On September 9, 2019 Eli Lilly and Company (NYSE: LLY) reported data from the LIBRETTO-001 clinical trial intended to support the registration of oral selpercatinib[1] monotherapy, also known as LOXO-292, for the treatment of RET fusion-positive non-small cell lung cancer (NSCLC) (Press release, Eli Lilly, SEP 9, 2019, View Source [SID1234539370]). In the registration dataset consisting of the first 105 enrolled RET fusion-positive NSCLC patients with prior platinum-based chemotherapy, selpercatinib treatment resulted in a 68 percent objective response rate (ORR) (95% CI: 58-76%). This population was heavily pretreated (median of three prior systemic regimens; 55 percent previously treated with an anti-PD-1/PD-L1 antibody and 48 percent previously treated with at least one multikinase inhibitor) and ORR was similar regardless of prior therapy. Up to 50 percent of RET fusion-positive NSCLCs can metastasize to the brain, and in the subset of patients with brain metastases in the registrational dataset, selpercatinib treatment demonstrated a CNS (Central Nervous System) ORR of 91 percent (95% CI: 59-100%).
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As of the data cut-off date of June 17, 2019, median duration of response (DOR) was 20.3 months (95% CI: 13.8-24.0) and median progression-free survival (PFS) was 18.4 months (95% CI: 12.9-24.9). Since the majority of patients remain in response or progression-free as of the data cut-off date, these medians will continue to mature over time. In a safety analysis of all 531 patients enrolled to LIBRETTO-001, selpercatinib was well-tolerated, with only 9 patients (1.7%) discontinuing therapy due to treatment-related toxicity. The most commonly observed adverse events, regardless of attribution, were dry mouth, diarrhea, hypertension, increased liver enzymes, fatigue, constipation, and headache. These results were presented in the Presidential Symposium Session at the 2019 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, hosted by the International Association for the Study of Lung Cancer (IASLC). Selpercatinib has received breakthrough therapy designation from the U.S. Food and Drug Administration.
"In this large cohort, selpercatinib’s response rate, durability, robust CNS activity, and safety show promise. Furthermore, this continues to confirm that RET fusions are clinically targetable alterations, placing them in the company of activating EGFR/ALK/ROS1 alterations. We are encouraged by these data as there is currently an unmet need to provide genomically-tailored therapy to patients with RET fusion-positive NSCLCs," said Alexander Drilon, M.D., lead investigator, Memorial Sloan Kettering Cancer Center in New York City.
Additional Data in Treatment-Naïve RET Fusion-Positive NSCLC Patients
Investigators also presented the results of selpercatinib in treatment-naïve RET fusion-positive NSCLC patients. In this analysis of 34 patients, selpercatinib treatment resulted in an 85 percent ORR (95% CI: 69-95%). Median DOR and PFS were not reached in this treatment-naïve population, as the majority of patients remain in response or progression-free.
"We’re seeing the importance of precision medicines, designed for specific patients, grow in oncology," said Anne White, president of Lilly Oncology. "The data from LIBRETTO-001 show that selpercatinib, also known as LOXO-292, represents an important new advance for patients with RET fusion-positive non-small cell lung cancer, emblematic of the kinds of new oncology medicines we hope to continue to bring forward at Lilly Oncology. We’re very excited to partner with Loxo Oncology to continue to accelerate this important medicine. In two and half years, Loxo Oncology advanced this molecule from first human dose to submission ready data, demonstrating the power of precision oncology to rapidly translate scientific discovery into treatments for patients."
"When we first started the selpercatinib discovery program, we hoped to build a RET inhibitor that would deliver for patients with RET-altered cancers in the way that medicines such as osimertinib and alectinib have delivered for EGFR-mutated and ALK-fusion patients, respectively. We believe that the selpercatinib data presented at World Lung validate these efforts," said Josh Bilenker, M.D., interim senior vice president of oncology research and early phase development at Lilly, and CEO of Loxo Oncology, a wholly owned subsidiary of Lilly. "We look forward to submitting the NDA later this year, and should selpercatinib receive regulatory approval, patients with RET fusion-positive NSCLC will finally have their first genomically-guided medicine."
Trial Background
The LIBRETTO-001 Phase 1/2 trial is the largest clinical trial of patients with RET-altered cancers treated with a RET inhibitor. The trial includes a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). The Phase 2 portion of the trial had a primary endpoint of objective response rate (ORR) and secondary endpoints of duration of response, progression free survival and safety. The primary analysis set for NSCLC regulatory submissions, as defined with the U.S. Food and Drug Administration, consists of the first 105 enrolled patients with RET fusion-positive non-small cell lung cancer who have experienced prior platinum-based chemotherapy. All data presented at WCLC were as of a data cut-off date of June 17, 2019, and all efficacy measures utilized investigator assessments.
About Selpercatinib (LOXO-292)
Selpercatinib, also known as LOXO-292, is a highly selective and potent, oral investigational new medicine in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. Selpercatinib was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms.
Selpercatinib has received breakthrough designation for the treatment of patients with:
Metastatic RET fusion-positive non-small cell lung cancer who require systemic therapy and have progressed following platinum-based chemotherapy and an anti-PD-1 or anti-PD-L1 therapy;
RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options; and for
Advanced RET-fusion-positive thyroid cancer who require systemic therapy, have progressed following prior treatment and have no acceptable alternative treatment options.
About RET-Altered Cancers
Genomic alterations in RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2 percent of non-small cell lung cancer, 10-20 percent of papillary and other thyroid cancers and a subset of other cancers. Activating RET point mutations account for approximately 60 percent of MTC. RET fusion-positive cancers and RET-mutant MTC are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as "oncogene addiction," renders such tumors highly susceptible to small molecule inhibitors targeting RET.