Articles
Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study

https://doi.org/10.1016/S2213-8587(21)00120-0Get rights and content

Summary

Background

Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.

Methods

ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis.

Findings

Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion–positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48–89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46–73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52–100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event.

Interpretation

Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer.

Funding

Blueprint Medicines.

Introduction

The incidence of thyroid cancer has increased over the past decade, with medullary thyroid cancer representing 1–5% of all thyroid cancer cases (75% sporadic and 25% hereditary) and papillary thyroid cancer accounting for 80–85% of all differentiated thyroid cancer.1, 2, 3 Despite its low prevalence, medullary thyroid cancer accounts for almost 14% of all thyroid cancer-related deaths.4 Activating alterations in the RET proto-oncogene (RET), which encodes a transmembrane receptor tyrosine kinase (proto-oncogene tyrosine-protein kinase receptor RET), are known oncogenic drivers in both medullary thyroid cancer and differentiated thyroid cancer, and represent a promising therapeutic target.5, 6 Medullary thyroid cancer originates from parafollicular C cells and can be hereditary, associated with two subtypes of multiple endocrine neoplasia syndrome type 2 (MEN2; MEN2A and MEN2B), or sporadic.7 RET mutations occur in more than 95% of hereditary and approximately 50% of sporadic medullary thyroid cancer.8 In the hereditary form, these include extracellular domain mutations (most commonly at the C634 codon), which promote ligand-independent activation of RET, and kinase domain mutations (primarily M918T, A883F, or V804L/M), which promote RET autoactivation and consequent oncogenic signalling.9, 10 In the sporadic form, the M918T mutation accounts for more than 75% of the RET alterations and might be associated with a worse prognosis.11, 12 In differentiated thyroid cancer, which originates from follicular cells, RET fusions are present in approximately 10–20% of papillary thyroid cancer,8 and less common (<10%) in other thyroid cancer subtypes such as follicular, Hürthle-cell, poorly differentiated, and anaplastic.13, 14 Among patients with papillary thyroid cancer, the most common RET fusion partners are CCDC6 (59%) and NCOA4 (36%).10, 15

Research in context

Evidence before this study

We searched PubMed for studies published in English between Jan 1, 2015, and July 31, 2020, investigating targeted treatment of RET-altered thyroid cancer. Search terms included ”RET” plus ”thyroid” and were filtered for clinical trials. Of the 16 entries returned, there were no clinical trials specifically done in patients with RET-altered thyroid cancer. In clinical trials enrolling patients with medullary thyroid cancer not limited to RET-alterations, the response rate with the standard-of-care multikinase inhibitor cabozantinib was 32% and with vandetanib was 46%. Furthermore, in clinical trials of patients with radioiodine-refractory differentiated thyroid cancer, response rates with the standard-of-care multikinase inhibitor lenvatinib was 65% and with sorafenib was 12%. Although these multikinase inhibitors have shown clinical activity in the respective indications, rates of adverse events leading to dose reduction and treatment discontinuation were generally high owing to their broad activity against many kinases.

Added value of this study

To the best of our knowledge, ARROW is the first prospective study to investigate treatment of RET-altered solid tumours, including RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer, with pralsetinib. Our data show that pralsetinib has clinical activity in patients with RET-mutant medullary thyroid cancer, including in patients who were treatment naive or had previously received cabozantinib or vandetanib, or both, as well as in patients with previously treated RET fusion-positive thyroid cancer (response rates of 71%, 60%, and 89%, respectively). In patients with RET-altered thyroid cancer who received the recommended phase 2 dose of 400 mg once daily, pralsetinib was well tolerated with a predictable safety profile, and rates of dose reductions and treatment discontinuations because of treatment-related adverse events were low when compared with available multikinase inhibitors. Overall, pralsetinib had a manageable safety profile in patients with RET-altered thyroid cancer and provided meaningful clinical activity in patients irrespective of previous treatment history.

Implications of all the available evidence

Patients with RET-altered thyroid cancer have few safe and effective treatment options outside of standard of care available for tumours without targetable oncogenic drivers. Findings from our study show that RET-targeted treatment with pralsetinib has antitumour activity in RET-altered thyroid cancer and a manageable safety profile. The utility of RET-targeted therapies is also validated by outcomes with selpercatinib, another targeted RET inhibitor, which were reported following the data cutoff for the present study. Approval of both of these agents in the USA provides new treatment options in this patient population.

Multikinase inhibitors were in the past standard of care for advanced medullary thyroid cancer (cabozantinib and vandetanib) and radioiodine-refractory differentiated thyroid cancer (lenvatinib and sorafenib).16 Although these multikinase inhibitors have shown clinical activity in the respective indications,17, 18, 19, 20 they are associated with significant dermatological, cardiovascular, and gastrointestinal side-effects owing to their broad activity against many kinases, including vascular endothelial growth factor receptors.17, 18, 19, 20, 21 These toxicities frequently lead to dose reductions and discontinuations, which might affect the quality of life and outcomes of patients.17, 18, 19, 20, 21

Pralsetinib (formerly BLU-667, Blueprint Medicines) is an oral, once daily, selective RET inhibitor that potently targets RET-altered kinases, including V804L/M gatekeeper mutations associated with resistance to other tyrosine kinase inhibitors.22, 23 Here, we report on the safety and efficacy of pralsetinib in patients with RET-altered thyroid cancer from the registrational phase 1/2 study (ARROW), which formed the basis of approval in the USA for treatment of advanced or metastatic RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer.24

Section snippets

Study design and participants

ARROW is a multicentre, open-label, first-in-human phase 1/2 study of pralsetinib. The study is being done in 13 countries globally across 71 sites in community and hospital settings. The phase 1 study portion established the maximum tolerated dose and recommended phase 2 dose.25 The ongoing phase 2 portion of the study consists of multiple expansion groups (figure 1).

Patients aged 18 years or over with unresectable, locally advanced or metastatic solid tumours were enrolled into each phase 2

Results

Between March 17, 2017, and the data cutoff date of May 22, 2020 (at which time the study was ongoing), 587 patients were screened and 521 were enrolled, of whom 147 had RET-mutant medullary thyroid cancer and 22 had RET fusion-positive thyroid cancer. A total of 142 patients with RET-mutant medullary thyroid cancer (n=122) or RET fusion-positive thyroid cancer (n=20) initiated the recommended phase 2 pralsetinib dose of 400 mg once daily and were included in the safety analyses (figure 1). Of

Discussion

In this phase 1/2 study in patients with advanced or metastatic RET-mutant medullary thyroid cancer or RET fusion-positive thyroid cancer, pralsetinib 400 mg administered as an oral dose once daily showed potent and durable clinical activity. Efficacy was maintained regardless of RET genotype or previous treatment history, and pralsetinib treatment was associated with a manageable safety profile.

The results of this study with pralsetinib in patients with RET-mutant medullary thyroid cancer

Data sharing

The anonymised derived data from this study that underlie the results reported in this article will be made available, beginning 12 months and ending 5 years after this article's publication, to any investigators who sign a data access agreement and provide a methodologically sound proposal to Blueprint Medicines [email protected]. The trial protocol will also be made available, as will a data fields dictionary.

Declaration of interests

VS reports grants from Blueprint Medicines and LOXO Oncology–Eli Lilly; research funding or grant support from Roche–Genentech, Novartis, Bayer, GlaxoSmithKline (GSK), Nanocarrier, Vegenics, Northwest Biotherapeutics, Berg Heath, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Medimmune, Altum, Dragonfly Therapeutics, Takeda, Immunogen, National Comprehensive Cancer Network (NCCN), NCI-CTEP and UT MD

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