On September 29, 2019 Eli Lilly and Company (NYSE: LLY) reported data from the LIBRETTO-001 clinical trial intended to support the registration of oral selpercatinib1 monotherapy, also known as LOXO-292, for the treatment of RET-altered thyroid cancers (Press release, Eli Lilly, SEP 29, 2019, View Source [SID1234539875]). RET-altered thyroid cancers are comprised of two different populations, RET-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancers. In the RET-mutant MTC registration dataset consisting of the first 55 enrolled patients with prior cabozantinib and/or vandetanib2, selpercatinib treatment resulted in a 56 percent objective response rate (ORR) (95% CI: 42-70%). This population was heavily pretreated (53 percent previously treated with ≥2 prior multikinase inhibitors), and ORR was similar regardless of prior multikinase inhibitor therapy. As of the data cut-off date of June 17, 2019, median duration of response (DOR) was not reached (95% CI: 11.1-NE) and median progression-free survival (PFS) was not reached (95% CI: 11.3-NE). Selpercatinib therapy also resulted in robust biochemical response rates (BRR) for serum tumor markers calcitonin (91% BRR) and carcinoembryonic antigen (64% BRR). In a safety analysis of all 531 patients enrolled to LIBRETTO-001, selpercatinib was well-tolerated, with only nine patients (1.7%) discontinuing therapy due to treatment-related adverse events. 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 today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019 in Barcelona, Spain, in session LBA93, Registrational Results of LOXO-292 in Patients with RET-Altered Thyroid Cancers, presented by Lori J. Wirth, M.D., medical director of head and neck cancers, Massachusetts General Hospital Cancer Center in Boston, Mass. Selpercatinib has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA).

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"Current therapeutic options are often challenging for patients with first-line RET-altered thyroid cancers and are limited for patients who relapse. 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," said Wirth, who is lead investigator on the trial.

Selpercatinib Data in Cabozantinib/Vandetanib-Naïve RET-Mutant MTC patients
Investigators also presented the results of selpercatinib in RET-mutant MTC patients who have received neither cabozantinib nor vandetanib. In this analysis of 76 patients, selpercatinib treatment resulted in a 59 percent ORR (95% CI: 47-70%). Median DOR and PFS were not reached in this treatment-naïve population, as the vast majority of patients remain in response or progression-free.

Selpercatinib Data in Heavily Pretreated RET Fusion-Positive Thyroid Cancer Patients
Investigators also presented the results of selpercatinib in heavily pretreated RET fusion-positive thyroid cancer patients. In this analysis of 26 patients, selpercatinib treatment resulted in a 62 percent ORR (95% CI: 41-80%). Median DOR and PFS were not reached in this population, as the vast majority of patients remain in response or progression-free.

"We’re pleased that selpercatinib may offer a meaningful advance for patients with RET-altered thyroid cancers," said Anne White, president of Lilly Oncology. "These patients have been a focus of the selpercatinib program from its beginning, as RET has been a known oncogene in these diseases for decades. With these data, selpercatinib has delivered on our vision, with unprecedented clinical outcomes in both first-line and relapsed patients, particularly in light of the difficult options for these patients."

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 DOR, PFS and safety. The primary analysis set for MTC regulatory submissions, as defined with the FDA, consists of the first 55 enrolled patients with RET-mutant medullary thyroid cancer who have experienced prior cabozantinib and/or vandetanib. All data presented at ESMO (Free ESMO Whitepaper) 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 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.