Retevmo (selpercatinib)

The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

Multikinase inhibitors (MKIs) with nonselective RET inhibition like Vandetanib and Cabozantinib were approved for the treatment of MTC, although the efficacy is limited due to the lack of specificity resulting in a higher rate of drug-related adverse events, leading to subsequent dose reductions, or discontinuation, and the development of a resistance mechanism like seen on the RET Val804 gatekeeper mutations. MTC is associated with mutations in the RET protooncogene, and new highly selective RET inhibitors have been developed including Selpercatinib and Pralsetinib, drugs that have demonstrate excellent results in clinical trials, and efficacy even in the presence of gatekeeper mutations. However, despite their efficacy and great tolerability, mechanisms of resistance have been described, such as the RET solvent front mutations. Due to this, the need of constant evolution and drug research is necessary to overcome the emergence of resistance mechanisms.

These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition.

We identified molecular alterations and immune-related features that distinguish wtRET from mutRET MTC. While RET mutation drives MTC in the absence of other alterations, we showed that wtRET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with oncology immune-oncology agents for selected patients with wtRET MTC.

We report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.

In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.

After 4 cycles of chemotherapy, the patient was transitioned to a clinical trial using selpercatinib, a RET inhibitor, as maintenance therapy...Proposed mechanisms of resistance include intrinsic resistance of the nuclear receptor co-activator 4-RET fusion to RET inhibition, the RET fusion representing a passenger alteration to another tumorigenic driver pathway and/or decreased efficacy of RET inhibition after platinum-based chemotherapy. Our patient's clinical course highlights the fact that "actionable" genomic alterations do not always equate to patient benefit.

In our case report, after pralsetinib dose reduction due to pulmonary toxicity, the therapeutic switch to selpercatinib allowed the patient to receive a full-dose treatment, eventually restoring disease control. Our case report and a few literature data suggest that switching from pralsetinib to selpercatinib may represent a therapeutic opportunity, especially for patients with brain metastases.

No abstract available

Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells...The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.

Perioperative immunotherapy is becoming the dominant treatment paradigm for resectable NSCLC, while increasing use of targeted drugs for actionable alterations necessitates upfront molecular profiling of early tumors for patient selection.

P3, N=170, Recruiting, Loxo Oncology, Inc. | Trial completion date: Nov 2032 --> Aug 2032 | Trial primary completion date: Aug 2028 --> May 2027

P2, N=248, Active, not recruiting, AstraZeneca | Trial completion date: Nov 2025 --> May 2025 | Trial primary completion date: Nov 2025 --> May 2025

As first in-label selective RET-Inhibitor, Selpercatinib showed promising efficacy in advanced MTC (first line) with RET mutations and rrDTC (second line) with RET fusions along with fewer side effects. Changes and new approaches for the treatment of ATC have been summarised in the current ATA guidelines.

More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. This year we celebrate the 30th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.

The associated incremental total and PMPM costs (Medicare) were estimated to be: $4,447,832 and $0.371 (Y1), $11,076,422 and $0.923 (Y2), and $12,637,458 and $1.053 (Y3), respectively. One-way sensitivity analyses across both perspectives identified drug costs, selpercatinib market share, incidence of RET, and treatment duration as significant drivers of incremental costs. Three-year incremental PMPM cost estimates suggest modest impact on payer-budgets associated with introduction of tumor-agnostic selpercatinib treatment.

© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma...Radioactive iodine treatment after surgery improves overall survival in patients at high risk of recurrence. Antiangiogenic multikinase inhibitors and targeted therapies to genetic mutations that give rise to thyroid cancer are increasingly used in the treatment of metastatic disease.

Of four patients with PD-L1 overexpression (>50%) one received pembrolizumab and the other three patients received pemetrexed, carboplatin, and pembrolizumab or camrelizumab. Fifteen patients received selective RET inhibitors (pralsetinib and selpercatinib), resulting in an ORR of 53.3% (8/15) and median PFS of 10.0 months (95% CI 5.2-14.9). ICIs for PD-L overexpression and treatment naive patients offer comparable benefits for RET fusion-positive NSCLC, warranting further investigation.

No abstract available

No abstract available

Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.

P1/2, N=875, Recruiting, Loxo Oncology, Inc. | Trial completion date: Sep 2024 --> Feb 2026 | Trial primary completion date: Mar 2024 --> Feb 2025

P1/2, N=50, Recruiting, Loxo Oncology, Inc. | Trial completion date: Jan 2025 --> May 2029 | Trial primary completion date: Aug 2024 --> Dec 2024

Following the modest success of repurposed RET-active multikinase inhibitors, the first selective RET inhibitors (SRIs), selpercatinib and pralsetinib, received regulatory approval in 2020. The ideal next-generation SRIs will be active against on-target acquired resistance alterations, including those that emerge in the CNS, and will have improved safety and tolerability relative to first-generation SRIs. In this review, we will provide an update on these candidates and their potential to meet the unmet clinical need for patients who progress on first-generation SRIs.

P4, N=200, Recruiting, Fudan University

P1, N=32, Completed, Eli Lilly and Company | Recruiting --> Completed

P2, N=49, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

The US Food and Drug Administration (FDA) approval of the selective RET inhibitors selpercatinib and pralsetinib has led to a paradigm change in the treatment of RET-altered lung and thyroid cancers through a higher response rate and a more tolerable safety and toxicity profile than multi-kinase inhibitors. Given the anticipated increase in the use of both drugs across multiple tumor types, it is crucial to recognize the possible side effects and approaches for their optimal management in order to maximize the clinical benefit for treated patients. In this review, we underscore potential toxicities associated with selective RET inhibitors and discuss strategies to mitigate them.

There are currently two selective RET tyrosine kinase inhibitors, pralsetinib and selpercatinib. Our narrative review aims to discuss the available clinical evidence on pralsetinib efficacy, particularly on brain metastases, and tolerability profile. In addition, our work explores the relevance of detecting RET fusions upfront in the disease history of patients with NSCLC.

After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China's clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians.

Small cell transformation was one mechanism by which EGFR-mutation NSCLC acquired resistance after tyrosine kinase inhibitors (TKIs) treatment. In addition, the APOBEC family of cytidine deaminases appeared amplification. Although RET rearrangement still existed, using another RET TKIs was ineffective, and etoposide plus platinum might be an effective rescue treatment.

Selpercatinib continued to demonstrate durable antitumor activity and tolerable safety in pts with RET fusion+ cancers across multiple tumor types and fusion partners, including difficult-to-treat GI cancers with poor results in standard-of-care options, such as pancreatic and colorectal. These results emphasize the importance of comprehensive genomic profiling across all tumor types in order to identify actionable oncogenic drivers, including RET fusions. Clinical trial information: NCT03157128.

No abstract available

Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.).

P2, N=250, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.

Amplification of wild-type RET represents a novel, targetable molecular subset of cancer.

This assay was co-validated with the quantification for brigatinib, lorlatinib, pralsetinib and selpercatinib. The method was validated over a linear range of 80-4000 ng/mL for adagrasib and 25-2500 ng/mL for sotorasib. The assay is therefore well-equipped for determining plasma concentrations in clinical practice.

Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.