Selpercatinib Demonstrates Robust ORR in Thyroid Cancer

Lori J. Wirth, MD

Lori J. Wirth, MD

Strong objective responses rates were seen in the phase I/II LIBRETTO trial, which studied RET inhibition with selpercatinib (formally LOXO-292) in patients withRET-mutant medullary thyroid cancer (MTC) and for those with otherRETfusion-positive thyroid cancer. The registrational findings were recently presented at ESMO Congress 2019.

In those with RET-mutant MTC who did not receive cabozantinib or vandetanib (n = 76), the ORR was 59% with selpercatinib (95% CI, 47%-70%), with a complete response (CR) rate of 1%. With 5.5 months of median follow-up, no patients had yet developed progressive disease (PD), and the median duration of response had not yet been 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.

Findings for patients with RET-mutant MTC and RET fusion-positive thyroid cancer from the LIBRETTO-001 trial will be submitted to the FDA for potential approval, according to lead investigator Lori J. Wirth, MD. Submission of the new drug application for selpercatinib is expected before the end of 2019.

"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 of patients with RET-mutant MTC, the ORR was 56%, with a CR rate of 6% and a partial response (PR) rate of 51%. Five percent of patients had developed 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.

Of assessable patients with cabozantinib/vandetanib naive RET-mutant MTC (n = 76), the ORR of 59% included a CR of 1% and a PR of 58%. With a short duration of follow-up, neither duration of response nor PFS were achieved in this group.

Of those enrolled, the first 55 from each disease cohort were included in a primary analysis set (PAS). The ESMO analysis focused on this group along with data for a larger cohort. In the PAS for those pretreated with cabozantinib or vandetanib, 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.

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.

Reference:

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.