Gavreto (pralsetinib)

P3, N=223, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Jun 2026 --> Jun 2025 | Trial primary completion date: Nov 2024 --> Jun 2025

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.

Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

We have developed a quick and effective method for concentration detection in both plasma and CSF, and it can be applied for drug monitoring in clinical practice. The method can also provide a reference for further optimization.

P1/2, N=589, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P2, N=146, Recruiting, Genentech, Inc. | N=85 --> 146

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.

P2, N=85, Recruiting, Genentech, Inc. | Trial primary completion date: Mar 2024 --> Dec 2025

The verified pralsetinib PBPK model was then applied to predict the effect of other inhibitors and inducers on the PKs of pralsetinib. This work highlights the challenges in understanding DDIs when enzyme-transporter interplay occurs, and demonstrates an important strategy for differentiating enzyme/transporter contributions to enable PBPK predictions for untested scenarios and to inform labeling.

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.

P2, N=252, Completed, Genentech, Inc. | Active, not recruiting --> Completed

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.

P3, N=221, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

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.

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.

No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

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.

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.

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

P3, N=0, Withdrawn, Hoffmann-La Roche | N=198 --> 0 | Recruiting --> Withdrawn

Furthermore, the LPCs derived from RET iPSCs exhibited a positive response to the RET inhibitor pralsetinib, evidenced by the downregulation of the cancer markers. This study provides a novel patient-derived off-the-shelf iPSC model of RET-driven NSCLC, paving the way for exploring the molecular mechanisms involved in RET-driven NSCLC to study disease progression and to uncover potential therapeutic targets.

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.

Importantly, JC-010a abolished acquired resistance induced by targeted therapies: in KRAS-mutant cancers, JC-010a abrogated selumetinib-induced adaptive resistance mediated by RTK/SHP2; in BCR-ABL-driven leukemia cells, we demonstrated JC-010a inhibited BCR-ABL T315I mutation-mediated imatinib resistance and proposed a novel mechanism of JC-010a involving the disrupted co-interaction of SHP2, BCR-ABL, and Hsp90; in non-small cell lung cancer (NSCLC) cells, JC-010a inhibited both EGFR T790M/C797S mutation and alternate RTK-driven resistance to gefitinib or osimertinib; importantly, we first proposed a novel potential therapeutic strategy for RET-rearranged cancer, we confirmed that JC-010a monotherapy inhibited cell resistance to BLU-667, and JC-010a/BLU-667 combination prolonged anticancer response both in vivo and in vitro cancer models by inhibiting the alternate MET activation-induced RAS/MAPK reactivation, thereby promoting cancer cell apoptosis. These findings suggested that JC-010a was a novel selective SHP2 allosteric inhibitor, and combing JC-010a with current targeted therapy agents provided a promising therapeutic approach for clinical resistant cancers.

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.

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.

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.

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.

Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

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

≥Grade 3 adverse events were seen in 28%-53% of the patients, with hypertension, change in ALT, QT prolongation, neutropenia, and pneumonitis among the common side effects. Hence, selpercatinib and pralsetinib were effective and well tolerated by most of the patients with RET-altered tumors.

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.

High expression of VEGFA and VEGFC showed favorable responses to various drugs, including BLU-667, which abrogates RET signaling, an oncogenic driver in liver and thyroid cancers. Our findings suggest potential roles of VEGF family genes in malignant processes related with hypoxia-induced angiogenesis.

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.

P2; Trial completion date: Aug 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

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 calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine appears elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.