Selective RET Inhibitors Research Articles

74 (PB064) - Molecular characterization of primary and secondary resistance to RET inhibitors in patients with advanced NSCLC and RET fusions

Background: RET fusions are a known tumor driver in 1–2% of patients with advanced non-small cell lung cancer (aNSCLC). The advent of selective RET inhibitors (RETi) significantly improved prognosis, but around 20% of patients show primary resistance. Moreover, secondary resistance inevitably occurs and molecular mechanisms are still incompletely characterized.

Clinical uptake of precision medicine advances in NSCLC: A case study in RET fusions.

32 Background: Precision medicine has revolutionized cancer care in advanced NSCLC and new actionable biomarkers and targeted therapies are emerging at an unprecedented pace, creating myriad opportunities to improve care and mitigate the often-dire sequelae of traditional cancer therapy. Delays in uptake of testing and biomarker-guided treatment for patients with NSCLC and EGFR activating mutations or ALK fusions are well documented despite clear evidence-based practice, guidelines, and expert recommendations. In this study, we analyze healthcare professionals (HCPs) awareness and application of RET fusion testing and integration of recently approved selective RET inhibitors into practice for appropriate patients with advanced NSCLC. Methods: From 1/2020-6/2022, multiple educational activities were developed to provide HCPs with evidence-based expert and guideline recommendations on assessment of and therapy selection for RET fusion–positive NSCLC. The activities comprised live symposia associated with 4 major oncology and pathology conferences (AMP, USCAP, ASCO, AACR), 3 regional live workshop series across the US, 3 live webinars, and 2 on-demand videos. Baseline polling questions designed to assess key aspects of HCP knowledge and practice patterns were repeated at each activity. Results: Across all activities at baseline, on average only 38% of responding HCPs correctly identified RNA NGS as the most sensitive testing assay for detection of RET fusions and 36% accurately selected the appropriate targeted therapy for patient case with a KIF5B-RET gene fusion. From 2020 through 2022, with each new group of learners across different scopes of practice, we found suboptimal awareness of optimal RET fusion testing methodology and choice of therapy for patients with RET fusion–positive NSCLC (table). Optimal responses were slightly higher among learners attending conference-associated symposia vs live workshop series and online education. Conclusions: The use of optimal testing assays for RET alterations across patients with NSCLC remains low and many HCPs continue to lack awareness of appropriate targeted therapy for patients with RET–fusion positive NSCLC > 2 years after the first approved indication for this biomarker. These results underscore a lag in adoption of optimal precision medicine approaches for NSCLC among oncology HCPs and the need for expert guidance and educational activities to optimize individualized, biomarker-driven treatment approaches. An analysis of patterns by HCP role (MD, NP/PA, RN, Pharmacist) will be presented.[Table: see text]

1124P Pralsetinib in RET fusion-positive non-small cell lung cancer: A real-world data (RWD) analysis from the Italian expanded access program (EAP)

The selective RET-inhibitor pralsetinib has shown therapeutic activity in early clinical trials in patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) gene fusions. To date, the efficacy of pralsetinib in this population in the real-world setting is unknown.

Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n= 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Alectinib for the treatment of pretreated RET-rearranged advanced NSCLC: Results of the ETOP ALERT-lung trial

BackgroundAlectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage. MethodsALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication. ResultsAll 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1.No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 – 7.3 months). Overall, three deaths (23 %) were reported.Seven patients (50 %) experienced grade ≥ 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported. ConclusionsAccrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

PurposeRearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown.MethodsData from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs).ResultsPatients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation.ConclusionSelective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting.

Treatment with Selective RET inhibitors in Medullary Thyroid Cancer - A Case series

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract 5363: The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor

Abstract Backgroud: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. The gatekeeper RET V804 mutation cannot be inhibited by selected next-generation RET inhibitors in development. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 <15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 < 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models. At 10 mg/kg BID, tumor regression was observed in these xenograft models (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg BID showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022. Citation Format: Alexander Drilon, Jun Zhong, Ying Lu, Yongbo Liu, Hao Wang, Minchun Chen, Xiaohu Chen, John Zhu, Shun Lu, Vivek Subbiah. The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5363.

A first-in-human phase 1 study of the next-generation RET inhibitor, LOXO-260, in RET inhibitor refractory patients with RET-altered cancers (trial in progress).

TPS8595 Background: RET fusions are found in 1-2% of lung adenocarcinomas and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancers (MTCs). Selpercatinib was the first selective RET inhibitor approved by the FDA and is indicated for patients (pts) with RET fusion-positive NSCLC and thyroid cancer, and RET mutant MTC. Despite marked and durable activity, acquired resistance can eventually develop through a variety of mechanisms. These include acquisition of RET G810X mutations at the solvent front of the ATP pocket. LOXO-260 is a highly potent and selective inhibitor of RET designed to have activity against both solvent front and gatekeeper mutations, expressed alone or together, while maintaining potency against RET fusions or mutations (Kolakowski GR. et al. 2021 Cancer Research 81 (13 Suppl) 1464). Methods: LOXO-NGR-21001 is a global, open-label, first-in-human phase 1 study of LOXO-260 in pts with RET fusion-positive advanced solid tumors and RET mutant MTC who received a prior selective RET inhibitor. Phase 1a dose escalation will utilize a modified i3+3 design, allowing for pt backfill to previously cleared dose levels. Phase 1b dose expansion will evaluate LOXO-260 in specific expansion cohorts: RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC. The primary objectives in dose escalation are to determine the MTD/RP2D and safety of LOXO-260. Key secondary objectives include characterization of PK and preliminary antitumor activity of LOXO-260 per RECIST v1.1. The primary objective of dose expansion is to assess the antitumor activity of LOXO-260 based on investigator-assessed overall response rate (ORR). Key secondary objectives are to characterize the PK and antitumor activity of LOXO-260 based on progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Eligible pts must have received a prior selective RET inhibitor, have a documented RET fusion or RET mutation and a diagnosis of locally advanced, unresectable and/or metastatic cancer per disease-specific criteria, and must have progressed or be intolerant to standard therapies or must have refused such a therapy. Pts must be ≥18 years old and have an ECOG PS of 0-2. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS metastases, or carcinomatous meningitis. Clinical trial information: NCT05241834.

Use of RET inhibitors among patients with advanced NSCLC: A real-world evidence analysis.

9079 Background: RET rearrangements are found in approximately 1% to 2% of patients with NSCLC. Two selective RET inhibitors have been FDA approved based on phase 1/2 data showing significant activity among patients with advanced NSCLC that have RETrearrangements. The objective of this retrospective analysis was to look at the prognostic outcome associated with the use of selective RET inhibitors (sRETi) and multikinase inhibitors (MKIs) that have been used to target RET fusions among pts with NSCLC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 84 million pt lives available through the TriNetX Research Network. We identified 1,215 pts with metastatic NSCLC treated with selpercatinib, praseltinib, cabozantanib or vandetanib. Overall survival (OS) was evaluated with Kaplan Meier statistics and compared between patients treated with either sRETi (selpercatinib or pralsetinib) vs either MKI (cabozantanib or vandetanib). Results: Mean age among all anti-RET treated patients was 67.6 years. 518 pts (43%) were female and 697 (57%) were male. 531 (39.6%), 205 (15.3%) and 605 (45.1%) pts had received selpercatinib, pralsetinib, and either cabozantinib or vandetinib, respectively. 56.6% of pts receiving pralsetinib received prior selpercatinib. Among pts receiving sRETi, 39.7%, 6.4%, 11.2%, and 32.4% received sRETi in the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis, respectively. Among pts receiving MKIs, 17.0%, 8.4%, 13.3%, and 44.9% received MKIs in the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis. Median OS after treatment with MKIs and sRETi during any time frame was 16.3m and 25.0m, respectively (p < 0.01). Among pts treated with MKIs vs sRETi during the 0-3, 3-6, 6-12, and 12+ months after metastatic diagnosis, 1-year survival probability after treatment was 59.7% vs 55.9% (p = 0.39), 45.0% vs 83.1% (p < 0.01), 53.9% vs 82.2% (p < 0.01), and 57.7% vs 87.1% (p < 0.01), respectively. 30% of pts of all anti-RET treated patients had brain metastases, and median OS from index metastasis among pts with and without brain metastases was 31.4m and 63.1m respectively (p < 0.01). Conclusions: To our knowledge this is the first real world data set to show a > 8m improvement in OS with the use of sRETi compared to MKIs among pts with metastatic NSCLC. OS improvements may be more significant in pts treated in later lines of therapy with sRETi.

The development of APS03118, a potent next-generation RET inhibitor for treating RET-inhibitor-resistant patients.

e15107 Background: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 < 15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited the proliferation of KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 < 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models at 10 mg/kg (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. The pharmacokinetic/pharmacodynamic relationship of APS03118 in Ba/F3 KIF5B-RET G810R and WT xenograft tumor model was investigated, and the sustained decrease of the phosphorylated RET were observed at 30 mg/kg with the plasma exposure exceed cell IC90. Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. APS03118 has received IND approval and Fast Track Designation from FDA, and a first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.

Pralsetinib in patients (pts) with advanced or metastatic RET-altered thyroid cancer (TC): Updated data from the ARROW trial.

6080 Background: Alterations in RET are targetable oncogenic drivers in TC. Pralsetinib is a highly potent, selective RET inhibitor, with demonstrated efficacy in pts with RET-altered TC. In a previous analysis of the Phase I/II ARROW trial (NCT03037385; data cutoff: 22 May 2020), overall response rates [ORR; measurable-disease population] with pralsetinib at 400 mg once daily (QD) were 60% (33/55) and 71% (15/21) in pts with RET-mutant medullary TC ( RET-mutant MTC) who had received prior multikinase inhibitors cabozantinib and/or vandetanib (C/V), and those who were treatment naïve, respectively, and 89% (8/9) in pts with previously treated RET fusion-positive TC ( RET-fp TC). Here we report an updated analysis of these cohorts in the intention-to-treat (ITT) population. Methods: Adult pts with RET-altered locally advanced/metastatic TC who had enrolled in ARROW and initiated pralsetinib at 400 mg QD, were included. Phase II primary endpoints: ORR (by blinded independent central review, per RECIST v1.1) and safety. Efficacy endpoints for this analysis were assessed in the ITT population. Safety was assessed in all pts with RET-altered TC who initiated pralsetinib at 400 mg QD. Enrolment cutoff: 23 August 2020 for the ITT population; data cutoff: 12 April 2021. Results: The ITT population comprised 145 pts with RET-mutant MTC (with or without prior systemic therapy, including C/V) and 22 pts with RET-fp TC, 21 of whom had received prior systemic therapy (including multikinase inhibitor[s] and/or radioactive iodine). In pts with RET-mutant MTC who had received prior C/V (n = 67), ORR was 51% (34/67; 95% CI 38–63; 2 complete responses [CR]; 32 partial responses [PR]), median duration of response (DoR) was 25.8 months (95% CI 18.0–not reached [NR]) and median progression-free survival (PFS) was 24.9 months (95% CI 19.7–31.2). In treatment-naïve pts with RET-mutant MTC, ORR was 72% (48/67; 95% CI 59–82; 4 CR; 44 PR), and median DoR and median PFS were not reached. In pts with previously treated RET-fp TC, ORR was 86% (18/21; 95% CI 64–97; 3 CR; 15 PR), median DoR was 17.5 months (95% CI 16.0–NR) and median PFS was 19.4 months (95% CI 13.0–NR). Median overall survival (OS) was not reached in any of the cohorts. The safety population comprised 172 pts with RET-altered TC treated at 400 mg QD. The most common treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (n = 67; 39%), anemia (n = 60; 35%), hypertension (n = 57; 33%) and decreased white blood cell count (n = 52; 30%). Serious TRAEs were reported in 27 pts (16%); the most frequent was pneumonitis (n = 5; 3%). Nine pts (5%) discontinued pralsetinib due to a TRAE and one patient ( < 1%) died due to a TRAE ( pneumocystis jirovecii pneumonia) following 44 days ( < 3 cycles) on pralsetinib. Conclusions: In this updated analysis including more pts, pralsetinib continues to be efficacious with a manageable safety profile in pts with RET-altered TC. Clinical trial information: NCT03037385.

AcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC.

TPS9159 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). Pralsetinib is a potent, selective RET inhibitor, approved in the US and EU for the treatment of metastatic RET fusion–positive NSCLC based on the phase 1/2 ARROW study (NCT03037385). In the ARROW study (data cutoff: Nov 6, 2020), patients who initiated 400 mg once daily (QD) of pralsetinib after platinum-based chemotherapy achieved an overall response rate (ORR) of 62%, per independent central review. In the treatment-naïve group, the ORR was 79%. Most treatment-related adverse events were grade 1–2 across the entire safety population treated at 400 mg QD (n=471). AcceleRET Lung, an international, open-label, randomized, phase 3 study (NCT04222972), will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Abstracts for this study were previously submitted to the European Lung Cancer Congress 2020, the American Society of Clinical Oncology 2020 annual meeting, and 2020 World Conference on Lung Cancer. Methods: Approximately 226 patients with metastatic RET fusion–positive NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab [at investigator’s discretion]; squamous histology: platinum/gemcitabine or platinum + pembrolizumab + paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET fusion–positive tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients with central nervous system metastases were permitted if asymptomatic and on a stable dose of corticosteroids. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Identification of potential biomarkers of antineoplastic activity and resistance was an exploratory endpoint. Recruitment has begun with sites (active or planned) in North America, Central America, Europe and Asia. Clinical trial information: NCT04222972.

Selpercatinib-Induced Hypothyroidism Through Off-Target Inhibition of Type 2 Iodothyronine Deiodinase.

The development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid. Thyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases. Upon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels. An off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

Clinical application of precision medicine among oncologists: A case study in RET-targeted therapy.

e18705 Background: Precision medicine has revolutionized cancer care across multiple tumor types and new actionable biomarkers and targeted therapies are emerging at an unprecedented pace, creating myriad opportunities to optimize care and mitigate the often-dire sequelae of traditional cancer therapy. Many oncology healthcare professionals (HCPs) in practice are not employing optimal testing methodologies to detect biomarkers in patients who could benefit from novel targeted therapies. In this study, we analyze HCP awareness and application of RET alteration testing and integration of recently approved, new-generation selective RET inhibitors into practice for appropriate patients with NSCLC and thyroid cancer. Methods: In August 2020 HCPs were surveyed on RET alteration testing and use of RET-targeted therapeutics in their current practice. Study eligibility criteria included active HCPs in an oncology, pulmonology, or pathology practice. A curriculum of live and online educational activities was then developed for any interested oncologists and pathologists on RET alteration testing and/or targeted therapy for RET-altered lung and thyroid cancers. These activities included case studies, polling, and evaluations that provided additional insight on self-identified practice trends. In June 2021, at the completion of the educational program, eligible HCPs were surveyed again on RET alteration testing and selection of RET inhibitor therapy for appropriate patients. Results: In August 2020, 123 practicing HCPs completed the initial survey and 33% were testing patients for RET gene alterations and 18% were aware of the most sensitive testing assay for detection of RET fusions. 25% and 7%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Self-identified practice trends identified among the unselected cohort of 12,537 individual HPCs participating in the educational activities also demonstrated similar lack of appropriate testing for RET alterations and use of RET inhibitors. In June 2021, 60 practicing HCPs completed the follow-up survey and 40% were testing patients for RET gene alterations and 25% were aware of the most sensitive testing assay for detection of RET fusions. 52% and 22%, respectively, were aware of the current indications for RET inhibitors in RET fusion–positive NSCLC and RET-altered thyroid cancer. Conclusions: The rate of broad testing for RET alterations across patients with NSCLC and thyroid cancer remains low and many HCPs lack understanding of when to consider treating with a RET inhibitor. These results underscore the lag in adoption of optimal precision medicine approaches in oncology and the need for expert guidance and educational activities to optimize individualized, biomarker-driven treatment approaches for patients with cancer.

Comparison of TAS0953/HM06 and selpercatinib in RET fusion-driven preclinical disease models of intracranial metastases.

2024 Background: Patients with RET fusion-positive NSCLC have an estimated 25% incidence of CNS metastasis at diagnosis, and up to 40% during disease progression. Effective anti-RET therapy that penetrates the blood-brain barrier is essential to extending survival. TAS0953/HM06 is a structurally distinct RET-specific inhibitor that exhibits a distinct binding mode to RET and is effective against RET solvent front (G810) and gatekeeper (V804) mutations. TAS0953/HM06 also inhibits growth of xenograft tumors established from RET fusion-driven tumors of multiple histologies. TAS0953/HM06, therefore, represents a potentially effective strategy to overcome the emergence of acquired resistance to first generation RET-selective inhibitors. Here, we compared the brain penetration and efficacy of TAS0953/HM06 to selpercatinib (FDA-approved RET inhibitor) in models of intracranial RET fusion-positive cancers, specifically NSCLC and sarcoma. Methods: We compared the brain: plasma ratio of unbound TAS0953/HM06 and selpercatinib in mice to determine the unbound partition coefficient, Kpuu, brain. We injected ECLC5 (NSCLC cell line, TRIM33-RET) and HMSC-RET (immortalized human mesenchymal stem cells in which SPECCL1-RET was introduced by CRISPR-Cas9 genomic engineering, sarcoma model) cells expressing luciferase into the cerebellum of mice. Tumor-bearing mice were treated with TAS0953/HM06 (50 mg/kg BID), selpercatinib (10 mg/kg BID) or vandetanib (multi-kinase RET inhibitor, 50 mg/kg QD), and assessed weekly for tumor growth via bioluminescence imaging. Results: Kpuu, brain, of TAS0953/HM06 and selpercatinib were 1.3 and 0.20, respectively. Substances with brain Kpuu > 0.3 in mice are regarded as brain-penetrable. TAS0953/HM06 was superior to selpercatinib at inhibiting growth of ECLC5 (p < 0.0001) and HMSC-RET (p = 0.0005) brain xenograft tumors, and increasing survival of tumor-bearing animals (ECLC5: TAS0953/HM06 139±0.5 days, selpercatinib 95+2.3 days, p = 0.002; HMSC-RET: TAS0953/HM06 41± 2.2 days, selpercatinib 20±3 days, p = 0.0001). Vandetanib, which is highly brain-penetrant, did not cause a significant decrease in growth of either brain tumor xenograft models. At the doses used, the 3 RET inhibitors induced similar regression in several peripheral subcutaneous xenograft tumor models. Conclusions: Our data in animal models suggest that TAS0953/HM06 penetrates the CNS more effectively than selpercatinib, and is superior at decreasing CNS disease and extending survival. TAS0953/HM06 represents a promising new therapeutic option for patients with RET fusions with acquired resistance mutations, including those with brain metastasis and those resistant to first-generation selective RET inhibitors. TAS0953/HM06 is currently undergoing a biomarker-driven phase 1/ 2 clinical trial for patients with solid tumors driven by RET alterations (NCT04683250).

The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046.

TPX-0046 is designed to overcome resistance to FDA approved RET inhibitors Selpercatinib and Pralsetinib. Early prediction of resistance mechanisms to investigational drugs may facilitate subsequent drug and trial designs. This study aims to predict potential mutations inducing resistance to TPX-0046. We conducted an in-silico analysis of TPX-0046 macrocyclic structure and predicted the binding mode on RET. We used as reference literary examples of resistance mechanisms to other macrocyclic inhibitors (Lorlatinib on ALK/ROS1) to construct RET secondary resistance mutations. We conducted docking simulations to evaluate impact of mutations on TPX-0046 binding. TPX-0046 binding mode on RET appears to not be influenced by Solventfront G810X mutation presence. Bulky Gatekeeper V804X mutations affect predicted TPX-0046 binding mode. Mutations in Beta 7 strand region L881F and xDFG S891L impair TPX-0046 docking. Our findings suggest that development of second generation RET inhibitors focused mainly on Solventfront G810X mutations granting resistance to selective RET inhibitors Selpercatinib and Pralsetinib. If these findings are confirmed by identification of Gatekeeper V804X mutations in patients progressing to TPX-0046, explanation of acquired resistance and loss of benefit will be easier These findings might accelerate development of third generation RET inhibitors, as well as clinical trial design in precision oncology settings.

Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib.

Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET-specific inhibitors in patients harboring RET indels has been provided. We present an update on the prevalence of RET indels in medullary thyroid cancer (MTC) and describe the efficacy of selpercatinib in patients with advanced MTC with RET indels. The MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by MutationTaster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel were treated with selpercatinib. Among 178 RET-positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by MutationTaster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment. These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indel-positive patients showed a partial response to the treatment with a highly selective RET inhibitor; thus, these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended.

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET–rearranged thyroid cancer.

Pralsetinib: A Review in Advanced RET Fusion-Positive NSCLC.

Activating mutations in the proto-oncogene RET have been identified as an oncogenic driver of non-small cell lung cancer (NSCLC) in a small subset of patients. Pralsetinib (Gavreto®) is an orally-administered, next-generation, small-molecule selective RET inhibitor that is approved for the treatment of RET fusion-positive metastatic NSCLC. In the pivotal phase I/II ARROW trial, pralsetinib demonstrated rapid and durable anti-tumour activity in patients with advanced RET fusion-positive NSCLC who were previously treated with platinum-based chemotherapy or were treatment-naïve. Pralsetinib also showed clinical activity against intracranial metastases arising from NSCLC. Pralsetinib had a manageable tolerability profile, with the most common grade 3 treatment-related adverse events being neutropenia, hypertension, anaemia and decreased white blood cell count. Currently available data indicate that pralsetinib is a promising new targeted treatment option for patients with advanced RET fusion-positive NSCLC.