LOXO-292 Highly Effective in RET-Positive Cancers

August 2018 Vol 11, Special Issue - Emerging Therapies
Chase Doyle

Chicago, IL—The investigational LOXO-292, a potent and highly selective RET kinase inhibitor, has demonstrated robust and durable antitumor activity against RET-activating fusions and mutations. This new agent has shown promising efficacy in patients with solid tumors (eg, lung cancer) and RET mutations, according to data presented at ASCO 2018. This activity was independent of tumor histology, previous therapy, RET fusion partner, or RET-activating mutation.

Results of the phase 1 LIBRETTO-­­­001 study showed a 77% overall response rate (ORR) in patients with RET fusion–positive cancer, with intracranial activity, and a 45% ORR in patients with medullary thyroid cancer (MTC) and RET mutation. Consistent with its high RET selectivity, LOXO-292 was also well-tolerated by patients at multiple dose levels, with minimal toxicity, which contrasts with significant off-target liabilities of previous multikinase inhibitor therapy, the investigators noted.

"Certainly, these promising results underscore the importance of screening for these alterations in the clinic," said lead investigator Alexander E. Drilon, MD, Clinical Director, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York City, who presented the results. "The activity of LOXO-292 is durable, with over 90% of patients still on treatment as of the data cutoff, including all responding patients. The longest duration of treatment exceeded 10 months."

First-in-Humans LIBRETTO-001

Initiated in May 2017, LIBRETTO-­­­001 is a first-in-human, phase 1 clinical trial of LOXO-292. Patients with advanced or metastatic solid tumors, including those with RET alterations identified by localized molecular testing, were eligible for the study. The investigators noted that 59% of the solid tumors harbored a RET fusion and 35% of the MTC tumors harbored a RET mutation.

The primary end point was the maximum tolerated dose or recommended dose for further study; the secondary end points included ORR assessment. At the April 2018 data cutoff, 82 patients had received treatment across 7 cohorts, with doses ranging from 20 mg daily to 240 mg twice daily.

LOXO-292: Impressive Safety and Response Rates

LOXO-292 was well-tolerated, consistent with its high preclinical selectivity for RET. Only 6 treatment-emergent adverse events were observed in at least 10% of patients. The majority of these events were grade 1 or 2 and were deemed unrelated to LOXO-292. The 2 treatment-related grade 3 adverse events reported were tumor lysis syndrome, which represented the only dose-limiting toxicity observed on this trial, and elevated liver enzymes. Both toxicities were reversible, the investigators noted.

The antitumor activity of LOXO-292 was equally impressive. The ORR and confirmed ORR exceeded 70% for cancers with RET fusion in patients with non–small-cell lung cancers and in those with other tumors, specifically thyroid and pancreatic cancers. In patients with MTC and RET mutation, the ORR and confirmed ORRs were 45% and 33%, respectively, including 2 complete responses. By contrast, no activity was observed in 3 evaluable patients without known activating RET alterations.

Disease regression was observed in the majority of patients with RET fusion, and this activity did not differ by cancer type, said Dr Drilon. Rather, responses occurred independent of the upstream RET-fusion partner. Furthermore, antitumor activity was observed across the entire range of dose levels, including at the first dose of 20 mg daily. Responses were also observed despite previous treatment with a variety of anti-RET multikinase inhibitors.

Disease regression also occurred in most patients with MTCs and RET mutation. This activity was independent of previous treatment with multikinase inhibitors, including the FDA-approved agents cabozantinib (Cabometyx) and vandetanib (Caprelsa), as well as other investigational drugs. Enrolled patients were heavily pretreated, with many having received ≥2 of these agents.
"This activity occurred across different starting doses and in diverse RET-activating mutations, including 2 cancers with a V804M gatekeeper mutation that causes resistance to clinically available anti-RET multikinase inhibitors," said Dr Drilon.

Activity in CNS Metastases

Finally, as a result of the high lifetime prevalence of brain metastases in patients with RET fusion, LOXO-292 was specifically designed to provide meaningful coverage of the central nervous system (CNS). The investigators reported that approximately 25% of patients with RET fusion–positive lung cancers in this study had brain metastases.

"All 12 RET fusion–positive cancers with CNS metastases at baseline remain on treatment," said Dr Drilon. "Of these, all 3 patients with measurable intracranial disease experienced confirmed intracranial responses to LOXO-292."

A dose-expansion portion of the LIBRETTO-001 study is currently enrolling patients with a variety of cancers and RET fusions or RET mutations.

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