Response to Szymczak et al. re: “A Case Report of Poor Response to Selpercatinib in the Presence of a 632_633 RET Deletion”

Dear Editor:

We appreciate the opportunity to respond to the letter to the editor from Szymczak et al., ¹ whose new data on the clinical efficacy of selpercatinib in metastatic medullary thyroid cancer (MTC) associated with RET p.632_633del we read with great interest. In Thyroid, we recently described a case report on a patient with metastatic MTC associated with RET p.632_633del, who initially responded to selpercatinib, but then progressed on treatment. ²

In this case, the RET p.632_633del variant allele frequency in cell-free DNA increased from 5.71% to 12.78% during this period of progressive disease, without detection of additional on-target resistance mutations, ² and this suggested loss of molecular target engagement on treatment. ³ Our in silico modeling provided some support for the hypothesis selpercatinib may not bind as effectively to RET containing p.632_633del. Our functional study showed approximately threefold higher IC₅₀ for selpercatinib or pralsetinib in HEK293 cells expressing RET p.632_633del compared with wild-type RET. ²

In reply to our case report, Szymczak et al. presented new data from the LIBRETTO-001 trial showing that the selpercatinib response in patients with metastatic MTC associated with RET p.632_633del is indistinguishable from MTCs with other RET oncogenic driver mutations. ¹ Their in vitro data showed IC₅₀ for selpercatinib in Ba/F3 cells expressing RET p.632_633del was threefold to fourfold higher than for RET p.Met918Thr and p.Cys618Arg, but showed complete suppression of RET-driven Ba/F3 cell proliferation at selpercatinib concentrations expected to be achieved in vivo.

Our case report described a single patient with metastatic MTC associated with RET p.632_633del who experienced disease progression after an initial response to selpercatinib. The data presented by Szymczak et al. ¹ provide reassurance that, in general, patients with MTC harboring this RET deletion variant still respond to selpercatinib. We are in full agreement that patients with metastatic MTC associated with RET p.632_633del should be offered selpercatinib as first-line treatment.

Nevertheless, we believe further research is still required to establish whether acquired resistance to selpercatinib is different in MTCs associated with RET p.632_633del, as compared with other RET variants. Such data will be needed to tailor therapy for those patients, such as ours, whose disease unfortunately does progress while under treatment with targeted therapies.