Promising Response Rates, Safety Found With LOXO-292 in RET-Altered Thyroid Cancers

Alexander Drilon, MD

Alexander Drilon, MD

At the 2018 ASCO Annual Meeting, results were presented from the phase I LIBRETTO-001 study on the safety of LOXO-292 for the treatment of patients with RET-altered cancers. This data caused a lot of excitement as it addresses a major unmet need in this patient population.

RET-activating point mutations are found in over 60% of medullary thyroid cancers. Additionally,RETgene rearrangements are found in over 10% of papillary thyroid cancers. Previously approved drugs in this setting only have about a 30% response rate and a very toxic side effect profile.

The LIBRETTO-001 study looked at 2 subsets of patients withRETalterations. One subset included only patients with medullary thyroid cancers, while the second consisted of patients withRETfusion-positive cancers, including patients with papillary thyroid cancer.

This dose-escalation trial sought to find the maximum tolerated dose for these patients, as well as get a better understanding of the safety profile. Investigators found LOXO-292 to have a very low toxicity profile with the only dose limiting-toxicity seen in 1 patient.

In an interview withTargeted Oncology,Alexander Drilon, MD, clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, discussed the data from this trial and how it will affect this patient population. He also highlights the next steps for this drug and its potential in the field.

TARGETED ONCOLOGY:There was a lot of excitement around LOXO-292 at this year's ASCO. Can you start by giving us some background on that study?

Drilon:There are 2 major ways that a gene called RET can be activated in cancer. It's either through fusions or through mutations. We have had older drugs forRETfusion-positive cancers orRET-mutant cancers, like cabozantinib (Cabometyx) and vandetanib (Caprelsa). However, the problem with the older drugs is that they're multikinase inhibitors and they're very dirty. While they can target RET, they also inhibit a bunch of other things that lead to side effects that impact tolerability in patients.

LOXO-292 is different in the sense that it is highly selective for RET and really has minimal off-target activity. It was designed to be a potent inhibitor of RET and because of its clean nature, it hopefully results in a very favorable side effect profile. The last thing I'll mention is that it also, in preclinical studies, was found to have activity in models whereRET-altered cancer was in the brain. These are many of the favorable features that you look for when you develop a newer generation agent.

TARGETED ONCOLOGY:Can you discuss the design of this trial?

Drilon:The LIBRETTO-001 study is a phase I study of LOXO-292, and the data that was presented was focused mainly on the dose escalation portion of the trial, where the primary endpoint was determination of the recommended phase II dose or 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.

TARGETED ONCOLOGY:What was the efficacy that we saw in this study?

Drilon:Talking about the efficacy of LOXO-292, it's a good look at the 2 distinct biologic subsets ofRETfusion-positive cancers andRET-mutant cancers. In theRETfusion-positive cancers, that, interestingly, included not just lung cancer and thyroid cancer, but pancreatic adenocarcinoma, the response rate that was confirmed was 74%. InRET-mutant cancers, which were predominantly all medullary thyroid cancers, the response rate was 33%. Just to put the former in perspective, with the older, dirtier drugs forRETfusion-positive lung cancers, we see about a 30% response rate with much more toxicity. Here, we are seeing a drug that is achieving outcomes that are really similar to what we might expect for targeted therapy in EGFR, ALK, and ROS1.

TARGETED ONCOLOGY:Can you hone in on the safety of LOXO-292?

Drilon:As I mentioned earlier, this drug is a highly-selective inhibitor of RET. The hope was that if you hit RET potently and avoid other things, you'll see a favorable safety profile in patients, and that is what we saw. There was a very low frequency of treatment-emergent adverse events (TEAEs). These were mostly grades 1 to 2. Many of them were not deemed related to LOXO-292. In fact, if you look at the TEAEs, it's really a short list of things, including fatigue and some gastrointestinal side effects, but by large, these were pretty mild. In fact, in this dose-escalation study, there was only 1 dose-limiting toxicity of a patient that developed tumor lysis syndrome. Only 1 other grade 3 AEs related to the drug was an increase in liver function tests.

TARGETED ONCOLOGY:What are the next steps following this study?

Drilon:The next steps for LOXO-292 are seeing what the drug does in many more patients. The trial is currently in its expansion phase and is again looking at those 2 major subsets ofRETfusion-positive cancers andRET-mutant medullary thyroid cancers. The hope is that we see confirmation of the activity that we've seen just on the escalation, which was interestingly a dataset that was collected over less than a year. If we see that activity and safety carried over in the further testing, my hope is that at some point in time, we will see a regulatory nod and maybe approval for these 2 subsets.

TARGETED ONCOLOGY:How common are RET fusions among patients?

Drilon:RETfusions are found in a variety of different cancers. In lung cancers, specifically non­—small cell lung cancer that are very common with over 200,000 cases in the United States every year, the frequency is up to 2%, which is comparable to ROS1. In papillary thyroid cancers, it's 10% to 20%, and there is also a smattering of fusions across other histologies. InRET-mutant medullary thyroid cancers, you expect to see that in the majority of cases. When you add all of those up, it's a sizable population.

TARGETED ONCOLOGY:What is the takeaway from this study?

Drilon:We've been waiting for a very long time for not only a highly active drug in theseRET-altered tumors, but a drug that's also very safe. I think that these early results are encouraging, and my hope is that this will eventually result in the approval of a drug like this. That will help many patients as this is an underserved population right now.

Reference:

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).