BLU-667 Targets RET-Altered Cancers

According to findings from the ongoing phase I ARROW study, BLU-667 (Blueprint Medicines), an investigational RET inhibitor, was safe, well tolerated, and showed promising activity in patients with advanced RET-altered cancers. The data were presented today by Vivek Subbiah, MD, of The University of Texas MD Anderson Cancer Center in Houston, during the American Association for Cancer Research (AACR) Annual Meeting 2018 in Chicago, IL.

Constitutive activation of RET, a receptor tyrosine kinase, occurs through two main mechanisms. Point mutations, including M918T, are common in medullary thyroid cancer (MTC). In addition, gene rearrangements yielding fusion proteins such as KIF5B–RET and CCDC6–RET are seen in diverse tumor types, including 1% to 2% of non–small cell lung cancers (NSCLC) and up to 20% of papillary thyroid cancers.

RET fusions in NSCLC “first came on our radar about 8 years ago, and we were excited that this could be another targetable alteration, analogous to ALK and ROS1,” said Alice Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, who was not involved with ARROW. To date, however, patients with RET-altered cancers “have not benefited from precision oncology,” Subbiah noted, and multikinase inhibitors, including cabozantinib (Cabometyx; Exelixis) and vandetanib (Caprelsa; Sanofi), remain the therapeutic mainstay.

“These inhibitors happen to hit RET among other targets, and we've seen some clinical efficacy, but nothing stellar,” Shaw said. The drugs are also associated with significant off-target toxicities—notably through VEGFR2 inhibition, which can provoke hypertension, thrombosis, and hemorrhage—that “really limit our ability to use them in patients with RET-driven disease,” she added.

Enter BLU-667, which Subbiah described as a “designer drug” that inhibits RET potently and selectively without blocking VEGFR2. In bench studies, this agent suppressed RET signaling and cancer cell proliferation in vitro; it also demonstrated strong antitumor activity in multiple mouse models. ARROW was then initiated for clinical proof-of-concept; characterization of the first four patients, along with the preclinical data, was also published today.

At the AACR meeting, Subbiah reported that among 40 evaluable patients, all with RET-altered cancers, the objective response rate (ORR) was 45%. Within the MTC and NSCLC cohorts, the respective ORRs were 40% and 50%. He highlighted several individual cases, including a 27-year-old man with MTC and “a tumor mass so huge, he needed a tracheostomy to breathe,” who nonetheless achieved a partial, durable response to BLU-667. Another patient with metastatic NSCLC “had a brain response upon first assessment” following treatment. As of April 6, 41 of 51 enrolled patients remain on therapy.

Subbiah observed that responses occurred in both those patients not previously given and those refractory to multikinase inhibitor therapy. BLU-667 also showed broad antitumor activity across different RET fusions and point mutations. The drug was “extremely well tolerated,” he added: Its main side effects, which were mild, included diarrhea, constipation, and elevated liver enzymes.

With cabozantinib and vandetanib, resistance arises through gatekeeper mutations, chiefly V804L/M, that sterically interfere with drug binding. BLU-667 has been shown to stop the proliferation of cell lines harboring these variants as well as a novel aberration, V804E, which Subbiah and his colleagues identified. Acquired resistance to BLU-667 too is likely inevitable, he remarked, but “we'll need to follow patients longer and continue with comprehensive genomic profiling to uncover the mechanisms involved.”

Besides BLU-667, another selective RET inhibitor currently in phase I evaluation is LOXO-292 (Loxo Oncology). During the 2017 World Conference on Lung Cancer in Yokohama, Japan, preliminary data on two patients with RET-altered NSCLC were presented. Both achieved partial responses to LOXO-292, which was also well tolerated.

“It's early days yet, but the results so far look encouraging,” Shaw said of these agents. “Our hope is that this field follows the ALK inhibitor trajectory, with more drugs developed that are really active and safe.” –Alissa Poh