Selpercatinib Shows Strong ORR in Thyroid Cancer, FDA Submission Expected

Lori J. Wirth, MD

The highly selective RET inhibitor selpercatinib (formally LOXO-292) demonstrated robust objective response rates (ORR) for patients with RET-mutant medullary thyroid cancer (MTC) and for those with other RET fusion-positive thyroid cancers, according to findings from the phase I/II LIBRETTO-001 study presented at ESMO Congress 2019.

Findings from the trial for the first 55 patients enrolled with RET-mutant MTC who received prior treatment with cabozantinib or vandetanib will be submitted to the FDA for potential approval. Submission of the new drug application for selpercatinib is expected before the end of 2019, according to lead investigator Lori J. Wirth, MD.

In this group, which was known as the primary analysis set (PAS), the ORR was 56%, with a CR rate of 6% and a partial response (PR) rate of 51%. Five percent of patients had developed progressive disease (PD). The median duration of response after 10.6 months of follow-up was not yet reached (95% CI, 11.1 months to not evaluable). The median follow-up for progression-free survival (PFS) was 11.1 months with a median PFS not yet reached.

"The outcomes with selpercatinib in patients with MTC who had progressed or had previous treatment on approved multikinase inhibitors [MKIs], I think, compares very favorably to MKls when they are used in the first-line setting, and I think the drug is much less toxic," said Wirth, from the Massachusetts General Hospital Cancer Center. "We are now initiating a randomized, global phase III trial of selpercatinib versus cabozantinib or vandetanib—investigator's choice—in kinase inhibitor naive RET-mutant MTC."

The LIBRETTO-001 trial enrolled 531 patients with various RET-altered cancers across doses of selpercatinib ranging from 20 mg per day to 240 mg twice daily. In addition to RET-mutant MTC and RET fusion-positive thyroid cancer, the trial also included patients with RET fusion-positive non—small cell lung cancer, although findings for this group were reported separately. The phase II dose for the study was identified as 160 mg twice daily.

In the PAS group, the median age was 57 years and the most common ECOG performance score was 1 (75%). The median number of prior therapies was 2 (range, 1-8). More than half of patients (53%) had received 2 or more MKIs.

The biochemical response rate (BRR) using calcitonin levels was 91% with selpercatinib (95% CI, 80%-97%). The BRR by CEA levels was 64% with the RET inhibitor (95% CI, 50%-77%).

"The biochemical responses were deep and sustained over time," Wirth noted. "We did see that the overall response rate, duration of response, and PFS were similar regardless of prior therapy and also similar regardless of RET mutation status, particularly M918T versus others."

In those with RET-mutant MTC who were cabozantinib or vandetanib naïve (n = 88), the median age was 58 years and the performance scores were split between 0 (49%) and 1 (48%). The median number of prior therapies was 0, although 8% of patients had receive another MKI other than cabozantinib or vandetanib.

Of assessable patients with cabozantinib/vandetanib naive RET-mutant MTC (n = 76), the ORR of 59% (95% CI, 47%-70%) included a CR of 1% and a PR of 58%. With a short duration of follow-up (5.5 months), neither duration of response nor PFS were achieved in this group. No patients had yet developed PD.

In those with RET fusion-positive thyroid cancer (n = 27), the median age of patients was 54 years. The histologies included papillary (78%), Hürthle cell (4%), poorly differentiated (11%), and anaplastic (7%). The most common ECOG performance score was 1 (59%) and the median number of prior therapies was 3 (range, 1-7). Eighty-nine percent of these patients had received prior radioactive iodine (RAI) therapy and 70% had receive other systemic therapy other than RAI. Twenty-six percent had brain metastases.

The ORR of 62% (95% CI, 41%-80%) consisted entirely of partial responses and was seen across histologies, including those with poorly differentiated tumors. Of the 2 patients with anaplastic histology, 1 had a PR and the other had stable disease. Across the full cohort, the median duration of response after a median follow-up of 9.3 months was not yet reached. For PFS, the median follow-up was 9.9 months and the median was not reached.

In pretreated patients with RET fusion-positive thyroid cancer (n = 26), which consisted primarily of papillary histology (78%), the ORR with selpercatinib was 62% (95% CI, 41%-80%), with no CRs. The median duration of response in this group also was not yet reached. With a median follow-up of 9.3 months, no patients had developed PD.

Across all patients and doses in the LIBRETTO-001 trial (N = 531), the most commonly observed all grade treatment-related AEs with selpercatinib were dry mouth (27%), increased AST (22%), and increased ALT (21%). The most common grade 3/4 AEs were hypertension (9%), increased ALT (7%), and increased AST (5%). The most common treatment-emergent grade 3/4 AEs were hypertension (15%), increased ALT (8%), and increased AST (7%).

Most of the adverse events (AEs) observed in the trial were low-grade and unrelated to selpercatinib, Wirth noted. Overall, only 1.7% of patients discontinued treatment due to AEs.

"The data for selpercatinib show demonstrative efficacy and safety in both the first-line and relapsed settings. Patients with thyroid cancer have long sought targeted therapy tailored to the molecular nature of their disease, and we are hopeful that selpercatinib may be used as the standard of care in the future," Wirth said.

In September and October of 2018, the FDA granted selpercatinib breakthrough therapy designations for all 3 indications explored in the LIBRETTO-001 trial. Under the designation, the potent RET inhibitor is eligible for an expedited review process and a rolling submission of data for a new drug application.

Wirth LJ, Sherman E, Drilon A, et al. Registrational results of LIBRETTO-001: A phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancers. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA93.

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