured on a weekly basis during pralsetinib therapy. Calcitonin continued to show steady increase, whereas CEA demonstrated a variable course, including modest reduction in weeks 2–4. CEA, carcinoembryonic antigen.

In this study, we demonstrate emergence of resistant clones in MTC during highly selective RET inhibitor therapy. Most importantly, the clinical course of this particular patient suggests subsequent highly selective RET inhibitor therapy may not be efficacious in all MTC patient previously treated with another highly selective RET inhibitor. Based on the preclinical studies and clinical experience published so far, RET G810S appears to be a gatekeeper mutation and thus unlikely to respond to further highly selective RET inhibitor therapy. Additional clinical experience from ongoing trials hopefully will inform us more definitively. While we await these data, clinicians should be observing patients closely for progressive disease with symptom assessment and cross-sectional imaging. Repeat somatic testing for assessment of gatekeeper mutation may be considered.