Pralsetinib in RET-Mutated Medullary Thyroid Cancer

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Pralsetinib (also known as BLU-667) showed activity in patients with advanced RET mutation–positive medullary thyroid cancer, including high rates of durable response, disease control, and 18-month progression-free survival. These findings were presented by Hu et al at the ESMO Virtual Congress 2020 (Abstract 1913O).

Pralsetinib is a highly potent, selective RET inhibitor targeting oncogenic RET alterations. The ARROW study is ongoing and is being conducted at 85 sites in 13 countries. The study consists of a phase I dose escalation that determined the recommended phase II pralsetinib dose as 400 mg orally once daily, and phase II expansion cohorts defined by RET-altered tumor type and/or treatment history.

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Primary objectives in phase II included overall response rate and duration of response by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1, as well as safety.

At ESMO 2020, efficacy findings were presented for response-evaluable patients with RET-positive medullary thyroid cancer and safety for all patients across RET-altered tumor types receiving oral pralsetinib at 400 mg daily.

Activity of Pralsetinib

As of the data cutoff date in February 2020, 92 patients with RET-positive medullary thyroid cancer were enrolled by July 2019. Of them, 61% had M918T, 29% had cysteine-rich domain, 3% had V804X, and 7% of patients had other RET mutations.

In 53 evaluable patients previously treated with cabozantinib and/or vandetanib, the overall response rate was 60% (95% confidence interval [CI] = 46%–74%), which included 2% complete responses and 58% partial responses. The disease control rate was 96% (95% = CI 87%–100%).

In 19 evaluable, treatment-naive patients, the overall response rate was 74% (95% CI = 49%–91%), including 5% complete responses and 68% partial responses. The disease control rate was 100% (95% CI = 82%–100%).

Responses were observed in patients with either somatic or germline RET genotypes, including five of six patients with a V804X gatekeeper mutation. Neither median progression-free survival nor duration of response was reached. In patients previously treated with cabozantinib or vandetanib, 18-month progression-free survival was 71% (95% CI = 58%–85%), and 18-month duration of response was 90% (95% CI = 77%–100%). In treatment-naive patients, 18-mo progression-free survival was 85% (95% CI = 65%–100%).

In patients previously treated with cabozantinib or vandetanib, 94% of responders remained on treatment. In systemic treatment-naive patients, 93% of responders remained on treatment.

The safety population was comprised of 438 patients; treatment-related adverse events were primarily grade 1 or 2. The most frequently reported any-grade treatment-related adverse events consisted of increased aspartate aminotransferase (34%), anemia (24%), increased alanine aminotransferase (23%), constipation (23%), and hypertension (22%). A total of 4% of patients discontinued treatment due to treatment-related adverse events.

Based on these results, the authors concluded that pralsetinib demonstrated potent and durable clinical activity in patients with advanced RET mutation–positive medullary thyroid cancer—regardless of prior treatment with approved multikinase inhibitors or RET mutation genotype—and was well tolerated.

Disclosure: The study was funded by Blueprint Medicines Corporation. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.