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

Efficacy and Safety of Pralsetinib in Patients With Advanced Ret Fusion-Positive NSCLC: Phase 1/2 ARROW Study Final Data (IASLC-WCLC 2025) - P1/2 | "No new safety signals were identified with this update. Conclusions : 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."

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

Pralsetinib (Phase 1/2 ARROW Trial) Compared With Best Available Therapy (External Control) in Pretreated RET Fusion+ NSCLC (IASLC-WCLC 2025) - P1/2 | "Most frequently received BAT were tyrosine kinase inhibitors (66.7%; 29.6% investigational agents, 25.9% cabozantinib, 7.4% vandetanib, 3.7% alectinib) and chemotherapy (25.9%)...Conclusions : This RW, multi-center study found that 2L+ treatment with pralsetinib in advanced RET fusion-positive NSCLC was associated with higher ORR and significantly improved OS and PFS compared to BAT, even after adjusting for population differences. Limitations of RW data include missing data and potential unmeasured confounding, which this study aimed to mitigate through rigorous analytical methods."

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • 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

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

Rigel Reports Second Quarter 2025 Financial Results and Provides Business Update (Rigel Press Release) - "For the second quarter ended June 30, 2025, total revenues were $101.7 million, consisting of $58.9 million in net product sales and $42.7 million in contract revenues from collaborations. Net product sales grew 76% compared to $33.5 million in the same period of 2024....GAVRETO net product sales were $11.8 million compared to $1.9 million in the same period of 2024. GAVRETO became commercially available from Rigel in late June 2024."

Sales • Non Small Cell Lung Cancer • Thyroid Gland 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

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

Multiple ctDNA- based biomarkers predict benefit from selective RET Inhibition in non-small cell lung cancer patients: exploratory analysis of a prospective study. (PubMed, Biomark Res) - P1/2 | "Selective RET inhibitors such as pralsetinib have become the standard of care for patients with RET fusion-positive non-small cell lung cancer (NSCLC)...These findings suggest that ctDNA-based surveillance using multiple metrics, enables early forecasting of tumor response and progression in RET fusion-positive NSCLC. Early ctDNA clearance and dynamic profiles provide non-invasive biomarkers for early intervention, warranting further validation with ctDNA-guided strategies."

Biomarker • Circulating tumor DNA • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PIK3CA • RET

CStone Announces NMPA Approval for Localized Manufacturing of GAVRETO (pralsetinib) in China (CStone Pharma Press Release) - "CStone Pharmaceuticals...announced that the National Medical Products Administration (NMPA) of China has approved the manufacturing localization application for GAVRETO (pralsetinib, 100mg). Commencing in 2026, supply for the Chinese market will transition gradually from imported to locally manufactured product."

Commercial • Non Small Cell Lung Cancer • Thyroid Gland Medullary Carcinoma

Effective treatment of non-fusion RET intragenic deletion lung adenocarcinoma with pralsetinib: a case report. (PubMed, Front Med (Lausanne)) - "The patient achieved a partial response to pemetrexed and platinum-based chemotherapy, but disease progression occurred 9 months later. Based on this finding, the patient was treated with pralsetinib and achieved radiological tumor regression, with a progression-free survival of 5 months to date. This case highlights a potential therapeutic role for RET inhibitors even in the absence of canonical fusions, and underscores the importance of reassessing the tumor's molecular profile following treatment failure, as acquired genomic alterations may provide new targets for precision therapy."

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

A Prospective Cohort Study of Pralsetinib or Anlotinib in the Treatment of Locally Advanced and/or Metastatic Medullary Thyroid Carcinoma With RET Gene Mutations (clinicaltrials.gov) - P=N/A | N=40 | Not yet recruiting | Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences

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

Case Report: Successful late-line pralsetinib treatment in an ALK-rearranged lung adenocarcinoma patient with KIF5B-RET fusion resistant to alectinib. (PubMed, Front Genet) - "This case highlights KIF5B-RET fusion as a potential resistance mechanism post alectinib treatment and suggested = pralsetinib, a RET inhibitor, as a viable therapeutic option in this context. These findings contribute to the evolving understanding of resistance management strategies in ALK-rearranged NSCLC."

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

Dynamic risk stratification-guided management of medullary thyroid carcinoma: integrating surgical precision with RET-targeted therapies and molecular surveillance. (PubMed, Int J Surg) - "Multi-kinase inhibitors (e.g. vandetanib and cabozantinib) have shown increased survival outcomes for metastatic MTCs and are approved as effective treatment options. More recently, selective RET inhibitors like selpercatinib and pralsetinib have demonstrated higher efficacy and better tolerability. Despite these advances, challenges persist in managing MTCs, including addressing biochemical recurrence, determining surgical scope, considering immunotherapy, and treating advanced cases. Personalized medicine approaches, incorporating genetic screening, and innovative therapies, are essential for improving survival and quality of life in MTC patients."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Medullary Carcinoma • CEACAM5

Beyond Transposons: TIGD1 as a Pan-Cancer Biomarker and Immune Modulator. (PubMed, Genes (Basel)) - "Furthermore, high TIGD1 expression was linked to resistance to several therapeutic agents, including Zoledronate, Dasatinib, and BLU-667. TIGD1 may serve as a promising diagnostic and prognostic biomarker, particularly in colon, gastric, liver, and lung cancers. Its strong associations with immune modulation and therapy resistance highlight its potential as a novel target for precision oncology and immunotherapeutic intervention."

Biomarker • IO biomarker • Journal • Pan tumor • Tumor mutational burden • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Immune Modulation • Immunology • Lung Cancer • Microsatellite Instability • Oncology • Solid Tumor

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