FDA Grants Priority Review to Selpercatinib for RET Fusion+ NSCLC and Thyroid Cancers

The FDA has granted a priority review designation to a new drug application (NDA) for selpercatinib (LOXO-292) for the treatment of patients with advanced RET fusion—positive non–small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), and RET fusion—positive thyroid cancer.¹

The application is based on findings from the phase I/II LIBRETTO-001 trial, which evaluated selpercatinib in RET-altered NSCLC and thyroid cancers. In the NSCLC study cohort of patients who received prior therapy, the agent demonstrated an objective response rate (ORR) of 68%, including a 2% complete response (CR) rate and a 66% partial response (PR) rate; the stable disease (SD) rate was 26%.² In treatment-naïve patients, the ORR with selpercatinib was 85%.

In the group of patients with RET-mutant MTC who received prior treatment with cabozantinib (Cabometyx) or vandetanib, which was known as the primary analysis set (PAS), the ORR with selpercatinib was 56%; the CR rate was 6%, the PR rate was 51%, and 5% of patients developed progressive disease (PD).³

The FDA is expected to make a decision on the NDA in the third quarter of 2020.

"We are pleased the FDA granted priority review status for the NDA for selpercatinib. This represents an important step toward providing a new precision therapy for people living with certain RET-driven cancers," Anne White, president of Lilly Oncology, the developer of selpercatinib, stated in a press release. "Combined with the recent opening of our two phase III selpercatinib clinical trials, we are thrilled with the positive momentum of this program and hope to deliver a practice-changing treatment to patients with RET-driven cancers as soon as possible."

Selpercatinib is a highly selective and potent, oral investigational agent for the treatment of patients with cancers that harbor abnormalities in the RET kinase; RET fusions and mutations occur across multiple malignancies with varying frequency. Additionally, selpercatinib is designed to inhibit native RET signaling and anticipated acquired resistance mechanisms.

The phase I/II LIBRETTO-001 trial included a dose-escalation phase as well as a dose-expansion phase. There were 253 patients with RET-fusion positive NSCLC, 184 of whom had evidence of prior platinum-based chemotherapy. The PAS included 105 patients after excluding those who received prior nonplatinum-based chemotherapy or who had nonmeasurable disease, as well as 39 patients with treatment-naïve disease. A separate analysis was conducted in the treatment-naïve patients.

In the phase II portion, the primary endpoint was ORR; secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety.

In the PAS, 2% of patients had progressive disease as their best response; the remaining patients were not evaluable. The median DOR was 20.3 months and the median PFS was 18.4 months; the median follow-up for both endpoints was less than 10 months. Of 11 patients who had central nervous system involvement, the ORR was 91%.

In the evaluable group of treatment-naïve patients (n = 34), the median DOR was not reached after a median follow-up of 4.8 months; the median PFS was also not reached after a median follow-up of 3.7 months.

Safety data, which comprised more than 500 patients who had been treated with selpercatinib, showed that adverse events were primarily low grade and were not treatment-related.

Results of the MTC cohort were presented during the 2019 ESMO Congress. In the PAS of patients with RET-mutant MTC who received prior treatment with cabozantinib or vandetanib (n = 55), the median DOR was not yet reached after 10.6 months of follow-up, and the median PFS was not yet reached at a median follow-up of 11.1 months.

Of assessable patients with cabozantinib/vandetanib-naïve RET-mutant MTC (n = 76), the ORR of 59% (95% CI, 47%-70%), which included a CR of 1% and a PR of 58%. At a median follow-up of 5.5 months and 5.7 months, the median DOR and PFS were both not reached, respectively.

In those with RET fusion-positive thyroid cancer (n = 27), the ORR of 62% (95% CI, 41%-80%), which consisted of a 62% PR rate and a 35% SD rate; 4% of patients were not evaluable. Across the full cohort, the median DOR after a median follow-up of 9.3 months was not yet reached. At a median follow-up of 9.9 months, the median PFS 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 DOR in this group also was not yet reached. At a median follow-up of 9.3 months, no patients developed PD.

Based on earlier LIBRETTO-001 results, the FDA granted a breakthrough therapy designation in September 2018 to selpercatinib for the treatment of patients with metastatic RET fusion—positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1/PD-L1 therapy; RET-mutant MTC who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment option; and advanced RET fusion—positive thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.

In 2019, selpercatinib received orphan drug designation for the treatment of RET fusion-positive NSCLC and for the treatment of RET fusion—positive and RET-mutant thyroid cancers including poorly differentiated thyroid cancer, undifferentiated or anaplastic thyroid cancer, MTC and locally advanced or metastatic follicular or papillary thyroid cancer.

The phase III LIBRETTO-431 trial (NCT04194944) is evaluating selpercatinib in patients with advanced or metastatic RET fusion—positive NSCLC, while the LIBRETTO-531 study (NCT04211337) is exploring the agent in patients with RET-mutant MTC. Both studies will enroll 400 patients.

References

1. Lilly receives FDA priority review for the selpercatinib new drug application [news release]: Indianapolis, IN. Eli Lilly and Company. Published January 29, 2020. https://bit.ly/36FZHR7. Accessed January 29, 2020.
2. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. J Thor Oncol. 2019;14(10):S6-S7. doi: 10.1016/j.jtho.2019.08.059.
3. 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. Ann Oncol. 2019;30 (suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.