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

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

Chylopericardium and chylous effusions during treatment with selective RET inhibitors, selpercatinib and pralsetinib, in non-small cell lung cancer (NSCLC). (ASCO 2025) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

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

Efficacy and safety of pralsetinib in RET fusion-positive solid tumors: Final data from the ARROW trial. (ASCO 2025) - P1/2 | "Clinical Trial Registration Number: NCT03037385 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Oncology • 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) - "The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

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

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 | "Clinical Trial Registration Number: NCT03037385 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

Clinical • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RET

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

Re-challenging pralsetinib following recovery from pneumocystis jirovecii pneumonia in a lung cancer patient: a Case Report. (PubMed, Front Pharmacol) - "The patient's condition was effectively treated with a combination of oral trimethoprim/sulfamethoxazole and intravenous caspofungin along with clindamycin. Prompt identification and timely intervention are essential to achieve better outcomes in patients with pralsetinib-induced PJP. Furthermore, it highlights the scenario where patients who have fully recovered from moderate-to-severe pralsetinib-induced PJP may undergo pralsetinib re-administration without requiring alternative treatment options."

Journal • Infectious Disease • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • KIF5B • RET

Fourth Quarter and Full Year 2024 Financial Update (PRNewswire) - "For the fourth quarter ended December 31, 2024, total revenues were $57.6 million, consisting of...$8.1 million in GAVRETO net product sales, and $11.1 million in contract revenue from collaborations....GAVRETO became commercially available from Rigel in June 2024....For the full year 2024, total revenues were $179.3 million, consisting of...$17.1 million in GAVRETO net product sales."

Sales • Non Small Cell Lung Cancer • Thyroid Gland 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

Comprehensive Analysis of APOBEC-Driven Mutagenesis in NSCLC Indicates Its Role in Resistance Beyond EGFR and ALK (IASLC-TTLC 2025) - "Of those, 9 patients were treated with targeted therapy: 6 patients were treated with EGFR TKI(s) for EGFR exon 19 deletions (osimertinib, 3; osimertinib/gefitinib combo, 2; or erlotinib, 1), one patient with lorlatinib for EML4::ALK fusion, one patient with selpercatinib for KIF5B::RET fusion and one patient with glesatinib for METex14 mutation.Putative resistance mechanisms were identified in 6/9 cases with acquired APOBEC mutagenesis: two cases of squamous cell transformation, one RET p.G810S in KIF5B::RET-positive NSCLC, one HRAS p.A59T in a case with EML4::ALK, one MET p.H1094Y occurring in an APOBEC-preferred trinucleotide context in a NSCLC with METex14, and a case of EGFR-mutant NSCLC that developed KRAS p.G12A and RAF1 p.S257L, the latter occurring in an APOBEC-preferred context. In one case, a tumor with KIF5B::RET and high APOBEC-MB at presentation developed APOBEC-attributable resistance mutation RET p.L730V upon progression on pralsetinib... APOBEC..."

Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • APOB • BRAF • EGFR • EML4 • HER-2 • HRAS • KIF5B • KRAS • MET • NTRK1 • NTRK2 • NTRK3 • RET • ROS1 • TMB

Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report. (PubMed, Oncotarget) - "Combination therapy targeting RET and ROS1 using pralsetinib and lorlatinib achieved a partial response with limited durability of only four months. This is the first reported case of a RET fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel RET fusion partner, and it emphasizes the importance of testing for acquired resistance mutations with both DNA and RNA at the time of progression in patients with targetable oncogenic drivers."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • RET • ROS1

Two patients suffering from NSCLC with a novel rearrangement mutation in RET (exon2-11del) and their response to pralsetinib as salvage treatment. (PubMed, Lung Cancer) - No abstract available

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

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 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion • 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

Previous treatment decreases efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer. (PubMed, Front Med (Lausanne)) - "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, immunotherapy, or MKIs."

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

Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R). (PubMed, Eur J Med Chem) - "Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. It also induces apoptosis and cell cycle arrest in a dose-dependent manner in BaF3 cells harboring CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R fusions. More significantly, CQ1373 exhibits promising in vivo anti-tumor efficacy in a CCDC6-RET-G810R mice xenograft model, highlighting its potentials for RET-driven cancers treatment."

Journal • Oncology • CCDC6

Real-World Outcomes of Pralsetinib in RET Fusion-Positive NSCLC. (PubMed, JTO Clin Res Rep) - "In this extensive real-world cohort of patients with advanced or metastatic NSCLC harboring RET fusions, we highlight the antitumor efficacy of pralsetinib, particularly when administered in later treatment lines. We also observe the aggressive nature of disease progression, frequent utilization of chemotherapy and antiangiogenic agents as initial subsequent therapies, and limited insight into resistance mechanisms due to infrequent rebiopsy and genomic profiling at progression."

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

Rearranged during transfection (RET) lung cancer - Update on targeted therapies. (PubMed, Lung Cancer) - "While multikinase inhibitors (MKIs) faced limitations in efficacy and tolerability, the introduction of selective RET inhibitors (SRIs) such as selpercatininb and pralsetinib has transformed patient outcomes, resulting in deep and durable responses. Ongoing clinical trials are exploring their potential benefits in the neoadjuvant and adjuvant setting. Early phase clinical trials endeavor to demonstrate next-generation selective RET inhibitors can effectively overcome SRI resistance mechanisms, offer improved safety profiles, and enhance patient outcomes."

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

RET-AREAL: a multi-center, real-world data analysis on the efficacy of pralsetinib in acquired RET fusion after resistance to EGFR/ALK-TKIs. (PubMed, Cancer Lett) - "Notably, patients with c-RET had a better prognosis than those with s-RET (median TTF: NR versus 5.67 months, P=0.037, median OS: NR versus 9.83 months, P=0.047). In conclusion, pralsetinib-based therapy may be a potential strategy to overcome acquired RET fusion after resistance to EGFR/ALK-TKIs."

Journal • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • CCDC6 • EGFR • KIF5B • RET

Rigel Provides Business Update and 2025 Outlook (PRNewswire) - "Rigel expects to report fourth quarter net product sales of $46.5 million, compared to $29.5 million for the same period of 2023, including: TAVALISSE (fostamatinib disodium hexahydrate) net product sales of $31.0 million compared to $25.7 million for the same period of 2023; REZLIDHIA (olutasidenib) net product sales of $7.4 million compared to $3.9 million for the same period of 2023; GAVRETO (pralsetinib) net product sales of $8.1 million. GAVRETO became commercially available from Rigel in June 2024."

Sales • Acute Myelogenous Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia