BLU-667 Controls RET-Altered Thyroid Cancers

In the phase II ARROW trial, the experimental RET inhibitor BLU-667 (Blueprint Medicines) elicited high overall response rates and durable responses in advanced RET-altered medullary and papillary thyroid cancers—with mild side effects. The findings were presented in June at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL.

RET alterations are common in thyroid cancers: About 90% of patients with advanced medullary thyroid cancer (MTC) have RET mutations, and about 20% of patients with papillary thyroid cancer (PTC) have RET fusions. Patients with both diseases are usually treated with multikinase inhibitors, namely cabozantinib (Cabometyx; Exelixis), vandetanib (Caprelsa; Sanofi), lenvatinib (Lenvima; Eisai), and sorafenib (Nexavar; Bayer). However, “these drugs are not directly designed to target RET, and they have a lot of toxicities due to off-target activity, so there was a need to develop selective RET inhibitors for these cancers,” says trial co-leader Vivek Subbiah, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Phase I of the ARROW trial established that the agent is safe and has antitumor activity in multiple RET-altered solid cancers, leading Subbiah and his team to expand cohorts of patients with MTC and PTC in phase II of the trial.

The 32 evaluable patients with advanced RET-mutated MTC treated daily with 400 mg of BLU-667 had an overall response rate (ORR) of 56% and a disease control rate of 97%; 16 patients previously treated with cabozantinib or vandetanib had an ORR of 63% and a disease control rate of 94%. Currently, 28 patients with MTC remain on treatment, and the median duration of response has not been reached. Five of six evaluable patients with advanced RET fusion–positive PTC responded to the therapy and have continued treatment for at least a year. Overall, side effects were generally mild, and no patients stopped treatment due to treatment-related toxicity.

“This is definitely encouraging for RET-altered papillary thyroid cancer, and medullary thyroid cancer as well,” Subbiah says, especially because patients responded after developing resistance to multikinase inhibitors. Next, Subbiah would like to test BLU-667 as a first-line therapy. Additionally, he sees a need for second-generation RET inhibitors and combination strategies to overcome or delay resistance to the drug that inevitably develops.

BLU-667 is not the only RET inhibitor under development: At the 2018 ASCO Annual Meeting, researchers presented results from the phase I LIBRETTO-001 trial testing LOXO-292 (Loxo/Eli Lilly) in patients with RET-altered solid tumors. The 22 evaluable patients with MTC had an ORR of 45% and experienced mild side effects. Both LOXO-292 and BLU-667 have also shown promising efficacy in patients with other RET-altered malignancies, notably RET fusion–positive non–small cell lung cancer.

“What makes these drugs really exciting is the fact that they seem to be as good as some of the other established drugs at a much lower cost in terms of side effects—I think it's really the best of both worlds,” says Jochen Lorch, MD, of Dana-Farber/Harvard Cancer Center in Boston, MA, who was not involved in either trial. He adds that he considers LOXO-292 and BLU-667 equivalent, and based on the results so far, “there's no doubt in my mind that for RET-mutant medullary thyroid cancer, one or both will become the standard of care” if approved.

The bigger question, he says, will be deciding which drug to use. “It seems that there may be cross resistance, which makes this whole discussion a little bit higher stakes, because it's not just which one are you going to use first, it's really which one are you going to use at all.” –Catherine Caruso