Gavreto (pralsetinib) / CStone Pharma, Allist, Rigel Pharmaceuticals, Sanofi - LARVOL DELTA

NeoLATC: Response to Neoadjuvant Treatment in Locally Advanced Thyroid Cancer (clinicaltrials.gov) - P=N/A | N=120 | Recruiting | Sponsor: Fujian Medical University

New trial • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma

Efficacy and safety of pralsetinib in patients with advanced RET-fusion-positive NSCLC: Final data from the phase 1/2 ARROW study. (ASCO 2025) - P1/2 | "Pralsetinib produced clinically meaningful and durable responses in patients with RET-fusion-positive NSCLC (regardless of prior therapies) with a manageable safety profile, confirming with this longer follow up previously published results. aPer FDA censoring rule."

Clinical • Metastases • P1/2 data • Anemia • Hypertension • Infectious Disease • Interstitial Lung Disease • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • RET

RET fusion–positive lung adenocarcinoma: Partner-specific clinicopathological characteristics, co-mutation profiles, and implications for targeted and immunotherapy (ELCC 2026) - "Notably, non-KIF5B patients demonstrated longer median PFS than KIF5B patients under pralsetinib (17.0 vs. 5.5 months, p = 0.0473)...KIF5B-RET fusions tend to occur at earlier stages, whereas non-KIF5B fusions are more frequently associated with CDKN2A co-mutations and appear to derive greater benefit from selective RET inhibition. Immunochemotherapy demonstrates comparable efficacy regardless of fusion partner, highlighting the need for partner-specific therapeutic strategies in RET fusion–positive LUAD."

Clinical • IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • CDKN2A • KIF5B • NCOA4 • RET • TP53

Real-world report of late presenting adverse events and its management strategies in patients with RET-altered tumours on selective RET inhibitors (ELCC 2026) - "Natural history of LPAEs and its management were reviewed.Results 53 pts (48 selpercatinib, 1 BOS172738, 1 selpercatinib & pralsetinib, 3 BOS172738 & pralsetinib) started RET TKI in Mar 2018 - Sep 2023 were included: 47 NSCLC (98% fusion; 2% exon 11 intron), 6 thyroid cancer (50% M918T, 33% fusion, 17% G634R/G533C). LPAEs like CE were manageable with supportive measures and DR without compromising efficacy. There is a need to be vigilantly recognized to differentiate from PD."

Adverse events • Clinical • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology

AcceleRET Lung: A Study of Pralsetinib Versus Standard of Care for First-Line Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov) - P3 | N=223 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; Early termination of the study resulted from organizational and commercial decisions that led to the discontinuation of pralsetinib's global marketing and development in all territories (excluding US and Greater China).

Trial termination • Embryonal Tumor • Germ Cell Tumors • Head and Neck Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thoracic Cancer • RET

Understanding and overcoming resistance of triple-negative breast cancer brain metastases to RET monotherapy (AACR 2026) - "The orally FDA-approved RET inhibitors, Pralsetinib and Selpercatinib, demonstrated brain penetration, with 70-91% intracranial response rates in lung cancer patients with BrainMet, suggesting their possible utility in treating TNBC-BrainMet. Our findings suggested that these co-inhibitions may overcome RET monotherapy resistance in TNBC-BrainMet. In summary, targeting RET is promising for preventive therapy; co-inhibition of RET and its associated pathways may overcome RET monotherapy resistance and advance TNBC-BrainMet treatment, providing preclinical evidence to support future clinical evaluation and development of new effective therapies for TNBC patient with brain metastasis."

Monotherapy • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Oral Cancer • Solid Tumor • Thyroid Gland Carcinoma • Triple Negative Breast Cancer • RET

Targeting breast cancer brain metastasis through novel combination of FDA-approved orally active BBB-permeable RET and tGLI1 inhibitors (AACR 2026) - "RET inhibitors Pralsetinib and Selpercatinib, FDA-approved for lung and thyroid cancers, exhibit intracranial activity. The underlying mechanism is under analysis through RNA-sequencing, and in vivo efficacy of the Pralsetinib+Ketoconazole combination therapy on BCBM remains to be validated with mouse models. Together, we report a novel mechanism and combination treatment for BCBM patients."

Breast Cancer • Glioma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • GLI1 • RET

SIPA1L3 loss induces TKI resistance via Rap1-MAPK activation in ALK-/RET-fusion positive NSCLC (AACR 2026) - "Still, in a significant number of cases, the mechanism of resistance remains unknown.To discover additional potential resistance mechanisms, we conducted a genome-wide CRISPR/Cas9 screening under floating culture condition culture conditions in CCDC6-RET fusion positive LC2/ad cells treated with selpercatinib or pralsetinib for nine days. Furthermore, loss of SIPA1L3 also conferred ALK-TKI resistance in the ALK-fusion H3122 cell line, accompanied by increased Rap1-GTP expression. Co-treatment with alectinib and avutometinib effectively suppressed DTP formation.In conclusion, this study identifies SIPA1L3 as a critical mediator of ALK- or RET-TKI resistance in NSCLC from genome-wide CRISPR screening and underscores the therapeutic potential of avutometinib in combination with ALK-/RET-TKIs to overcome drug-tolerant persistence and improve treatment outcomes in ALK-/RET-rearranged NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CCDC6 • RET

Targeting RET fusions in sarcomas with vepafestinib, a 3rd generation RET inhibitor with superior blood-brain barrier penetration (AACR 2026) - P1/2 | "While selpercatinib and pralsetinib also inhibited the growth of the RET fusion-driven sarcoma cells, they showed more off-target effects in the control HMSC cells relative to vepafestinib.In both PDX and cell line xenograft models, vepafestinib (50 mg/kg BID) caused tumor growth inhibition comparable to selpercatinib (10 mg/kg BID) and pralsetinib (15 mg/kg BID)...Intracranially, vepafestinib was significantly more effective than selpercatinib at blocking tumor growth (p=0.042) and improving survival (median: 56 vs 32 days, p=0.0025).ConclusionsOur preclinical results support vepafestinib as a promising, CNS-active therapy for RET fusion-driven sarcomas. Vepafestinib is currently being evaluated in the ongoing phase 1/2 margaRET trial for advanced RET-altered solid tumors (NCT04683250)."

Oncology • Sarcoma • Solid Tumor • RET • SPECC1 • SPECC1L

Regulatory divergence in EMA approvals for targeted therapies in oncogene addicted NSCLC (ESMO-TAT 2026) - "Investigation of the factors behind divergent regulatory outcomes could help clarify the regulatory pathway for future drugs targeting molecularly-defined subsets of NSCLC. Comparative review of CHMP/EC documents and EPARs for crizotinib (Xalkori®), entrectinib (Rozlytrek®), repotrectinib (Augtyro®), sotorasib (Lumykras®), adagrasib (Krazati®), selpercatinib (Retsevmo®), pralsetinib (Gavreto®), trastuzumab deruxtecan (Enhertu®), tepotinib (Teptmeko®) and capmatinib (Tabrecta®). EMA approvals for oncogene-addicted NSCLC show inconsistency across biomarkers. A clear and consistent application of a framework for small-population settings is essential to (1) define when ORR/DoR benchmarks from robust single-arm studies justify line-agnostic approval; (2) align post-authorisation obligations to residual uncertainty; and (3) enable a similar developmental approach to first- and later line targeted therapies that address unmet..."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HER-2 • KRAS • MET • ROS1

Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up (ESMO.org) - "Osimertinib is the preferable first-line treatment option for patients with a classical activating EGFR mutation (exon 19 deletion or exon 21 L858R), especially for patients with CNS metastases; Afatinib or osimertinib is a recommended treatment option for patients with a major uncommon, non-exon 20 insertion, sensitising EGFR mutation [III, B; ESMO-MCBS v1.1 score: 4 for afatinib; ESCAT: I-B]; Alectinib is recommended in patients who progress on treatment with, or are intolerant to, crizotinib [I, A; ESMO-MCBS v1.1 score: 4; ESCAT: I-A]...Treatment with selpercatinib or pralsetinib is recommended as first-line therapy for patients with RET fusion-positive NSCLC..."

Clinical guideline • Non Small Cell Lung Cancer

Sequential targeted therapy in synchronous dual-primary lung adenocarcinomas with EGFR and RET alterations: a 5-year follow-up case report. (PubMed, Front Oncol) - "Following the development of resistance, combination therapy with pralsetinib and anlotinib successfully achieved a partial response again. This case underscores the importance of comprehensive molecular testing across multiple lesions to guide precision therapy and provides clinical insights into RET fusion-positive lung cancer treatment and post-resistance combination strategies."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Oral Cancer • Solid Tumor • EGFR • RET

Not All That Ret Inhibits Is Gold: Pralsetinib-associated Pneumonitis in NSCLC (ATS 2026) - No abstract available

Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Pneumonia • Solid Tumor

Patterns of Tyrosine Kinase Inhibitor–Associated Pneumonitis in EGFR-Mutated and Other Driver-Positive NSCLC (IASLC-TTLC 2026) - "Pneumonitis was also diagnosed in patients with MET Exon 14 skipping mutation (capmatinib four patients of 40, 10%), RET (selpercatinib two patients and pralsetinib one patient of 12, 25%), and ROS1 (entrectinib one patient of 12, 8.3%). We reviewed electronic medical records of 476 patients with AGA metastatic NSCLC. Among them, 27 patients (5.67%) developed pneumonitis of varying grades (1-3). The majority of patients, 348, had EGFR mutations."

Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR • MET • ROS1

Efficacy of RET inhibitors in the management of advanced, RET mutated, pheochromocytoma. Pooled analysis of published cases with the addition of 2 new cases. (PubMed, Endocrine) - No abstract available

Journal • Retrospective data • Oncology • Solid Tumor • RET

Activity of Bevacizumab Combined with Chemotherapy in Advanced RET-Rearranged Non-Small Cell Lung Cancer (IASLC-TTLC 2026) - "Functional studies used selpercatinib- and pralsetinib-resistant Lc2/AD-derived cell lines (BluR, LoxoR) exposed to bevacizumab ± platinum-based chemotherapy, assessing vasculogenic mimicry, 3D spheroid viability, apoptosis and migration...SRI-resistant cells exhibited VEGF-axis hyperactivation (↑VEGFA/VEGFC; ↑p-VEGFR1/2) and intrinsic vasculogenic mimicry; bevacizumab impaired mimicry dose-dependently and, combined with carboplatin/pemetrexed or carboplatin/paclitaxel, reduced viability, increased apoptosis, limited migration, and shrank viable spheroid cores (Figure C)... These findings reveal angiogenesis as a therapeutic vulnerability in RET-rearranged NSCLC and support bevacizumab plus chemotherapy as a clinically meaningful strategy where selective RET inhibitors are unavailable or after resistance, providing a compelling rationale for clinical trials testing angiogenesis inhibition in this underserved population."

IO biomarker • Metastases • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FLT1 • KDR • VEGFC

Gavreto: Newly added patent in Orange Book (Orange Book) - Expiry on Jul 7, 2042

Patent • Endocrine Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • Thyroid Gland Carcinoma

Real-World Outcomes of RET Inhibitor Switching in RET Fusion–Positive NSCLC Patients (IASLC-TTLC 2026) - "BACKGROUND The receptor tyrosine kinase RET (REarranged during Transfection) inhibitors (RETi) pralsetinib and selpercatinib are approved for metastatic RET fusion positive NSCLC. CONCLUSION Among patients who switched RETi's due to an AE, response rates exceeded 60%, aligning with the 50% response rate observed in the RET MAP registry. Collectively, these results underscore that switching from one RET inhibitor to another can be efficacious, particularly for patients who must discontinue initial therapy because of adverse events."

Clinical • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • RET

Intracranial Efficacy of Pralsetinib in Patients with RET Fusion-Positive NSCLC: ARROW Study Subanalysis (IASLC-TTLC 2026) - P1/2 | "Pralsetinib demonstrated a CNS ORR of 55%, including 5 CRs, and a median response duration of 14.8 months, supporting its clinical utility in the treatment of RET fusion-positive NSCLC with CNS involvement."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • RET

Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET-Altered Solid Tumors: Analysis of the RETgistry Global Consortium (IASLC-TTLC 2026) - "Selective RET inhibitors (SRIs) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. In RETgistry, secondary RET mutations after SRIs were uncommon, underscoring predominance of off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream MAPK and PI3K regulators were identified, with MET amplification being the most common. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies."

Clinical • Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS • MET • PI3K • RET • TP53

Intestinal Lymphangiectasia with RET Tyrosine Kinase Inhibitor Therapy (IASLC-TTLC 2026) - "Keywords. – Intestinal Lymphangiectasia: RET tyrosine kinase inhibitor; Selpercatinib; Pralsetinib; Non–Small Cell Lung Cancer; Protein-Losing Enteropathy"

Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

Molecular pathogenesis and therapeutic advances in RET fusion-positive papillary thyroid carcinoma. (PubMed, Pathol Res Pract) - "Furthermore, the review elaborates on the clinical efficacy of highly selective RET inhibitors (selpercatinib and pralsetinib), including their breakthroughs in pediatric patients and radioactive iodine-refractory cases. Primary and acquired resistance mechanisms (on-target mutations, bypass activation) and corresponding strategies (next-generation inhibitors, combination therapies) are also analyzed. By integrating recent advances in basic and clinical research, this review provides a comprehensive reference for the precision diagnosis and treatment, mechanistic investigation, and drug development for RET fusion-positive PTC."

Journal • Review • Oncology • Pediatrics • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CCDC6 • NCOA4 • RET

A Real-world Study of Pralsetinib Combined With Leucogen in the Treatment of RET Fusion-positive NSCLC (clinicaltrials.gov) - P=N/A | N=25 | Not yet recruiting | Sponsor: Fudan University

New trial • Real-world evidence • Lung Adenocarcinoma • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET

RET Fusion-Positive Lung Adenocarcinoma: Partner-Specific Clinicopathological Characteristics, Co-Mutation Profiles, and Implications for Targeted and Immunotherapy. (PubMed, Lung Cancer) - "RET fusion-positive LUAD comprises biologically heterogeneous subsets defined by fusion partners. KIF5B-RET tend to occur at earlier stages, whereas non-KIF5B are more frequently associated with CDKN2A co-mutations and may derive greater benefit from selective RET inhibition. Immunochemotherapy demonstrates comparable efficacy regardless of fusion partner, highlighting the need for partner-specific therapeutic strategies in RET fusion-positive LUAD."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • CDKN2A • KIF5B • NCOA4 • RET • TP53

Design, synthesis, and activity evaluation of RET protein degradation based on PROTAC and HyTTD techniques. (PubMed, Bioorg Med Chem Lett) - "Although selective RET inhibitors such as selpercatinib and pralsetinib have been clinically approved, the emergence of resistance mutations limits their durable efficacy, underscoring the need for novel therapeutic modalities. We report the design and synthesis of the first RET-targeting HyTTD, compound B2, which achieves 91.4% degradation of CCDC6-RET fusion protein in TPC-1 cells at 10 μM within 48 h. These results not only validate hydrophobic tag tethering as a feasible strategy for RET degradation but also propose a new therapeutic direction for RET-driven cancers."

Journal • Oncology • Targeted Protein Degradation • CCDC6 • RET