RET Inhibitor Tested in Multiple Tumor Types

Alexander Drilon, MD

Investigators are evaluating the potential of LOXO-292, an oral small molecule inhibitor of RET signaling, to improve outcomes in patients with RET fusion—positive non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other tumors with increased RET activity. RET mutations drive tumor proliferation and growth and are particularly common in NSCLC and MTC.

These cancers represent an unmet need because no targeted agents are currently approved for patients with RET mutation—specific tumors, according to Alexander Drilon, MD, clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York. “It’s a substantial population,” he said. “RET fusions are found [commonly] in NSCLC, papillary thyroid cancers, and other tumors; RET point mutations are enriched in medullary thyroid cancers.”

The phase I/II open-label LIBRETTO-001 clinical trial (NCT03157128) is currently testing LOXO-292 in these patient populations (Table). The phase I portion of the trial sought to determine the safety and recommended dosage of the drug. This is still ongoing, but a recommended phase II dose for LOXO-292 was determined to be 160 mg twice per day.

The trial was recently expanded to a phase II portion, which will involve 5 cohorts, all of which will receive LOXO-292 monotherapy. Cohorts 1 to 4 will include patients with a RET mutation in their tumor and at least 1 measureable lesion. In cohorts 1 and 3, patients must have received prior standard therapy for their cancer and would be unlikely to derive benefit from further standard of care treatment. Patients in cohort 4 must have radiographic progressive disease within 14 months before starting the trial. Finally, cohort 5 will include patients who do not have measureable disease, have any other RET-altered solid tumor or RET alteration/activation, and have cell-free DNA positive for a RET gene alteration not known to be present in their tumor sample.

Gene fusions, or chromosomal rearrangements, and activating mutations promote overactive RET signaling and uncontrolled cell growth. LOXO-292 is designed to inhibit RET signaling and acquired resistance mechanisms that would limit the effectiveness of this approach. “Although these alterations are bona fide cancer drivers, unfortunately, the clinical activity of approved or investigational anti-RET multikinase inhibitors has been limited,” Drilon said when presenting interim results of LIBRETTO-001 during the 2018 American Society of Clinical Oncology Annual Meeting. He is the principal investigator at MSK.

Figure. LOXO-292 LIBRETTO-001 Trial

Multikinase inhibitors that are approved for NSCLC or MTC are sometimes referred to as “dirty” drugs because they attack multiple targets along with RET signaling, leading to a greater incidence of adverse events (AEs). “For the older, ‘dirtier’ drugs, we see about a 30% response rate [in RET fusion—positive NSCLC], with much more toxicity,” Drilon said. “Here we are seeing a drug that is achieving outcomes that are similar to what we might expect from a targeted therapy for EGFR, ALK, and ROS1 [mutations or fusions].”Unlike prior multikinase inhibitors, LOXO-292 is a highly selective potent RET inhibitor that has little inhibition of other targets. It is also potent in vitro and in vivo against diverse RET fusions and mutations, including the V804M gatekeeper mutation.¹

Interim results of LIBRETTO-001 demonstrated an objective response rate (ORR) of 77% (95% CI, 61%-89%) per RECIST 1.1 criteria among 49 patients with RET fusion-positive tumors, including 38 with NSCLC, 9 with thyroid cancer, and 2 with pancreatic cancer. In 29 patients with RET-mutated MTC, the ORR was 45% (95% CI, 24%-68%), with 1 complete response (CR) and 1 additional CR awaiting confirmation. In 4 participants with no known activating RET alteration, there was no response with LOXO-292.¹

Antitumor activity was observed across all dose levels, including at the smallest dose of 20 mg daily. Responses were observed despite prior treatment with a variety of anti-RET multikinase inhibitors. This is notable because the majority of patients were heavily pretreated with approved systemic therapies, including chemotherapy and immunotherapy for both, and radioactive iodine for patients with MTC.

“There was no maximum tolerated dose and the drug showed a favorable safety profile,” Drilon said. Most AEs were grade 1 in severity.

There were only 2 treatment-related grade 3 AEs and no grade 4 AEs. The 2 grade 3 AEs were tumor lysis syndrome and increased alanine aminotransferase levels, both of which were resolved. The most common AEs in the study were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (9%). The most common AEs directly related to treatment were fatigue (13%), dry mouth (6%), nausea (5%), diarrhea (2%), and constipation (2%).¹

Also, LOXO-292 has shown activity in the central nervous system against RET fusion-positive tumors. In a study presented at the 2017 International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer, 2 patients with NSCLC and brain metastases achieved partial responses with LOXO-292. The drug was also well tolerated, with no dose-limiting toxicities for these patients.²

“I think this is encouraging data,” Drilon said. “Certainly, this new class of drugs has already shown, even in phase I testing, meaningful activity different from the older agents. Putting all patients on the same dose and confirming the safety and efficacy of the drug are the next major steps.

References

1. Drilon AE, Subbiah V, Oxnard GR, et al. LIBRETTO-001: a phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 2018;36(suppl; abstr 102). meetinglibrary.asco.org/record/161573/abstract.
2. Velcheti V, Bauer T, Subbiah V, et al. LOXO-292, a potent, highly selective RET inhibitor, in MKI-resistant RET fusion-positive lung cancer patients with and without brain metastases. J Thorac Oncol. 2017;12(suppl 2; abstr OA 12.07). loxooncology.com/docs/presentations/2017_LOXO292_IASLC_Presentation.PDF.