Could Triapine With Lutetium 177 Dotatate Improve Outcomes for Neuroendocrine Tumors?

Aman Chauhan, MD

Advancements in treating well-differentiated somatostatin receptor-–positive neuroendocrine tumors (NETs) with lutetium Lu 177 dotatate (Lutathera) have been promising. However, there is still a need to boost efficacy, especially in advanced cases. Experts are now combining lutetium Lu 177 dotatate with radiation sensitizers to see if this can help better tumor response.

In a phase 2, randomized trial, investigators are assessing the combination of triapine with lutetium 177 dotatate vs Lutetium 177 dotatate alone for the treatment of well-differentiated somatostatin receptor–-positive neuroendocrine tumors. The trial is currently ongoing, and the early findings suggest that the combination therapy is safe, with no new safety concerns identified so far, according to Aman Chauhan, MD.

“[Lutetium Lu 177 dotatate] is attractive because of its excellent safety profile and ease of administration. It requires only 4 [intravenous] infusions, spaced 2 months apart, which is a refreshing break for patients compared with the weekly treatments they often expect with cancer therapies,” Chauhan, leader of neuroendocrine oncology and co-leader of radiopharmaceutical drug development at Sylvester Comprehensive Cancer Center at the University of Miami, told Targeted OncologyTM in an interview.

Still, efficacy data from the study are still maturing, with progression-free survival and response rates being monitored as secondary end points. The study is also exploring other promising sensitizers for future research, with the goal of improving outcomes for patients with advanced neuroendocrine tumors.

In the interview, Chauhan discussed the phase 2 study and what oncologists should keep an eye on in this space moving forward.

Targeted Oncology: Can you discuss the unmet needs in the neuroendocrine cancer treatment paradigm that your study addressed?

Chauhan: Neuroendocrine cancers are considered rare cancers, affecting about 7 or 8 people per 100,000 in the population. However, one unique aspect of neuroendocrine cancer is the overall burden of the disease. In the US alone, there are over 170,000 patients with neuroendocrine cancer because these patients tend to live longer, making the cumulative prevalence much [higher than expected]. Despite this, treatment options have not kept pace with the growing burden of disease. We are still looking for better, innovative treatments that can prolong the lives of this large population, both in the US and worldwide.

Microscopic, photorealistic image of neuroendocrine tumor cells - Generated with Google Gemini AI.jpeg

What was your study evaluating, and what was the methodology?

We presented a trial-in-progress, an ongoing, randomized, phase 2 study, and a multi-center trial sponsored by the National Cancer Institute. I have been working on this concept for several years. One very effective treatment for neuroendocrine cancer is called Lutathera [lutetium Lu 177 dotatate], a radiopharmaceutical drug that latches onto somatostatin receptors on neuroendocrine tumors and effectively controls the disease for a prolonged period. We are working on enhancing [lutetium Lu 177 dotatate’s] effectiveness by adding radiation sensitizers—medications that make [lutetium Lu 177 dotatate] work even better.

Our journey began with testing promising radiation sensitizers in neuroendocrine tumor animal models and then moving to multi-center phase 1 studies. We were able to demonstrate that we can safely add these sensitizers to [lutetium Lu 177 dotatate]. Now, in our randomized phase 2 study, half of the patients are being treated with the combination of [lutetium Lu 177 dotatate] and a new drug called triapine, while the other half receives the standard care of [lutetium Lu 177 dotatate] alone. The study is enrolling rapidly across the US at 14 different cancer centers, and I am the co-principal investigator nationally.

Are there any known safety concerns with Lutathera, either previously reported or currently observed in your trial?

[Lutetium Lu 177 dotatate] is attractive because of its excellent safety profile and ease of administration. It requires only 4 [intravenous] infusions, spaced 2 months apart, which is a refreshing break for patients compared with the weekly treatments they often expect with cancer therapies. We have treated hundreds of patients with [lutetium Lu 177 dotatate] since its FDA approval, and the long-term safety data is exceptional, showing minimal toxicity to the kidneys, liver, and bone marrow. We have also treated about 60 patients with the combination of phase 1 and phase 2 of our trial. So far, we have not observed any significant safety concerns or new risks associated with the addition of triapine. However, since this is an ongoing trial, we will update the public next year with interim analysis data.

Based on preliminary findings, what does the efficacy of the combination appear to be compared with the standard [lutetium Lu 177 dotatate] treatment?

That is the million-dollar question, but unfortunately, we do not have mature data yet. The primary end point in phase 1 was safety and finding the recommended phase 2 dose. Secondary end points included progression-free survival and response rates. These data are still maturing, and many patients are continuing long-term follow-up to evaluate the efficacy. We expect to conduct an interim analysis of the ongoing phase 2 data, but it will take time before we can draw definitive conclusions about the combination's effectiveness.

What are the next steps in this area of research?

Radiopharmaceuticals are rapidly becoming a key tool in oncology, and this field is growing tremendously. We expect radiopharmaceuticals to be used in many types of cancers beyond neuroendocrine tumors. The use of radiation sensitizers, particularly DNA-damaging agents, will be crucial for other diseases as well. What we are learning from this study could be applied to other solid tumors. We are also investigating other promising sensitizers, like an DNA protein kinase inhibitor that works by blocking the cancer cell's ability to repair the DNA damage caused by [lutetium Lu 177 dotatate].

We recently completed a phase 1 study with this drug at 30 sites, and we are waiting for safety data. This is just the beginning. We are exploring how to combine current theranostic agents like Lutathera with other drugs that have synergistic effects without overlapping toxicities. This approach could improve the effectiveness of these agents significantly.

We are excited to see how these studies progress and are optimistic about the potential of combining radiopharmaceuticals with radiation sensitizers and other targeted therapies. We look forward to continuing our journey, especially with the upcoming randomized phase 2 study.

REFERENCE:

1. Chauhan A, Kunos C, Arnold Sm, et al. A phase II randomized control trial of triapine plus lutetium 177 DOTATATE versus lutetium 177 DOTATATE alone for well-differentiated somatostatin receptor-positive neuroendocrine tumors. J Clin Oncol. 2024;42(suppl 16):TPS4202 doi:10.1200/JCO.2024.42.16_suppl.TPS4202