A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma

Hida, Toyoaki; Velcheti, Vamsidhar; Reckamp, Karen L.; Nokihara, Hiroshi; Sachdev, Pallavi; Kubota, Tomoki; Nakada, T.; Dutcus, Corina E.; Ren, Min; Tamura, Tomohide

doi:10.1016/j.lungcan.2019.09.011

Cited by 83 publications

(50 citation statements)

References 35 publications

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“…It is administered orally at a standard dose of 24 mg/day. In a phase 2 clinical trial, Hida et al 34 evaluated the efficacy of lenvatinib in 25 patients with RET fusion-positive NSCLC. The median age was 63 years; most patients were women (72%), never-smokers (56%), and had received previous chemotherapy (92%).…”

Section: Vandetanib Vandetanib Inhibits Ret Egfr and Vegfr;mentioning

confidence: 99%

RET Fusion: Joining the Ranks of Targetable Molecular Drivers in NSCLC

Osta

Ramalingam

2020

JTO Clinical and Research Reports

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The era of precision medicine has resulted in the identification of a number of genomic alterations that can be targeted with novel therapies. In lung adenocarcinomas, a histology structure that accounts for nearly 50% of all cases of lung cancer, and a number of genomic targets have been linked with effective targeted therapies. For patients with advanced-stage lung adenocarcinomas, molecular testing is now a standard part of diagnostic workup; for patients that have specific driver molecular events, targeted therapies have resulted in substantial improvement in efficacy without excessive toxicity. RET gene fusions are present in approximately 1% to 2% of NSCLC. It is emerging as a new targetable driver for this population. Despite sensitivity to platinum-based chemotherapy and conflicting small reports regarding the efficacy of immune checkpoint inhibitors, there have been limited treatment approaches for this subset of patients. Multiple nonselective RET tyrosine kinase inhibitors exhibited modest anti-RET activity with an increased off-target toxicity profile that often required dose interruption, reduction, or treatment cessation. Recently, novel selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) have exhibited promising clinical activity with low adverse effect profile in early clinical trials. These new agents are poised to represent a new hope for this special subgroup with unmet needs.

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Section: Vandetanib Vandetanib Inhibits Ret Egfr and Vegfr;mentioning

confidence: 99%

RET Fusion: Joining the Ranks of Targetable Molecular Drivers in NSCLC

Osta

Ramalingam

2020

JTO Clinical and Research Reports

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“…There have been prospective studies investigating multikinase inhibitors (MKIs) such as vandetanib, cabozantinib, lenvatinib, sorafenib, and RXDX-105, which revealed modest clinical activity. [5][6][7][8][9] More importantly, differential responses were observed on the basis of the specific fusion partner KIF5B verus non-KIF5B in RETþ NSCLC. The KIF5B-RET variant in NSCLC seems to be more resistant to MKIs than the other dominant CCDC6-RET fusion variant.…”

Section: Introductionmentioning

confidence: 99%

Catalog of 5′ fusion partners in RET+ NSCLC Circa 2020

Zhu

2020

JTO Clinical and Research Reports

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Since the discovery of RET fusion-positive (RETþ) NSCLC around late 2011 to early 2012, clinical trials of multikinase inhibitors and highly potent and selective RET tyrosine kinase inhibitors have indicated that RET fusion is an actionable oncogenic driver in NSCLC. There seems to be a differential response to multikinase inhibitors depending on the fusion partner (KIF5B-RET versus non-KIF5B-RET); thus, knowledge of the fusion partners in RETþ NSCLC is important. To date, we identified 48 unique fusion partners in RET from published literature and congress proceedings. Two of the novel fusion partners (CCNYL2 and TRIM24) were identified in RET fusions that emerged as resistant to EGFR tyrosine kinase inhibitors. In addition, multiple intergenic rearrangements were identified.

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“…1,4,6 Initial efforts to target RET in lung cancer involved repurposing readily available multikinase inhibitors (MKIs) with potency against RET such as cabozantinib or vandetanib. [7][8][9][10][11][12] However, these MKIs were limited by modest efficacy and substantial toxicities. In 2017, two novel, potent RET-selective TKIs, selpercatinib (LOXO-292) and pralsetinib (BLU-667), entered clinical testing in patients with advanced RET-altered solid tumors, including RET fusionpositive NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

et al. 2020

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Background: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. Patients and methods: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by nextgeneration sequencing (NGS) or MET FISH. Results: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n ¼ 10; pralsetinib, n ¼ 7; pralsetinib followed by selpercatinib, n ¼ 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6e10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. Conclusions: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

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A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma

Cited by 83 publications

References 35 publications

RET Fusion: Joining the Ranks of Targetable Molecular Drivers in NSCLC

RET Fusion: Joining the Ranks of Targetable Molecular Drivers in NSCLC

Catalog of 5′ fusion partners in RET+ NSCLC Circa 2020

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

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