PRRT has become a standard of care for inoperable SSTR-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, achieving a complete response is rare, and the progression-free survival (PFS) benefit of these therapies is unclear, leading to attempts to improve PRRT and to identify an optimal therapeutic index.

In the United States, PRRT is a standard of care for some patients with midgut GEP-NETs based on results from the NETTER-1 trial. However, complete responses practically never happen with PRRT, and most of the responses in NETTER-1 were partial responses. I think that it is very reasonable to question the importance of radiographic responses, the relationship between radiographic response and PFS or overall survival, and if radiographic responses and PFS or overall survival are linked as tightly in GEP-NETs as they are in other diseases.

Patients can benefit from achieving a radiographic response, as it is commonly coupled with feeling a lot better, and that is really important. Patients who do not achieve a radiographic response often have hormone hypersecretion, and sometimes bulky tumors press on the capsule of the liver or the celiac plexus. So, achieving disease control and stability is frequently worthwhile, and that is why we focus on PFS so much.

Identifying an optimal therapeutic index of PRRT is really important from a safety perspective because GEP-NETs are not the only cells in the body with SSTRs, meaning that other nontumor cells can have a significant uptake and retention of ¹⁷⁷Lu-dotatate during therapy, leading to side effects such as marrow toxicity and kidney toxicity. In addition, particularly bulky tumors may essentially absorb all the PRRT, not leaving enough of the dose to reach other smaller tumors. In these cases, surgery and perioperative therapy might play a role in reducing tumor volume so that there is more PRRT remaining for the other tumors.

Some studies have tested PRRT in combination with capecitabine and/or temozolomide. The CONTROL NET study, for instance, was a small randomized trial evaluating the use of capecitabine plus temozolomide (CAPTEM) and/or PRRT with the relevant primary end point of PFS. In midgut and pancreatic NETs, PFS was essentially identical between the arms. This suggests that combination and sequential treatments may yield a similar overall course of disease, although further research is needed.

An interesting finding from the CONTROL NET study is that patients with pancreatic NETs achieved a complete or partial response at a significantly higher rate (ie, roughly double) with the combination of CAPTEM plus PRRT vs CAPTEM alone. I wonder whether the same patients respond to both therapies. For example, do 30% to 40% of patients respond to CAPTEM, 30% to 40% of patients respond to PRRT, and, when combined, you get a response rate of approximately 70%, as was seen in the trial?

Other work has combined PRRT with DNA damage response inhibitors. A randomized, phase 2, National Cancer Institute (NCI)–sponsored study is evaluating triapine in combination with PRRT, with a primary end point of overall response rate. I think that the core question with any sensitizing agent is: Does it meaningfully increase the therapeutic index as opposed to having a purely tumor response? I hope we learn that from this study.