Retevmo (selpercatinib) / Pfizer, Eli Lilly, Innovent Biologics - LARVOL DELTA

Early Access Program in oncology: Retrospective study at a Portuguese hospital (ECOP 2024) - "During the study period were submitted 163 EAP requests for abiraterone, amivantamab, bevacizumab, durvalumab, encorafenib, enfortumab, everolimus, erdafitinib, lenvatinib, lurbinectedin, niraparib, nivolumab, olaparib, pembrolizumab, pertuzumab, ramucirumab, sacituzumab govitecan, selpercatinib, trifluridine/tipiracil, trametinib+dabrafenib, trastuzumab-deruxtecan and tucatinib. Conclusion Most cases correspond to metastatic disease, EAPs facilitate timely access to innovative therapies for patients with high unmet medical needs. The majority of situations were financed, which confirms the importance of EAPs in an era where oncology is constantly innovating."

Retrospective data • Gastrointestinal Disorder • Oncology

Molecular Testing and Targeted Therapies in Hepatobiliary Cancers: A Review. (PubMed, JAMA Surg) - "Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue-agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease."

IO biomarker • Journal • Tumor mutational burden • Biliary Cancer • Biliary Tract Cancer • Hepatocellular Cancer • Hepatology • Microsatellite Instability • Oncology • Solid Tumor • BRAF • HER-2 • MSI • NTRK • RET • TMB

LIBRETTO-432: A Study of Selpercatinib After Surgery or Radiation in Participants With Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P3 | N=170 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET

Proteolysis targeting chimeras (PROTACs) of oncogenic RET protein (AACR 2025) - "Two RET-selective protein tyrosine kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been approved for treating RET-alteration-positive cancer. In the BaF3/KIF5B-RET tumor model, YW-N-7 inhibited and degraded KIF5B-RET oncoprotein in xenograft tumors in animals, and significantly inhibited tumor growth. This work illustrates the potential of developing a RET PROTAC for simultaneously inhibiting and degrading oncogenic RET kinase for cancer therapy."

Oncology • CCDC6 • KIF5B • RET

Preclinical evaluation of SNH-110: A potent, selective, next-generation RET inhibitor overcoming adaptive drug resistances (AACR 2025) - "Despite the remarkable efficacy of pralsetinib and selpercatinib in treating various cancers, resistances due to newly surfacing on-target mutations pose a challenge. SNH-110 stands out as a powerful contender in the field of next-generation RET inhibitors. It showcases impressive efficiency in both in vitro and in vivo studies, working against a broad array of RET mutations. Importantly, it effectively combats resistance prompted by solvent front mutations, while retaining selectivity over JAKs and VEGFR2."

Preclinical • Oncology • KIF5B • RET

Selpercatinib plus trametinib overcomes resistance to single-agent RET inhibitors inRET-mutant medullary thyroid carcinoma [WITHDRAWN] (AACR 2025) - "RETi-resistant cells were generated by maintaining TT cells under continual vandetanib (a RET inhibitor) pressure. Secondary genomic alterations in RET lead to elevated MAPK signaling and resistance to RETi. MEK inhibition synergized with RET inhibitors in preclinical models of MTC. These findings are the biological rationale for conducting a Phase I clinical trial at the National Cancer Institute for the treatment of RETi relapsed/refractory patients with MTC or RET-mutation-driven cancers."

Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • MAP2K2 • NF1 • RET

Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3/Stat5 activation (AACR 2025) - "Additionally, to investigate the direct correlation between Jak3 and IL-2 release, JT cells were treated with ritlecitinib, a Jak3-selective inhibitor, for ~2 weeks. Pralsetinib, not Selpercatinib, inhibits additional IL-2 production by blocking Jak3/Stat5 activation triggered by IL-2 released during early T cell activation. Consequently, Jak3 inhibition by pralsetinib suppresses IL-2 release by inhibiting the activation of transcription factors for IL-2, such as JunB/c-Jun and Stat5, thereby inducing opportunistic infections, including invasive pulmonary aspergillosis (IPA), cytomegalovirus (CMV) pneumonia, CMV viremia, and pneumocystis pneumonia."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL2 • JAK3 • JUN • JUNB • RET • STAT5 • STAT5AWqe

DNA damage repair pathways enable a drug-tolerant persister state in RET-fusion NSCLC and precedes TKI resistance (AACR 2025) - "Treatment with selinexor, an FDA-approved XPO1 inhibitor, in combination with selpercatinib strongly reduced the number of DTPs in vitro, and overexpression of the DDR genes BRCA1, MSH6, and Rad18 rescued this effect. Our research highlights DDR pathways as a critical mechanism of resistance via Rb1 inactivation in TKI-treated RET-driven lung cancers and identifies XPO1 inhibition as a promising therapeutic strategy to overcome this resistance. Finally, we also found upregulation of DDR proteins upon treatment with lorlatinib and osimertinib in ALK and EGFR driven LUAD PDXs, respectively, suggesting that targeting DDR pathways could be an effective strategy against resistance in a pan-TKI setting across other RTK-driven LUADs."

IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRCA1 • EGFR • MSH6 • RB1 • RET

A Case of Stevens-Johnson Syndrome Induced by Selpercatinib. (PubMed, J Dermatol) - "To the best of our knowledge, this is the first report of SJS caused by selpercatinib. We herein present and discuss this case to raise awareness."

Journal • Cardiovascular • Dermatology • Endocrine Cancer • Hepatology • Hypertension • Liver Failure • Mucositis • Oncology • Solid Tumor • Steven-Johnson Syndrome • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Pincer Nail in all 20 Nails in a Patient on Selective RET Inhibitor Selpercatinib Treated With Partial Avulsion and Matricectomy. (PubMed, Dermatol Surg) - No abstract available

Journal

A Study of Effects of Selpercatinib in Hepatically Impaired Participants and Healthy Participants (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Eli Lilly and Company | N=25 ➔ 36

Enrollment change • Hepatology

Tumour-agnostic kinase inhibitors. (PubMed, Nat Rev Drug Discov) - "Consequently, a biomarker-based therapy model, untethered from tumour histology and organ of origin, has been established, which has led to transformative regulatory approvals of tumour-agnostic kinase inhibitors such as larotrectinib, selpercatinib, dabrafenib-trametinib and pemigatinib. Moreover, clinical trials to assess these compounds are challenging because genomic sequencing of hundreds or thousands of tumours may be required to find eligible patients whose malignancy bears the targeted genetic alterations. In this Review, we describe the precision medicine paradigm that has successfully launched tumour-agnostic drug development, concentrating on small-molecule inhibitors that target kinase pathway aberrations, and we discuss the challenges in developing tumour-agnostic agents."

Journal • Pan tumor • Review • Hematological Disorders • Hematological Malignancies • Oncology

Identification and investigation of hits targeting the N-methyl-D-aspartate receptor via drug repurposing: A plausible approach for anti-Alzheimer drug discovery. (PubMed, J Mol Graph Model) - "The high throughput virtual screening (HTVS) followed by molecular docking and molecular mechanics studies enabled us to identify two drugs, Ertugliflozin (Dock Score: -9.43 kcal/mol, MMGBSA: -104.50 kcal/mol) and Selpercatinib (Dock Score: 8.11 kcal/mol, MMGBSA: 83.62 kcal/mol), with a high affinity towards the NMDAR. The work is further supported by strong literature evidence that concludes the impact of antidiabetic molecules on AD progression, along with the evidence that Ertugliflozin possesses efficacy against AD with unequivocal evidence on the biological target and the mechanism. Further work, however, is required to establish this association in the in vivo or suitable model that could mimic the AD microenvironment as a part of future research."

Journal • Alzheimer's Disease • CNS Disorders

Treatment of non-small cell lung cancer with RET rearrangements. (PubMed, Cancer) - "Two highly potent and selective RET small-molecule inhibitors, selpercatinib and pralsetinib, were granted accelerated approval for advanced RET fusion-positive NSCLC by the US Food and Drug Administration, and have been shown to be highly effective both in treatment-naive and previously treated patients with NSCLC. Selpercatinib has shown superiority over chemotherapy in a phase 3 study (LIBRETTO-431) in previously untreated patients with RET fusion-positive NSCLC, which established its place as the standard of care in this patient population. This review discusses the biology and clinical characteristics of RET-rearranged NSCLC and summarizes the evolution of treatment strategies, current understanding of mechanisms of resistance, and development of new-generation agents to overcome resistance."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET

Systemic Therapies for Advanced Medullary Thyroid Carcinoma. (PubMed, Recent Results Cancer Res) - "Cabozantinib and vandetanib, multikinase inhibitors (MKIs) that exert their therapeutic effect mainly through antiangiogenesis by targeting the vascular endothelial growth factor receptor, have mild anti-RET activity...Potent and selective RET inhibitors, selpercatinib and pralsetinib, demonstrate significant efficacy in RET-altered cancers and more tolerable side effect profiles than MKIs...Thus, development of more effective treatments for advanced, progressive MTC remains an urgent priority. In this chapter, we describe the current spectrum of systemic therapies for MTC, their limitations, and ongoing investigations."

Journal • Review • Endocrine Cancer • Oncology • Rare Diseases • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Overview of management and therapeutic advances in medullary thyroid cancer. (PubMed, Endocr Oncol) - "Since 2011, systemic treatment options have expanded with multikinase inhibitors (MKIs), such as vandetanib and cabozantinib, and selective RET inhibitors such as selpercatinib and pralsetinib...Effective MTC management, particularly given its rarity, benefits from specialized high-volume centers. Precision medicine, standardized therapy selection and ongoing research are essential for improving outcomes in both RET-positive and RET-negative MTC patients."

Journal • Review • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Selpercatinib for Advanced RET-Driven Advanced Thyroid Cancer (Oncology Learning Network) - "Lori J Wirth, MD, Massachusetts General Hospital, Boston, Massachusetts, discusses the use of selpercatinib, a highly selective, potent RET inhibitor, for patients with advanced RET-mutant medullary thyroid cancer and RET fusion-positive, radioactive iodine-refractory differentiated thyroid cancer."

Video

Uncovering Uncommon Pleural Complications of RET Tyrosine Kinase Inhibitor Therapy: A Case of Selpercatinib-Induced Chylothorax in a Patient with Metastatic Medullary Thyroid Carcinoma (ATS 2025) - No abstract available

Clinical • Metastases • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Rapid and sensitive HPLC with fluorescence detection method for quantifying selpercatinib in liver microsomes and rat plasma: Implications for drug-drug interaction studies. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "After treatment with dexamethasone, the clearance of selpercatinib was enhanced in both female and male rat liver microsomes, suggesting potential drug-drug interaction. These findings suggest the need to investigate these potential drug interactions in clinical settings, as they may affect selpercatinib efficacy and toxicity. This HPLC-FLD method offers a rapid, sensitive, and cost-effective alternative to LC-MS/MS for studying pharmacokinetics in various in vitro and in vivo models."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Acute severe hypocalcaemia after initiation of a selective RET-inhibitor in medullary thyroid cancer. (PubMed, Endocr Oncol) - "Although rare, the development of hypocalcaemia with RET inhibitors may necessitate dose interruptions and adjustments. Our experience has also illustrated that re-challenge with selpercatinib is feasible with appropriate management strategies."

Journal • Endocrine Cancer • Endocrine Disorders • Hypoparathyroidism • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Uterine Neoplasms, Version 3.2025. (NCCN)

NCCN guideline • Endometrial Cancer • Uterine Cancer • Uterine Sarcoma

Retevmo: Protection of compound patents in US/EU until 2037 and Japan until 2038 (Eli Lilly) - Annual Report 2024: Regulatory data protection in US until 2025 and EU/Japan until 2031

Commercial • Patent • Neuroendocrine Tumor • Oncology • Solid Tumor • Thoracic Cancer • Thyroid Gland Carcinoma

Response to neoadjuvant selpercatinib in a pediatric patient with advanced papillary thyroid carcinoma: a case report. (PubMed, Pediatr Hematol Oncol) - No abstract available

Journal • Endocrine Cancer • Oncology • Pediatrics • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

Comparative study of degree, neighborhood and reverse degree based indices for drugs used in lung cancer treatment through QSPR analysis. (PubMed, Sci Rep) - "This study focuses on the selection of drugs used to treat lung cancer, including dacomitinib, selpercatinib, tepotinib, trametinib, sotorasib, etoposide, alectinib, paclitaxel, dabrafenib, entrectinib, crizotinib, ceritinib, lorlatinib, afatinib, pralsetinib, brigatinib, erlotinib, adagrasib, gefitinib, vinorelbine, gemcitabine, docetaxel, and pemetrexed. Using molecular structural measures such as degree, neighborhood degree sum, and modified reverse degree, we have developed QSPR models to predict physicochemical properties through the topological indices derived from these structural measures. We then conducted a comparative analysis, incorporating correlation analysis, to identify the model with the highest predictive accuracy."

Clinical • Journal • Lung Cancer • Oncology • Solid Tumor

Personalized Therapy in a Patient With EGFR-Mutated NSCLC Developing Sequential CCDC6-RET Fusion and BRAF V600E Mutation as Bypass Resistance Mechanisms. (PubMed, JTO Clin Res Rep) - "In this case report, we describe a case of sequential acquired CCDC6 -RET fusion and BRAF V600E mutation observed in a patient with EGFR-mutated NSCLC treated with osimertinib and with combined selpercatinib and osimertinib. When a novel BRAF V600E mutation was detected at progression, the molecular tumor board suggested the administration of triple therapy, adding trametinib (anti-MEK). Nevertheless, treatment was discontinued for toxicity, highlighting the challenges of using multiple drug combinations to address complex resistance."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • CCDC6 • EGFR • RET