Drilon Discusses Promise of LOXO-292 in RET-Altered Solid Tumors

Alexander Drilon, MD

Phase I findings from the LIBRETTO-001 study (NCT03157128) in patients with RET-altered solid tumors showed signals of clinical activity with LOXO-292. The addition of a drug like this to the paradigm could help an underserved population of patients with cancer, said Alexander E. Drilon, MD.

At the 2018 ASCO Annual Meeting, Drilon reported an objective complete response rate of 77% (95% CI, 58%-90%) with the highly selection RET inhibitor for patients with RET fusion—positive non–small cell lung cancer (NSCLC), and 45% for patients with RET-mutated medullary thyroid cancer. Eighty-two patients had been treated with LOXO-292 across 7 cohorts by the April 2018 data cutoff.

Drilon also explained that there was a manageable safety profile with LOXO-292, something not previously seen with multikinase inhibitor therapy in patients with RET alterations.

“The problem with the older drugs is that they are multikinase inhibitors,” said Drilon, a medical oncologist at Memorial Sloan Kettering Cancer Center. “While they can target RET, they also inhibit a bunch of other things that lead to side effects, which impacts tolerability in patients.”

LIBRETTO-001 has moved into an expansion phase and is currently enrolling patients with RET fusion—positive and RET-mutant tumors.

OncLive: Can you provide some background information on this study?

In an interview with OncLive, Drilon, who is also lead study author of LIBRETTO-001, discussed the data with LOXO-292 thus far and the promise for this agent in patients with RET alterations.Drilon: There are 2 major ways that the RET gene can be activated in cancer, either through fusions or mutations. We have had older drugs for RET fusion—positive cancers or RET-mutant cancers, such as cabozantinib (Cabometyx) and vandetanib (Caprelsa).

What is the prevalence of RET fusions and mutations in patients with cancer?

LOXO-292 is different in the sense that it is highly selective for RET and has minimal off-target activity. It was designed to be a potent inhibitor of RET, and because of its clean nature, it will hopefully result in a very favorable side effect profile. In preclinical studies, it was also found to have activity in models where RET-altered cancer was in the brain. This is one of many favorable features that you look for when you develop a newer-generation agent. RET fusions are found in a variety of different cancers. In lung cancer, specifically NSCLC, they are common—about 200,000 cases in the United States every year. The frequency is up to 2%, so it is comparable with ROS1 fusions. In papillary thyroid cancer, it is 10% to 20%, and then there is a smattering of fusions across other histologies.

What was the design of this trial?

What was the efficacy observed in this study?

In medullary thyroid cancer, you expect to see RET mutations in the majority of cases. Add all of those up and it is a sizable population. The LIBRETTO-001 study is a phase I study of LOXO-292. The data that were presented were focused mainly on the dose-escalation portion of the trial, where the primary endpoint was determination of the recommended phase II dose or the maximum-tolerated dose. This trial accrued patients with a variety of solid tumors, the vast majority of whom harbored a RET alteration in their cancers.When talking about the efficacy of LOXO-292, it is good to look at the 2 distinct biologic subsets of RET fusion—positive cancers and RET-mutant cancers. In the RET fusion—positive cancers, which interestingly included pancreatic adenocarcinomas in addition to lung and thyroid cancers, the confirmed response rate was 74%. In RET-mutant cancers, which was all medullary thyroid cancers, there was a confirmed response rate of 33%.

Can you discuss the safety profile of LOXO-292?

Just to put the former in perspective, with the older and "dirtier" multikinase inhibitors for RET fusion—positive cancers, we see a 30% response rate with much more toxicity. Here, we are seeing a drug that is achieving outcomes that are similar to what we would expect for targeted therapy in EGFR, ALK, and ROS1. This drug is a highly selective inhibitor of RET, and the hope is that if you hit RET potently and avoid other things, then you will see a favorable safety profile in patients. That is what we saw. There is a very low frequency of treatment-emergent adverse events (TEAEs); these were mostly grade 1/2 and many of them were deemed unrelated to LOXO-292.

What are the next steps following these findings?

What would be your take-home message about this study thus far?

In fact, if you look at the TEAEs, it is really a short list of 6 things, including fatigue and some gastrointestinal side effects. But by and large, these were pretty mild. In fact, in this dose-escalation study, there is only 1 dose-limiting toxicity, which was in a patient who developed tumor lysis syndrome. There was only 1 grade 3 AE related to the drug, which was an increase in liver function tests.The next steps for LOXO-292 are seeing what the drug does in more patients. The trial is currently in its expansion phase and is looking again at those 2 major subsets of RET fusion—positive cancers and RET-mutant medullary thyroid cancer. This data set was interestingly collected in less than 1 year, and if we see that activity and safety carried into further testing, my hope is that we will eventually see a regulatory nod and maybe an approval of an agent like this for those 2 subsets. We have been waiting for not only a very highly active drug, but a drug that is very safe in these RET-altered tumors for a very long time. These early results are encouraging, and my hope is that this will eventually result in the approval, which will help many patients, as this is an underserved population right now.

Drilon AE, Subbiah V, Oxnard GR, et al. 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).