BLU-667 exhibits durable activity in RET-altered thyroid cancer
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CHICAGO — BLU-667 demonstrated durable and potent antitumor activity among patients with RET-altered advanced medullary thyroid cancer or RET-fusion positive papillary thyroid cancer, according to results of the ARROW study presented at ASCO Annual Meeting.
Researchers observed responses regardless of treatment history or RET mutation genotype.
BLU-667 (Blueprint Medicines), an investigational selective RET inhibitor that received breakthrough therapy designation from the FDA, also appeared well-tolerated, regardless of whether patients were resistant to multikinase inhibitors.
“This is a big step forward having an effective drug that is well-tolerated to treat patients with medullary thyroid cancer with RET mutations, as well as differentiated thyroid cancer with RET fusions,” researcher Matthew H. Taylor, MD, program director for phase 1 clinical trials at Oregon Health & Science University Knight Cancer Institute, told HemOnc Today. “It’s exciting to see that this is such a relevant molecular target, and that it can be targeted with a highly selective specific drug that doesn’t cause as many off-target side effects as the other drugs in the market.”
Approximately 90% of patients with advanced medullary thyroid cancer and 20% of those with advanced papillary thyroid cancer have RET alterations, according to study background.
Despite the prevalence of these targetable oncogenic drivers, no selective RET inhibitors have received FDA approval.
The registration-enabling ARROW study evaluated BLU-667 for patients with unresectable, advanced RET-altered solid tumors, including thyroid cancer. All patients had an ECOG performance status of 0 or 1, with no additional driver mutation.
A dose-escalation phase evaluated 30-mg to 600-mg daily doses. A dose expansion phase evaluated a 400-mg daily dose.
Overall response rate and safety served as primary outcomes.
At data cutoff, 64 patients with RET-mutated medullary thyroid cancer (median age, 59 years; range, 19-81; 66% men) had received the 400-mg daily starting dose. Two-thirds (66%) had ECOG performance status of 1 or 2, and all patients had metastatic disease.
Most patients (78%) had undergone prior anticancer treatment (median prior systemic regimens, 1; range, 0-10). Two-thirds (67%) had received cabozantinib (Cabometyx, Exelixis) or vandetanib (Caprelsa, Sanofi Genzyme), and 20% had received both of those agents.
In the medullary thyroid cancer group, treatment-related toxicity with BLU-667 generally was low-grade and reversible, according to researchers. No patients discontinued therapy due to treatment-related toxicity.
The most common treatment-related adverse events in this group were hypertension (any grade, 30%; grade 3 or higher, 16%), neutropenia (any grade, 23%; grade 3 or higher, 11%), constipation (any grade, 19%; grade 3 or higher, 2%), leukopenia (any grade, 17%), aspartate aminotransferase increase (any grade, 14%) and alanine aminotransferase increase (any grade, 13%).
An analysis of antitumor activity in RET-mutated medullary thyroid cancer included 32 patients. Researchers reported an overall response rate of 56% (95% CI; 38-74), with one complete response and 17 partial responses. Thirteen patients exhibited stable disease and one experienced progressive disease, equating to a disease control rate of 97% (95% CI, 84-100). Ninety-four percent of patients experienced tumor shrinkage.
All 18 patients with tumor response remained on treatment at data cutoff, and median duration of response had not been reached.
Sixteen patients with medullary thyroid cancer had received prior cabozantinib or vandetanib. In that group, researchers reported an ORR of 63% (95% CI, 35-85), with no complete responses and 10 partial responses. Five patients exhibited stable disease and one experienced progressive disease.
Researchers reported a disease control rate of 94% (95% CI, 70-100). All 16 patients experienced tumor shrinkage.
Nine patients (median age, 66 years; range, 23-70; 56% men) with RET fusion-positive papillary thyroid cancer received BLU-667 at any starting dose. More than half (56%) had an ECOG performance status of 1 or 2, and all nine had metastatic disease. Eight (89%) had received prior systemic therapy (median prior systemic regimens, 2; range, 0-8). Three (33%) had received sorafenib (Nexavar, Bayer) or lenvatinib (Lenvima, Eisai), and eight (89%) had received radioactive iodine.
Among these nine patients, BLU-667 exhibited a safety profile similar to that observed in the medullary thyroid cancer group, and no patients discontinued therapy due to treatment-related toxicity.
Six patients with RET fusion-positive papillary thyroid cancer were evaluable for antitumor activity. Five (83%) achieved response, five received treatment for 1 year or longer, and eight of nine remained on treatment at data cutoff.
Enrollment in the expansion cohort is continuing with registrational intent.
“My hope is that this will become a first-line treatment option for patients with these alterations,” Taylor told HemOnc Today. – by Mark Leiser
References:
Taylor MH, et al. Abstract 6018. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Taylor reports speakers’ bureau roles with Bristol-Myers Squibb and Eisai, as well as consultant/advisory roles with ArQule, Array BioPharma, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Eisai, Loxo and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.