Gavreto (pralsetinib) / Blueprint Medicines, CStone Pharma, Allist, Rigel - LARVOL DELTA

Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma. (PubMed, bioRxiv) - "The tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapies for RET+ lung cancers and have markedly improved clinical outcomes in these patients, but acquired resistance remains a hurdle to their durable management. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 78% of TR.1 tumors and a prolonged duration of response in TR.2 tumors. The findings highlight the failings inherent in treating acquired resistance mechanisms at progression and the potential therapeutic impact of predicting and targeting dominant mechanisms of resistance prior to or early after initiating oncogene-targeting TKI treatment in RTK-driven LUAD."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Transplantation • ERBB4 • GAB1 • HER-2 • NRG1 • NRP1 • PTPN11 • RET • TRIM24

Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy. (PubMed, RSC Med Chem) - "RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Among three compounds (HSN748, HSND19, and HSN608) evaluated for B/KR(G810C) brain tumors, HSN748 exhibited significant intracranial tumor inhibition. PK analysis indicated that HSN748 has a brain/plasma partition coefficient (K p) of 0.4, demonstrating its capability to penetrate the central nervous system (CNS)."

Journal • Brain Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCDC6 • KIF5B • RET

Genotype-Driven Neoadjuvant Therapy for Locally Advanced Thyroid Cancer: A Real-World Cohort Study (clinicaltrials.gov) - P4 | N=335 | Not yet recruiting | Sponsor: Fujian Medical University

IO biomarker • New P4 trial • Real-world evidence • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma

Chylopericardium and chylous effusions during treatment with selective RET inhibitors, selpercatinib and pralsetinib, in non-small cell lung cancer (NSCLC). (ASCO 2025) - "We identified chylous effusion as an AE following RETi exposure in 12% of pts in our cohort, including 2 cases of chylopericardium. These adverse events can occur with either selpercatinib or pralsetinib, and making a differential diagnosis, including ruling out disease progression, is crucial for effective management."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KIF5B • RET

Efficacy and safety of pralsetinib in RET fusion-positive solid tumors: Final data from the ARROW trial. (ASCO 2025) - P1/2 | "In the phase 2 portion of this trial, responses were observed in many tumor types (Table). Pralsetinib demonstrated robust and durable anti-tumor activity with an ORR of 46.4%. These data validate RET fusions as a tissue-agnostic target with sensitivity to RET inhibition and activity beyond NSCLC and thyroid cancer, further supporting the promising potential of pralsetinib to address the unmet medical need in these patients."

Clinical • Anemia • Endocrine Cancer • Hypertension • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thyroid Gland Carcinoma • RET

Picking needles in a haystack: Exploring rare variants of a pan-cancer target in the RET landscape from 229,453 adult cancer patients. (ASCO 2025) - "RET alterations, including mutations and fusions, are relatively rare events, however, potent and selective RET inhibitors such as selpercatinib and pralsetinib have demonstrated remarkable efficacy and changed clinical practice in RET-driven NSCLC, thyroid cancer and other cancers. RET fusions are rare events across cancers; however, most are characterized as oncogenic. RET missense mutations occur in 2.4% of malignancies, and while most RET missense variants are described as variants of uncertain significance, oncogenic RET variants are diverse, occurring across codons. We confirm multiple documented oncogenic drivers of on-target resistance, and their distinct and diverse mechanisms underline the urgent need to develop next generation RET inhibitors."

Clinical • Pan tumor • Brain Cancer • Colorectal Cancer • Endocrine Cancer • Endometrial Cancer • Glioma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • CCDC6 • KIF5B • NCOA4 • RET

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

Rechallenge with first-generation RET inhibitors in RET-rearranged NSCLC pre-treated with selpercatinib or pralsetinib: Results from the RET MAP registry. (ASCO 2025) - "Rechallenge a different RETi of the same class is effective after initial discontinuation due to toxicity, though recurrent toxicity may occur in one-third of patients. In contrast, RETi rechallenge after progression demonstrates limited efficacy, primarily in selected cases treated with combination therapies."

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

Matching-adjusted indirect comparison of selpercatinib and pralsetinib in RET fusion-positive non-small cell lung cancer. (PubMed, Future Oncol) - "Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 39.3% and 62.6% of patients, with discontinuations due to TRAEs in 3.6% and 10.0% of patients, respectively. Outcomes were similar; however, PFS was significantly prolonged with selpercatinib, with fewer grade ≥ 3 TRAEs."

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

RET fusion driven (RETfus+) non-small cell lung cancer: a comprehensive genomic profiling study with histologic correlation. (PubMed, Front Oncol) - "RET fusions have also been well-described as acquired resistance mutations in cases of EGFR-driven NSCLC treated with anti-EGFR tyrosine kinase inhibitors including erlotinib and osimertinib. RETfus+ NSCLC features a unique genomic signature which can further impact therapy selection. With recent expanded approval of more specific RET kinase targeting inhibitors (selpercatinib and Pralsetinib) in the pan-cancer treatment setting, further study of RETfusion+ NSCLC histology and genomic/biomarker status appears warranted."

IO biomarker • Journal • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • BRCA1 • FGFR1 • KEAP1 • KMT2D • KRAS • NF1 • NSD3 • PD-L1 • PIK3CA • RB1 • RET • SETD2 • TMB • TP53

ASCO Poster Presentations:…Title: Efficacy and Safety of Pralsetinib in RET Fusion-positive Solid Tumors: Final Data from the ARROW Trial (PRNewswire) - P1/2 | N=589 | ARROW (NCT03037385) | Sponsor: Hoffmann-La Roche | "Final results from the Phase 2 portion of ARROW in patients with RET fusion-positive solid tumors other than NSCLC and thyroid cancer showed an ORR of 46.4% (13/28), including an ORR for pancreatic cancer of 100% (5/5). Overall, 10.7% (3/28) achieved complete response (pancreatic cancer, n=2; cancer of unknown primary, n=1) and 35.7% (10/28) achieved partial response. Median PFS was 7 months and median DOR was 11.1 months. Median OS was 10.3 months. Pralsetinib demonstrated robust and durable anti-tumor activity, with responses observed in many tumor types."

P2 data • Non Small Cell Lung Cancer

AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors. (PubMed, J Exp Clin Cancer Res) - "This study elucidates EGFR's role in mediating resistance to RET inhibitors in NSCLC patients. These findings offer insights into therapeutic adaptation and explore personalized combinations of RET and EGFR inhibitors for improved clinical outcomes."

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

ASCO Poster Presentations:…Title: Efficacy and Safety of Pralsetinib in Patients with Advanced RET-fusion-positive NSCLC: Final Data from the Phase 1/2 ARROW Study (PRNewswire) - P1/2 | N=589 | ARROW (NCT03037385) | Sponsor: Hoffmann-La Roche | "Final top-line efficacy and safety in RET fusion-positive NSCLC patients produced clinically meaningful and durable responses regardless of prior therapies, with a manageable safety profile. These results support the findings in previously published results, with a longer follow up period. Overall response rate (ORR) was 70.3% and median duration of response (DOR) was 19.1 months in the measurable disease population (n=259). In the efficacy population (n=281), median overall survival (OS) was 44.3 months with median follow up of 47.6 months. Median progression-free survival (PFS) was 13.1 months overall but was longer in the United States (25.9 months) vs. Asia (12.6 months) or Europe (12.9 months)."

P1/2 data • Non Small Cell Lung Cancer

Efficacy and safety of RET-kinase inhibitors in RET-altered thyroid cancers: a systematic review and single-arm meta-analysis. (PubMed, Endocr Relat Cancer) - "Some important grade ≥3 adverse events were hypertension (16%; 95% CI, 11-22; I2 = 43%), diarrhea (3%; 95% CI, 2-5; I2 = 0), increased ALT (11%; 95% CI, 8-14; I2 = 0) and increased AST (6%; 95% CI, 4-10; I2 = 0). In conclusion, these findings suggest that selpercatinib and pralsetinib are efficacious and safe for use in patients with RET-altered thyroid cancer."

Journal • Retrospective data • Cardiovascular • Endocrine Cancer • Hypertension • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • RET

Rigel Reports First Quarter 2025 Financial Results and Provides Business Update (Rigel Press Release) - "For the first quarter ended March 31, 2025, total revenues were $53.3 million, consisting of $43.6 million in net product sales and $9.8 million in contract revenues from collaborations. Net product sales grew 68% compared to $26.0 million in the same period of 2024....GAVRETO net product sales were $9.0 million. GAVRETO became commercially available from Rigel in June 2024. REZLIDHIA net product sales were $6.1 million, growth of 25% compared to $4.9 million in the same period of 2024."

Sales • Acute Myelogenous Leukemia • Non Small Cell Lung Cancer • Thyroid Gland Carcinoma

Previous use of chemotherapy or multikinase inhibitor decreases efficacy of Pralsetinib in RET fusion-positive non-small-cell lung cancer (ESTRO 2025) - "Pralsetinib was effective in RET fusion-positive NSCLC with tolerable AEs in real-world practice. Efficacy of pralsetinib was decreased in patients previously treated with PBC or MKIs."

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

Post-marketing safety of pralsetinib: a real-world disproportionality analysis based on the FDA adverse event reporting system database. (PubMed, Int J Clin Pharm) - "Our study identified some known and new significant AE signals associated with pralsetinib, emphasizing the importance of continued pharmacovigilance. While the findings provide valuable insights for clinical practice, further validation through large-scale prospective studies is needed."

Adverse events • Journal • P4 data • Real-world evidence • Cardiovascular • Constipation • Endocrine Cancer • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hypertension • Infectious Disease • Lung Cancer • Myocardial Infarction • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thyroid Gland Carcinoma • Tuberculosis • 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

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

Monotherapy vs combination therapy evaluation of FDA-approved TKIs targeting PDGFR for the treatment of thyroid cancer. (PubMed, J Biomol Struct Dyn) - "On 4th May, 2018, a combination of Dabrafenib and Trametinib/Dab-Tra has been approved by US FDA for the treatment of anaplastic thyroid cancer (ATC) that highlights the importance of combination therapy in its treatment...We found that the best combination amongst all is of Pralsetinib and Trametinib/Pra-Tra with a docking score of -14.47 kcal/mol...We also found that a combinatorial approach with TKIs could prove to be better than monotherapy. Further in-vitro and in-vivo studies are required to strengthen the results obtained through in-silico experiment."

FDA event • Journal • Monotherapy • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • PDGFRA

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

Pathologic complete response to pralsetinib in stage IV RET-positive non-small cell lung cancer: A case report. (PubMed, Respir Med Case Rep) - "This case highlighted potential application of Pralsetinib in locally advanced RET-positive NSCLC to prime surgical resection. Postoperative Pralsetinib adjuvant therapy should also be considered."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • 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