LOXO-292, a selective and potent RET inhibitor, led to tumor shrinkage in RET fusion–positive and RET-mutant cancers alike, according to phase I data reported at the 2018 American Society of Clinical Oncology Annual Meeting.
A selective and potent RET inhibitor, LOXO-292 (Loxo Oncology), is showing early signs of efficacy, yielding responses across a range of RET alterations and tumor types, and a favorable safety profile, according to interim phase I data presented on June 2 at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL (J Clin Oncol 36, 2018 [suppl; abstr 102]).
“It's very exciting to see a drug like this that's not only active but also highly tolerable,” said lead trial investigator Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who made the presentation. “It really lends itself to prolonged dosing, especially considering that these patients can have long-term benefit with this treatment.”
Gene fusions involving RET occur in approximately 10% of papillary thyroid cancers (PTC), 2% of non–small cell lung cancers (NSCLC), and a small fraction of other malignancies, whereas activating point mutations in RET are found in some 60% of medullary thyroid cancers (MTC), including hereditary and sporadic cases alike.
Several multikinase inhibitors with some activity against RET have been tried in these patients, with limited effect. Response rates tend to be low and off-target toxicities high, leading to a push to develop safer, more potent RET blockers.
Enter LOXO-292, “a purpose-built inhibitor of RET and nothing else,” as Loxo CEO Josh Bilenker, MD, described it. “It can deeply inhibit the pathway as opposed to lightly tickle it, as a lot of repurposed drugs have been doing.”
In April, Drilon and his colleagues reported on the first two patients to receive the drug; in each case, the RET-altered tumors regressed on LOXO-292 despite having received multiple prior therapies (Ann Oncol 2018 Apr 18 [Epub ahead of print]). The researchers also showed, in both cell lines and mouse models, that LOXO-292 has preclinical activity against various RET alterations, resistance mutations, and brain metastases.
At the ASCO meeting, Drilon provided a more detailed clinical picture of LOXO-292, offering data from the phase I trial for 61 response-evaluable patients with RET-altered cancers. For the 30 patients with RET fusion–positive NSCLC, tumor regression occurred regardless of RET's fusion partner, with an overall response rate (ORR) of 77% and another 13% experiencing stable disease. Among other patients with RET fusions, all seven with PTC responded and both patients with pancreatic cancer had stable disease. In the RET-mutant MTC cohort, the ORR in 22 patients was 45%, with another 41% experiencing stable disease. Only two patients experienced serious adverse events, and the other side effects were mostly benign and infrequent.
Notably, at the time of data analysis, more than 90% of the trial participants remained on therapy—an indicator that “disease control was durable in many cases,” Drilon said.
The data for LOXO-292 compare favorably to interim phase I results for another early clinical-stage RET-targeted agent, BLU-667 (Blueprint Medicines). As reported at the American Association for Cancer Research Annual Meeting 2018 in April, that drug was well tolerated, with a 50% ORR among patients with NSCLC and a 40% ORR among those with MTC.
“Both of these drugs look like they're very promising,” said Justin Gainor, MD, of Massachusetts General Hospital in Boston, MA, who has been involved in testing both agents. “We are seeing higher response rates than what we've seen with the multikinase inhibitors, and it does look like the toxicity profiles are more favorable.” –Elie Dolgin
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