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

Personalised immunotherapy strategies informed by single cell profiling in thyroid cancer: a mini review. (PubMed, Front Immunol) - "Early lenvatinib-pembrolizumab or selpercatinib-nivolumab trials show ~40% ORR but grade-3 hypertension >60%, prompting staggered-start designs. These advances sharpen pathogenetic resolution, refine patient selection and accelerate translational pipeline design. By integrating single-cell biology, immunology and endocrine oncology, this review identifies diagnostic blind spots, spotlights drug-repurposing opportunities and charts a roadmap toward personalised immunotherapeutic strategies capable of improving outcomes across the diverse spectrum of thyroid cancer."

IO biomarker • Journal • Review • Cardiovascular • Hypertension • Oncology • Solid Tumor • Thyroid Gland Carcinoma • AXL • CSF1R • CXCL13 • GAS6 • IFNG • LAG3 • PD-L1 • SPP1

Comprehensive genomic profiling to guide personalized targeted and immunotherapy in gastrointestinal tumors: Subgroup analysis of the ROME trial (ESMO-GI 2025) - P2 | "Funding: Erlotinib, Pertuzumab, Vemurafenib, Trastuzumab Emtansine, Alectinib, Vismodegib, Cobimetinib, Atezolizumab, Trastuzumab, Ipatasertib (GDC-0068), Entrectinib and Pralsetinib were provided by Roche; Everolimus, Lapatinib, Alpelisib were provided by Novartis, Palbociclib and Talazoparib were provided by Pfizer, Ipilimumab and Nivolumab were provided by Bristol Myers Squibb (BMS); Brigatinib was provided by Takeda Pharmaceutical Co.; Ponatinib, Itacitinib (INCB039110), Pemigatinib (INCB054828) were provided by Incyte; Selpercatinib was provided by Eli Lilly; Tepotinib was provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). CGP with MTB-guided TT may identify patients with GI cancer who benefit from targeted therapies not routinely available in clinical practice. The roles of TMB and potential disease-specific thresholds deserve further investigation."

IO biomarker • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA • TMB

A Retrospective and Prospective Real-world Study of Molecular Typing in the Treatment of Advanced Thyroid Cancer (clinicaltrials.gov) - P4 | N=800 | Recruiting | Sponsor: Fudan University | N=200 ➔ 800 | Trial completion date: Apr 2027 ➔ Dec 2028 | Trial primary completion date: Apr 2026 ➔ Dec 2026

Enrollment change • Real-world evidence • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

LC-MS/MS method development and validation for novel targeted anticancer therapies adagrasib, capmatinib, ensartinib, entrectinib, larotrectinib, lorlatinib, pralsetinib, selpercatinib and sotorasib. (PubMed, J Pharm Biomed Anal) - "After the validation, 74 plasma samples were measured in the application phase and all results but one fell within the validated ranges. This assay allows simultaneous quantification of nine novel targeted therapies and supports therapeutic drug monitoring."

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

Advancing RET-targeted therapy in thyroid cancer: insights and implications from the LIBRETTO-001 study. (PubMed, Transl Cancer Res) - No abstract available

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Phase 1 Study of FHND5071, a Novel Selective RET Inhibitor, in RET Fusion-Positive Advanced NSCLC (IASLC-WCLC 2025) - P1 | "In preclinical studies, FHND5071 exhibited significantly higher tumor and brain tissue exposure: the AUC0−t of FHND5071 in tumor tissue was approximately 28-time higher than that of selpercatinib, and its brain concentration was ~33-time higher at 4 hours post-dose. At baseline, 29% (14/48) had brain metastases and 77% (37/48) had received prior treatment. One enrolled patient did not receive study drug and was excluded from the intent-to-treat (ITT) population."

Metastases • P1 data • Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • RET

Retrospective Multicenter Study Within the German Network Genomic Medicine Lung Cancer on RET Fusions as Resistance in EGFR-Mutant Lung Cancer (IASLC-WCLC 2025) - "For three patients, a combination of RET (Pralsetinib) and EGFR-TKIs (Osimertinib) was chosen, yielding a PFS of 3.9 months, 6.0 months (ongoing) and 10.5 months (ongoing)...However, following treatment with Osimertinib and Selpercatinib, neither alteration was detectable...Early detection via individualized EGFR and RET-specific cDNA-assay may enhance therapeutic decision-making. While combinatorial EGFR- and RET-TKI therapy holds promise, further research is essential to refine treatment strategies and evaluate long-term efficacy."

Retrospective data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • EGFR • KIF5B • NCOA4 • RET

Multicenter Retrospective Study of Selpercatinib Treatment for Advanced or Recurrent RET Fusion-Positive NSCLC in Japan (IASLC-WCLC 2025) - "Regarding adverse events, this study reported a higher frequency of severe liver dysfunction compared to the LIBRETTO-001 and LIBRETTO-431 trials, while the incidence of hypertension and QT prolongation remained relatively similar. These findings suggest that liver dysfunction may be more severe in the Japanese population, highlighting the need for careful dose management strategies."

IO biomarker • Metastases • Retrospective data • Hepatology • Hypertension • Liver Failure • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • PD-L1 • RET

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer Cells Harbouring RET Fusions (IASLC-WCLC 2025) - "In recent years, two selective RET tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug Administration (FDA), selpercatinib and pralsetinib. In addition, the activation of AKT and the clonal expansion of a new gene fusion suggest the existence of multiple simultaneous resistance mechanisms to RET-TKIs. Altogether, these observations can help us to better understand the resistance processes in order to design future strategies for the treatment of these patients"

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • KIF5B • KRAS • NRAS • RET

YAP-Driven Modulation of HER3-Mediated Adaptive Resistance to RET Inhibitors in RET-Altered Cancer (IASLC-WCLC 2025) - "Methods : Four RET-aberrant cancer cell lines were tested for sensitivity to selpercatinib and pralsetinib...In vivo, co-administration of selpercatinib and afatinib significantly suppressed tumor growth compared to selpercatinib alone...This novel therapeutic strategy has the potential to advance personalized medicine by refining patient selection and optimizing treatment regimens, ultimately leading to improved clinical outcomes for patients with RET-aberrant cancers. Further studies are warranted to validate these findings and explore the clinical applicability of YAP and HER3 inhibition in combination with RET-TKIs."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • ERBB3 • FGFR1 • MET • RET

Patient-Reported Tolerability of Selpercatinib Compared to Cabozantinib/Vandetanib: A Secondary Analysis of the LIBRETTO-531 Randomized-Controlled Trial in RET-Mutant Medullary Thyroid Cancer. (PubMed, Thyroid) - P3 | " This study demonstrated superior PRT for selpercatinib compared with control in patients with RET-mutant MTC, further supporting selpercatinib use as the first-line treatment for patients with advanced RET-mutant MTC. Comparative PRT deserves further adoption as a complement to traditional endpoints in future randomized-controlled trials."

Journal • Dermatology • Fatigue • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Intolerance to RET inhibitors in a patient with aggressive sporadic medullary thyroid carcinoma with metastatic infiltration of bone marrow and concurrent acute myeloid leukemia. (ATA 2025) - "Then treated with vandetanib for 18 months until discontinuation for prolonged QTc...Received HiDAC (high-dose cytarabine) plus GO (gemtuzumab ozogamicin) consolidation...Immunotherapy (pembrolizumab) was initiated but MTC progressed after two months. Then transitioned to pralsetinib, but it was held due to severe thrombocytopenia...Development of pancytopenia on selpercatinib in the patient could be an early sign of AML, drug-related adverse effect, or a consequence of MTC infiltration the BM. BM biopsy should be considered in patients with aggressive MTC who develop pancytopenia given that BM infiltration by MTC is rare."

Clinical • IO biomarker • Late-breaking abstract • Metastases • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Thrombocytopenia • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Targeting RET in medullary thyroid cancer. (PubMed, Endocr Relat Cancer) - "Multikinase inhibitors such as vandetanib and cabozantinib were the first few effective inhibitors which have been shown to slow disease progression in the treatment of advanced MTC. In more recent years, these have been followed by highly-selective RET inhibitors selpercatinib and pralsetinib which have made their way into the clinic, demonstrating high efficacy and a more favourable side-effect profile due to their reduction in off-target effects. In spite of these successes, there remains a continued need to develop strategies to overcome treatment resistance."

Journal • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Discovery of an orally bioavailable, CNS active pan-mutant RET kinase heterobifunctional degrader. (PubMed, RSC Med Chem) - "RET-selective kinase inhibitors (selpercatinib, pralsetinib) are in current clinical use for RET-driven tumors. We sought to exploit the event-driven pharmacology of targeted protein degradation to achieve pan-mutant activity against RET-driven cancers with a single selective RET degrader, while utilizing non-phthalimide cereblon (CRBN) ligands to discover orally bioavailable heterobifunctional degraders. Here we describe the medicinal chemistry efforts that led to compound 20, an orally bioavailable, brain-penetrant, pan-mutant and pan-fusion RET heterobifunctional degrader."

Journal • Oncology • Targeted Protein Degradation • CRBN • RET

Overcoming resistance in RET-altered cancers through rational inhibitor design and combination therapies. (PubMed, Bioorg Chem) - "Traditional multi-kinase inhibitors (MKIs, such as cabozantinib and vandetanib) exhibit significant side effects due to non-selective inhibition of targets like VEGFR, and also suffer from resistance associated with RET mutations (e.g., V804L/M, G810C/S/R), both of which limit their clinical application...To overcome drug resistance, the design strategies of novel inhibitors focus on multi-target inhibition (such as PLM-101 targeting RET/YES1/FLT3, TPX-0046 targeting RET/SRC), structural optimization (such as helical ring derivatives enhancing binding stability), and natural compound screening (such as ZINC series molecules)...For instance, selpercatinib combined with crizotinib can inhibit MET amplification-driven resistance, while arsenic trioxide combined with pralsetinib restores sensitivity by inhibiting the HH-Gli pathway. Current clinical trials show that novel RET inhibitors such as SY-5007 have a significant objective response rate in advanced RET..."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FGFR • FLT3 • MET • RET • STAT1

Real-world safety and efficacy of selpercatinib in advanced medullary thyroid carcinoma patients (ATA 2025) - "This real-life experience confirmed the efficacy and safety of selpercatinib in treating RET-mutant MTC patients. Durability of response is still an open issue, but, in this series, survival is strongly influenced by worse clinical condition before selpercatinib treatment."

Clinical • Metastases • Real-world • Real-world evidence • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Real-world safety and efficacy of selpercatinib in advanced medullary thyroid carcinoma patients (ATA 2025) - "This real-life experience confirmed the efficacy and safety of selpercatinib in treating RET-mutant MTC patients. Durability of response is still an open issue, but, in this series, survival is strongly influenced by worse clinical condition before selpercatinib treatment."

Clinical • Metastases • Real-world • Real-world evidence • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Final update for safety and efficacy of selpercatinib in first line patients with RET-fusion positive thyroid cancer: Data from LIBRETTO-001 (ATA 2025) - P1/2 | "With longer follow-up selpercatinib continues to demonstrate durable responses and strong 5-year rates of PFS and OS in patients with RET-fusion systemic treatment-naive thyroid cancer, further highlighting selpercatinib as the standard of care for the first line treatment of RET-fusion TC. The safety remained tolerable despite longer duration on treatment. Testing for RET-fusion in TC before systemic therapy should be done to identify who can benefit from selpercatinib treatment."

Clinical • Late-breaking abstract • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Neoadjuvant Treatment With Selpercatinib for RET-Altered Thyroid Cancer: A Multicenter Phase 2 Clinical Trial (ATA 2025) - "No grade 4 or 5 adverse events were observed. Discussion/Conclusion : Neoadjuvant selpercatinib was efficacious and safe in patients with RET-altered, locally advanced thyroid cancer, with reduction in TNMC score and complete (R0/R1) resection in 90% of patients."

Clinical • P2 data • Gastrointestinal Disorder • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Selpercatinib for RET fusion-positive non-small cell lung cancer. (PubMed, Aust Prescr) - No abstract available

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

KEAP1 mutations activate the NRF2 pathway to drive cell growth and migration, and attenuate drug response in thyroid cancer. (PubMed, bioRxiv) - "We also demonstrate that loss of KEAP1 reduced sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this report, we comprehensively profile KEAP1 mutations in thyroid tumors, showing they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as potential novel oncogenic drivers in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks."

Journal • Oncology • Pediatrics • Solid Tumor • Thyroid Gland Carcinoma • AKR1C3 • KEAP1 • NQO1 • RET

Inhibitory Effects of Vandetanib on Catecholamine Synthesis in Rat Pheochromocytoma PC12 Cells. (PubMed, Int J Mol Sci) - "Recently, TKIs, namely, sunitinib and selpercatinib, which were clinically used to target PPGLs, have been reported to decrease catecholamine levels without reducing tumor size. Moreover, both an MEK inhibitor U0126 and a PI3K/AKT inhibitor LY294002 suppressed catecholamine synthesis without decreasing viable cells. This study in rat pheochromocytoma PC12 cells reveals the direct inhibitory effects of vandetanib on catecholamine synthesis via the suppression of RET-ERK and RET-AKT signaling."

Journal • Preclinical • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

FEATHER: Feasibility Study for Repurposing RET Inhibitors (clinicaltrials.gov) - P1 | N=7 | Not yet recruiting | Sponsor: University of Oklahoma

New P1 trial • Anorexia • Cachexia • Oncology

A Case of Micro-medullary Thyroid Carcinoma Presenting as Cancer of Unknown Primary. (PubMed, Cureus) - "Given the rapidly progressive disease, vandetanib was initiated while awaiting molecular testing for rearranged during transfection (RET)-alteration. Following the detection of the RET M918T mutation, treatment was switched to selpercatinib, and rapid tumor response and endocrine symptom resolution were observed. This case highlights the importance of evaluating serum calcitonin, specifically in patients with neuroendocrine carcinoma of unknown primary, where MTC should be considered as a critical differential diagnosis. Thyroid ultrasound should be performed to identify even small lesions of medullary thyroid carcinoma (micro-MTC). Identification of MTC not only leads to targeted therapies that may improve prognosis, but also allows for genetic risk assessment and early intervention in family members when multiple endocrine neoplasia type 2 (MEN2) is suspected."

Journal • Cushing’s Disease • Endocrine Cancer • Endocrine Disorders • Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • RET

Retevmo: Completion of P3 LIBRETTO-531 trial (NCT04211337) for RET fusion positive NSCLC in Feb 2026 (Eli Lilly) - Q2 2025 Results: Completion of P3 LIBRETTO-431 trial (NCT04194944) for RET fusion-positive NSCLC in June 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology