Hepatocellular carcinoma

Cohort

Vandetanib

Receptor

Thyroid cancer

Tyrosine kinase

Internal medicine

Sorafenib

Oncology

Medicine

Cabozantinib

Cancer

Medullary thyroid cancer

Thyroid

The Lancet Diabetes & Endocrinology

<h2>Summary</h2><h3>Background</h3> Oncogenic alterations in <i>RET</i> 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 <i>RET</i>-altered thyroid cancers. <h3>Methods</h3> 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 <i>RET</i>-altered locally advanced or metastatic solid tumours, including <i>RET</i>-mutant medullary thyroid and <i>RET</i> 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 <i>RET</i>-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated <i>RET</i> fusion-positive thyroid cancer; safety was assessed for all patients with <i>RET</i>-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with <i>RET</i> fusion-positive thyroid cancer was ongoing at the time of this interim analysis. <h3>Findings</h3> Between Mar 17, 2017, and May 22, 2020, 122 patients with <i>RET</i>-mutant medullary and 20 with <i>RET</i> 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 <i>RET</i>-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 <i>RET</i> fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with <i>RET</i>-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. <h3>Interpretation</h3> Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with <i>RET</i>-altered thyroid cancer. <h3>Funding</h3> Blueprint Medicines.

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