Phase 1 RNL-186 Shows Promise in Leptomeningeal Metastases: Andrew Brenner, MD, PhD

New findings from a phase 1 trial presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) showed significant improvements in overall survival and a decrease in disease symptoms in patients who had developed leptomeningeal metastases (LM).¹

These metastases are a systemic cancer complication often stemming from cancer of the breast, lung, or melanoma. There are limited treatment options for patients with LM, but research data presented at SABCS showed promise for this setting. Rhenium-186 NanoLiposome (RNL-186), administered through an intraventricular catheter, showed “excellent safety and promising activity” for LM. The abstract encompassed the results from the ReSPECT-LM phase 1 trial (NCT05034497) and was presented by Andrew Brenner, MD, PhD, a breast and neuro-oncology specialist and professor of medicine in the division of hematology and oncology at the University of Texas Health Science Center.

Brenner explained, in an interview with The American Journal of Managed Care^®, that the primary end points of this trial were safety and dosage, with efficacy as a secondary end point. The recommended dosage, researchers concluded, based on the trial results, was 44.10 mCi with a maximum dose of 66.14 mCi. There were no serious adverse events reported in the 44.10 mCi dose cohort, and the majority of adverse events across the trial were grade 1 and 2.

The phase 2 trial will use the recommended dosage established in phase 1 and will seek an optimal dosage schedule for patients. The biggest hurdle researchers encountered during phase 1 was disease symptoms recurring after they had been reduced, leading Brenner and his team to explore fractionation dosage in phase 2 of the trial.

“We’re going to be escalating the dose, as well as in terms of multiple doses, but also try to determine the best frequency of dosing, and so hopefully that will help more patients get a more durable response,” he said.

This transcript was lightly edited. Captions are auto-generated.

Transcript

What factors influenced the decision to select 44.10 mCi as the recommended phase 2 dose, given that activity was seen at higher dose levels?

What we saw, even in our very first patient, was about a 90% decrease in those cell counts from pretreatment to about 48 hours after treatment that persisted 28 days after treatment. Even in the very first patient, we were seeing responses that you would expect with radiation. But what was especially exciting was that throughout this dose doubling, and even in these later cohorts, we saw no neurologic toxicity, essentially. We had patients who had low-grade adverse events in terms of some headache and nausea and things like that, but there’s a natural tendency for these patients to have headaches associated with their disease, and so it wasn’t necessarily clearly treatment-related. In any case, they were very low grade, but there was no evidence of any neurologic complications whatsoever.

When we got to the highest doses at 66 mCi, what we did see is about 1 in 6 patients had low platelet counts. And when we did dosimetry, looking at the absorbed radiation dose throughout the body, not just the spinal system or CNS [central nervous system], we saw that there was a blood absorbed dose probably in the 3 to 4 Gy range.

What was happening as we were getting higher doses was that some of it was not being retained because of the large amount and was being exposed in the blood. And when we saw that at the 66-mCi dose, we decided we’re just going to go up a tiny bit for the next cohort. We went from 66 mCi to 75 mCi and took a more moderate dose of escalation. And at that 75 mCi, 1 in 3 had that same problem. And we realized that, probably, our safest doses were below the 66 mCi dose. And we determined the 44 mCi dose to be the recommended phase 2 dose, but the maximum tolerable dose would be 66 mCi.

What were the primary outcomes observed in the trial, and did the therapy show signs of efficacy?

Good safety in terms of, well, this is a phase 1 study, and efficacy is not the primary end point. Obviously, safety and determining the best dose are. We did have secondary objectives of looking at outcomes. We saw prolonged survival in quite a few of our patients. As a matter of fact, some of our patients did so well without any additional treatment with control of their CNS disease that they actually requested additional doses when the tumor started to look like it was growing again, 9 months or 10 months later.

For example, some patients received multiple doses in a compassionate use fashion. And our longest survivor was beyond 3 years for a disease that usually claims people’s lives in a few months. The median overall survival for the entire group, as well as for the breast cancer patients in particular—we had about 10 breast cancer patients who were enrolled—was 9 months, so pretty supportive of the activity in this patient population.

We also saw that nearly all of our patients had a reduction in their cell counts in the spinal fluid, and we saw some radiographic responses, which are difficult to achieve in this disease, with nearly one-third of patients having a radiographic response. And we actually had some patients that had even clinical improvement, which is really difficult to come by, because a lot of times, neurological deficits can be permanent once damage occurs, and some of our patients actually had improvement in their neurologic symptoms. All that supports the continued development of this for leptomeningeal metastases.

Among patients who achieved a partial response of stable disease, how durable were these benefits beyond day 112?

One thing we didn’t notice is that a lot of times, for example, I mentioned that the very first patient we treated had a 90% decrease, but by day 56, it started coming back up, and he started becoming symptomatic, and now there’s a question of what’s the best way to do these treatments.

In some cases, patients had benefits lasting 9 months, right? We had patients who received multiple doses, and they were patients who did well for a long period of time, but not in all cases. In some cases, we saw a dip, and then patients dealing with progressive disease at day 56. So, responses weren’t always durable. We did have durable responses in several patients, and if you look at our swimmers’ plots, you’ll see that some of these patients, especially in the first few cohorts, did really well over a long period of time. But we do need to address that.

One thing in terms of radiotherapeutics that we’re seeing with other studies is fractionation. In other words, instead of giving one big whopping dose, which we tried to determine was the maximum dose we could give, we are saying, “Hey, if we break it up and give it in a few divided doses, maybe we’ll get better outcomes, and for those patients that have responses, we can make them more durable.” That’s where we are right now. We’re doing a multidose study, and we’re administering it every 56 days, and we also have 28-day intervals and 14-day intervals built into that protocol. We’re going to be escalating the dose, as well as the number of doses, but also try to determine the best frequency of dosing, and so hopefully that will help more patients get a more durable response.

Reference

1. Brenner A, Youssef M, Kumthekar P, et al. Rhenium (¹⁸⁶Re) obisbemeda (rhenium nanoliposome, ¹⁸⁶RNL) for the treatment of leptomeningeal metastases: phase 1 dose escalation study results. Abstract presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX.