The New Drug Application for selpercatinib was granted FDA Priority Review for the treatment of patients with advanced RET fusion–positive non–small cell lung cancer, RET-mutant medullary thyroid cancer, and RET fusion–positive thyroid cancer, based on data from the phase I/II LIBRETTO-001 trial, Eli Lilly and Company announced in a press release.
The New Drug Application (NDA) for selpercatinib (LOXO-292) was granted FDA Priority Review for the treatment of patients with advancedRETfusionpositive non–small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), andRETfusionpositive thyroid cancer, based on data from the phase I/II LIBRETTO-001 trial, Eli Lilly and Company announced in a press release.1
The latest results from patients with NSCLC andRETfusions who were treated on the trial were presented at the 2019 World Conference on Lung Cancer (WCLC). Out of 105 of the patients in the NSCLC cohort, the investigator-assessed ORR was 68% (95% CI 58%-76%). At the time the data was reported, 2 partial responses (PRs) were pending confirmation. The median duration of response observed in these patients was 20.3 months (95% CI 13.8-24.0), with a median follow-up of 8 months. The DOR was not considered to be statistically significant because the number of events was low with only 16 patients out of 36 who responded. Additionally, the intracranial ORR was 91% with responses in 10 out of 11 patients who had measurable brain metastases. The intracranial ORR responses included 2 confirmed complete responses (CRs) and 8 PRs.2
In a subgroup of patients with naïveRETfusion NSCLC, the ORR in 29 out of 34 patients was 85% (95% CI 69%-95%). At the time these data were reported, 7 PRs were pending confirmation.
For patients withRET-mutant medullary thyroid cancer (MTC), the investigator-assessed ORR was 56% (95% CI, 42%-70%) in 31 out of 55 patients. There was 1 confirmed CR and 2 confirmed PRs in 3 patients with aRETV804M/L gatekeeper mutation and 2 PRs were pending confirmation at the time these data were reported. The median DOR in this group, which was based on 6 DOR events was not reached (95% CI 11.1 months- not reached) with a median follow-up of 10.6 months. In patients withRETfusion-positive thyroid cancer, the ORR was 62% ( 95% CI, 41%-80%) in 16 out of 26 evaluable patients, which included 2 pending PRs. Data from these populations were presented at the 2019 European Society for Medical Oncology (ESMO) Annual Meeting.3
In the overall population of patients in the LIBRETTO-001 trial (n = 531), there were 5 treatment-related adverse events (TRAEs), which occurred in 15% of the patients. The TRAES included dry mount, diarrhea, hypertension, increased aspartate aminotransferase, and increased alanine aminotransferase. Most of the TRAEs observed were grades 1 and 2. Treatment with selpercatinib was discontinued in 1.7% of patients due to TRAEs (n = 9).2,3
LIBRETTO-001 is an ongoing open-label, multicenter, first-in-human study. The phase II primary end point is ORR and the secondary end points included central nervous system (CNS) ORR, DOR, CNS DOR, progression-free survival, overall survival, best change in tumor size from baseline, frequency, severity, and relatedness of TRAES and severe adverse events, and plasma concentration of selpercatinib, and pharmacokinetic parameters.
The study is actively enrolling patients with a locally advanced solid tumors who have progressed on standard therapy or are intolerant to the standard-of-care, for whom no standard treatment exists, cannot derive benefit from standard treatment based on an investigator’s opinion, or those who decline standard therapy. Patients are required to show evidence ofRETgene alteration in tumor or blood once adequate pharmacokinetic exposure is achieved, and these patients must also have measurable disease as determined by RECIST 1.1 or RANO, an ECOG performance status of 0 to 2, or a Lanksy Performance status ≥ 40% with no sudden deterioration 2 weeks before the first dose of study treatment. Patients are also required to have adequate hematologic, hepatic and renal function, and a life expectancy of at least 3 months.
The key reasons for exclusion from the study were having an additional oncogenic driver and having prior treatment with a selective RET inhibitor.
The results for theLIBRETTO trial have previously led to FDA Breakthrough Therapy Designationsfor patients with metastatic RET-fusion-positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy,RET-mutant MTC who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment option, and those withadvancedRET-fusion-positive thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options. Additionally, selpercatinib was granted orphan drug designation by the FDA for the treatment ofRETfusion-positive NSCLC and the treatment of RETfusion-positive andRET-mutant thyroid cancers including poorly differentiated thyroid cancer, undifferentiated or anaplastic thyroid cancer, MTC and locally advanced or metastatic follicular or papillary thyroid cancer.1
The FDA has filed the NDA for selpercatinib and the Prescription Drug User Fee Act date is set for 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 certainRET-driven cancers," said Anne White, president of Lilly Oncology. "Combined with the recent opening of our two Phase 3 selpercatinib clinical trials, we are thrilled with the positive momentum of this program and hope to deliver a practice-changing treatment to patients withRET-driven cancers as soon as possible."