Lilly's Tumor-Agnostic RET Inhibitor Retevmo Demonstrates Robust Efficacy Across Diverse RET Fusion-Positive Cancers

April 12, 2021 News /Bio ValleyBIOON/ ---Eli Lilly(Eli Lilly) recently announced for the first time at the 2021 American Association for Cancer Research (AACR) Annual Meeting the data from the Phase 1/2 clinical study LIBRETTO-001 of the precision oncology drug Retevmo (selpercatinib), demonstrating encouraging anti-tumor activity of Retevmo in a broad range of advanced RET fusion-positive solid tumors beyond lung and thyroid cancers, including multi-drug refractory gastrointestinal (GI) malignancies.TumorEfficacy and Safety: Therapeutic responses were observed across nine distinct cancer types, with a confirmed objective response rate (ORR) of 47%. At a median follow-up of 13 months, the median duration of response (DOR) had not been reached; among the 15 patients who achieved a response, 11 maintained their response. The safety profile of Retevmo in this study was consistent with its known safety profile.

The LIBRETTO-001 study is the largest clinical trial to date evaluating a RET inhibitor in patients with cancers harboring RET alterations. The enrolled population included treatment-naïve patients as well as those who had received multiple prior therapies, across various advanced solid tumors, including RET fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancer, and other advanced solid tumors with diverse RET alterations.

Based on the lung cancer cohort and thyroid cancer cohort data from this study, Retevmo was approved in the United States in May 2020FDAAccelerated approval for the treatment of three types of tumors with genetic alterations (mutations or fusions) in specific genes (rearranged during transfection gene, RET gene)TumorPatient: Non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), other types of thyroid cancer. In the European Union, selpercatinib was approved in February 2021 and is marketed under the brand name Retsevmo.

Retevmo/Retsevmo is the first drug approved specifically for the treatment of cancer patients with RET gene alterations., this drug is a selective RET kinase inhibitor that can block RET kinase and prevent cancer cell growth.

Eli LillyDavid Hyman, Chief Medical Officer of Oncology, stated, “We are pleased to expand the evidence for Retevmo in RET fusion-positive cancers beyond lung cancer and thyroid tumors. These encouraging results, including in hard-to-treat gastrointestinal malignancies, support the growing body of evidence that RET fusions are a viable therapeutic target across a broad range of tumor types. These findings further demonstrate the extensiveTumorThe Importance of Features in Advanced Cancer. We look forward to discussing these new data with regulatory authorities this year.”

In the phase 1/2 LIBRETTO-001 trial, as of the efficacy cutoff date of September 19, 2020, a total of 32 adult patients with 12 distinct types of advanced RET fusion-positive cancers were enrolled in the study, with follow-up conducted until March 19, 2021. The cancer types treated included pancreatic cancer, colorectal cancer,Breast Cancer, salivary gland carcinoma, sarcoma, carcinoid tumor, rectal neuroendocrine carcinoma, small intestine cancer, xanthogranuloma, ovarian cancer, pulmonary carcinosarcoma, and cancer of unknown primary. Among the 32 patients, 62.5% had gastrointestinalTumor(defined as pancreatic [n=9], colonic [n=9], small intestinal [n=1], and rectal neuroendocrine [n=1]). Among all 32 patients, the confirmed objective response rate (ORR) was 47% (95% CI: 26–65%). Confirmed responses were observed across nine distinct types of advanced RET fusion-positive cancers. With a median follow-up of 13 months, the median duration of response (DoR) was not reached. Among patients who achieved a response, 73% (11/15) maintained their response.

The safety profile of patients in this cohort was consistent with the known safety profile of Retevmo. In this cohort, the most common treatment-emergent adverse events (TEAEs) of any grade (≥20%) included elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and dry mouth,Hypertension, diarrhea, fatigue, nausea, and abdominal pain. No patients in the cohort discontinued treatment due to treatment-related adverse events.

Dr. Vivek Subbiah of The University of Texas MD Anderson Cancer Center stated, “Although uncommon, RET fusions occur in various solid tumors beyond lung and thyroid cancers, and there is currently no approved targeted therapy for these patients to address the underlying genomic drivers of their cancer. These results demonstrate the potential of selpercatinib in this patient population and reaffirm the importance of comprehensive genomic profiling in identifying actionable oncogenic drivers, including RET fusions.”

It is estimated that RET fusions are present in approximately 2% of non-small cell lung cancer (NSCLC) cases, 10–20% of papillary thyroid carcinoma (PTC) and other types of thyroid cancer, as well as in subgroups of other cancers (such as colorectal cancer); RET point mutations are present in approximately 60% of medullary thyroid carcinoma (MTC) cases. Cancers harboring RET fusions or RET point mutations primarily rely on the activation of the RET kinase to maintain their proliferation and survival, a dependency commonly referred to as “oncogene addiction,” making suchTumorHighly sensitive to small-molecule RET inhibitors.

Retevmo/Retsevmo is a potent, oral, highly selective inhibitor of the rearranged during transfection (RET) kinase, indicated for the treatment of patients with RET-altered cancers. The RET gene, a proto-oncogene that undergoes rearrangement during transfection and derives its name from this process, encodes a cell membrane receptor tyrosine kinase; alterations in this gene serve as rare driver events in various tumor types. Retevmo/Retsevmo is designed to inhibit native RET signaling and anticipated acquired resistance mechanisms, and was developed for the treatment ofTumorpatients harboring abnormal RET kinase.

In the United States,FDASelpercatinib has previously been granted Breakthrough Therapy Designation (BTD) for three patient populations, specifically: (1) those who have received platinum-based chemotherapy and a PD-1 or PD-L1Tumor(1) Patients with metastatic RET fusion-positive NSCLC who have experienced disease progression following immunotherapy and require systemic therapy; (2) Patients with RET-mutant MTC who have experienced disease progression after prior treatment, have no acceptable alternative therapeutic options, and require systemic therapy; (3) Patients with advanced RET fusion-positive thyroid cancer who have experienced disease progression after prior regimens, have no acceptable alternative therapeutic options, and require systemic therapy.

Selpercatinib is a drug developed by Loxo Oncology, which was acquired by Eli Lilly and Company for $8 billion in January 2019. In December 2019,Eli LillyTwo confirmatory Phase III trials of selpercatinib have been initiated: the LIBRETTO-431 trial for the treatment of treatment-naïve patients with RET fusion-positive non-small cell lung cancer (NSCLC), and the LIBRETTO-531 trial for the treatment of treatment-naïve patients with RET-mutant medullary thyroid cancer (MTC). Each trial will enroll 400 patients. (Bioon.com)

Original Source: Lilly Presents New Data on Retevmo (selpercatinib) in Advanced RET Fusion-Positive Gastrointestinal and Other Cancers at 2021 American Association for Cancer Research (AACR) Annual Meeting