Gavreto (pralsetinib)

Using two mouse studies modeling multi-organ metastases and breast tumor formation in the brain, we observed that RET inhibition significantly prevented the circulating tumor cells from forming brain metastases and suppressed the growth of intracranially implanted tumor cells. Together, our findings demonstrated that RET functions as a novel mediator of BCBM and that RET inhibitors showed promising efficacy for BCBM.

The observation is hypothesis-generating rather than proof of sensitivity. This case provides a reference for precision treatment strategies after resistance to RET inhibitors.

Pralsetinib and selpercatinib are novel, highly selective RET tyrosine kinase inhibitors (RET-TKIs). Given the low prevalence of RET gene alterations (＜5%), which are regarded as rare genetic mutations, clinical experience in the use pf RET-TKIs and and patient management remains limited. Base on the current status of adverse event management of RET-TKIs in China, and integrating the latest international evidence and clinical experience, the Chinese Medical Doctor Association Tumor Multidisciplinary Diagnosis and Treatment Professional Committee and the Shenzhen Medical Doctor Association Tumor Multidisciplinary Diagnosis and Treatment Professional Committee organized discussion among experts from medical oncology, respiratory medicine, radiation oncology, thoracic surgery, and other related disciplines to formulate this expert consensus on the management of adverse events of RET-TKIs.

RET signaling promotes metastatic phenotypes in vitro, all of which are suppressed by Pralsetinib, a potent RET-selective inhibitor...Proteomic profiling reveals novel GDNF-mediated signaling interactions, including PLCγ, P70S6K, STAT3, and CREB. These findings identify RET as a targetable driver of BrM from ER + BC and support therapeutic targeting of RET in affected patients.

Our results demonstrate that the enhanced colony formation caused by the distinct ANKRD261-1405-RET713-1114 pathomechanism was fully suppressible by RXDX-105/agerafenib and BLU-667/pralsetinib treatments but the increased cell proliferation responded merely moderately. This may suggest that the ANKRD261-1405-RET713-1114-intrinsic pathomechanisms may not be solely brought about by aberrant RET kinase activity but that putative therapeutic interventions may additionally need to focus on ANKRD26 dysfunctions.

Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors...Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.

RET fusions represent a rare mechanism of acquired resistance in EGFR-mutant NSCLC. Combined RET and EGFR inhibition may offer clinical benefit, particularly in patients with co-occurring alterations. Personalized ddPCR-based liquid biopsy is a promising tool for real-time, non-invasive monitoring of treatment response and resistance evolution.

P4, N=25, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

Early multi-kinase inhibitors such as vandetanib and cabozantinib demonstrated modest efficacy with significant toxicity, whereas the selective RET inhibitors selpercatinib and pralsetinib have achieved improved response rates and tolerability...Nonetheless, resistance, driven by secondary mutations and bypass signaling, presents a major therapeutic challenge. Ongoing development of next-generation inhibitors and combination strategies aims to overcome resistance and improve patient outcomes.

Drug-induced IL occurs with selpercatinib or pralsetinib treatment. The frequency increases with longer drug exposure. Serial monitoring is essential and when necessary, dose modification. Most cases do not lead to treatment discontinuation.

P2, N=920, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 7 of 9 TR.1 tumors and both deepened and prolonged the duration of response in TR.2 tumors. The findings provide new insight into mechanisms of acquired resistance through bypass signaling and highlight the therapeutic benefit of simultaneous upfront blockade of driver oncogenes and dominant resistance mechanisms in LUAD.