RET positive

In RET-negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).

Case Presentation and We report two cases with RAI-resistant lung metastases treated with larotrectinib: 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation)...In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.

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.

The recently published results of LIBRETTO-4311 pave the way for a new standard of care in the first-line setting for RET-fusion-positive NSCLCs, which raises important clinical questions not only in the therapeutic landscape of advanced NSCLC but also in the drug development process in the era of uncommon molecular subtypes.

Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Higher exposure was also associated with an increased risk of grade ≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400 mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.

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.

These data suggest that RET fusions represent a negative prognostic factor in patients with metastatic solid tumors and highlight the need for wider genomic testing and use of RET-specific TKIs that could improve patient outcomes. Our study also highlights the value of real-world data when studying rare cancers or cancers with rare genomic alterations.

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Multivariate logistic regression analysis identified ddCq and ΔCq as significant predictors of DNA and RNA NGS success rates, respectively. Quality assessment of nucleic acid extracted from archival tissue samples is important for achieving high NGS success rates in clinical practice, especially for samples ≥3 years old.

Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1-2% among all NSCLC), we illustrate how QBA can be applied to external control arms. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several 'tipping-point' scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided.

This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.

In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer.

P=N/A, N=70, Recruiting, Hunan Province Tumor Hospital | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

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.

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.).

In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer.

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Opportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.

The recorded side effects were expected in patients receiving this type of medicine. Clinical Trial Registration: NCT03037385 (ARROW) (ClinicalTrials.gov).

The 2-, 5-, 10-year disease-specific survival rates were 99%, 96%, and 95%, respectively. RET fusion-positive carcinomas were associated with high invasiveness and metastatic activity, but probably due to intensive treatment with low patient mortality.

P3, N=261, Active, not recruiting, Loxo Oncology, Inc. | Completed --> Active, not recruiting | Trial completion date: May 2023 --> Jun 2026

P3, N=291, Active, not recruiting, Loxo Oncology, Inc. | Completed --> Active, not recruiting | Trial completion date: May 2023 --> Feb 2026

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P3, N=291, Completed, Loxo Oncology, Inc. | Active, not recruiting --> Completed | Trial completion date: Nov 2026 --> May 2023

P3, N=261, Completed, Loxo Oncology, Inc. | Active, not recruiting --> Completed | Trial completion date: Feb 2026 --> May 2023

In separate trials, the RET inhibitor selpercatinib showed superiority over standard of care in RET-mutated medullary thyroid cancer and in RET fusion-positive non-small cell lung cancer-although researchers say more follow-up is needed. The findings highlight the importance of tumor sequencing.

Based on current pricing, neither PRL as first-line nor second-line therapy was found to be cost-effective for patients with RET fusion-positive advanced NSCLC compared to chemotherapy. Reserving PRL until second-line therapy may be a compromise approach to maintaining control over healthcare expenses yet still achieving favorable clinical outcomes.

Conclusions PRO data were consistent with the favorable efficacy of selpercatinib compared with platinum-based chemotherapy +/- pembro. Selpercatinib significantly delayed TTCD of pulmonary symptoms and physical function and was well-tolerated in these patient populations.

It also raises the prospect of repositioning pralsetinib to target wildtype RET in ER-positive breast cancer. See related article by Gou et al., p. 3237.

Clinical trials are currently underway to determine the optimal sequencing of selpercatinib in RET fusion-positive lung and RET-mutated medullary thyroid cancer in the first-line setting compared to the current standard of care. Selpercatinib has shown promising anti-tumor activity in various RET-altered solid tumors opening a new treatment option for these patients.

To the best of our knowledge, we are the first to report, that a switch of RET Inhibitor selpercatinib to pralsetinib doesn’t prevent chylous effusions to reoccur. The underlying pathomechanism is currently unknown.

The 2-, 5-, 10-year disease-specific survival rates were 99%, 96%, and 95%, respectively. RET fusion-positive carcinomas were associated with high invasiveness and metastatic activity, but probably due to intensive treatment with low patient mortality.

Methods LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing first-line selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. LIBRETTO-431 is the first randomized study to demonstrate superior PFS with a targeted therapy vs chemotherapy + a checkpoint inhibitor in a biomarker selected patient population. These data support comprehensive genomic testing at diagnosis and treatment with first-line selpercatinib in patients with advanced RET+ NSCLC.

Selpercatinib increases RAI avidity in adolescents with metastatic RET fusion‐positive PTC. Further investigations into the use of targeted therapies prior to RAI therapy or to resensitize patients to RAI therapy in patients with metastatic fusion positive PTC are warranted.