NETTER-1 Clinical Trial Overview

Pamela Kunz, MD: PRRT [peptide receptor radionuclide therapy] was FDA approved in January of 2018, specifically with agent lutetium 177Lu-DOTATATE. This was based on an article from the New England Journal of Medicine by Jonathan Strosberg. It was an international study done primarily in Europe and the United States that randomized about 229 patients with midgut neuroendocrine tumors to receive either 177Lu-DOTATATE or a high-dosage octreotide, at 60 mg monthly. The 177Lu-DOTATATE was given in 4 doses, each separated by 2 months. Each dose was 7.4 giga-becquerels or 200 millicuries. A full treatment course of the 177Lu-DOTATATE was 4 doses.

The results favored the experimental arm of 177Lu-DOTATATE across the board. Progression-free survival [PFS] was the primary end point. At the time the study was published, and even in updated analysis, the median progression-free survival had not been reached, whereas the median progression-free survival for octreotide was 8.4 months. This was a hazard ratio of .21, so it was really a significant reduction in risk of progression for patients who received the 177Lu-DOTATATE. Overall survival also favored the 177Lu-DOTATATE arm. Median overall survival was also not reached at the time of the publication for either arm, but the difference between the arms was statistically significant favoring the 177Lu-DOTATATE arm.

Response rate was also higher in the 177Lu-DOTATATE arm at 18%, versus 4% for the octreotide arm. It’s also important to talk about adverse effects. The serious or grade 3/4 adverse events for the 177Lu-DOTATATE arm were higher than for octreotide but were relatively well tolerated. The main adverse effects included myelosuppression, primarily lowering of white blood cells—lymphopenia in particular—and lowering of platelets. In addition, patients had some nausea and vomiting.

At the time that the trial was conducted, a mixture of many amino acids used in that amino acid solution has since been modified to use only arginine and lysine. Those tend to be less emetogenic, so much of that nausea and vomiting was due to the amino acid solution that was given to protect the kidneys. There is about a 3% risk of a long-term effect on the bone marrow of myelodysplastic syndrome or acute leukemias, and this has long been a concern of many oncologists.

We still don’t have very long-term data on that, so that’s something to be aware of and to mention to patients. The risk is real but thought to be relatively low at this point. I also want to mention that a subsequent study, which was sort of a companion study to the original in the New England Journal of Medicine, came out also indicating quality-of-life benefit for patients who received the 177Lu-DOTATATE.

I think PRRT and 177Lu-DOTATATE specifically have been game-changers for neuroendocrine tumors. Even though the median PFS was not reached, or at least at the time of that publication, it’s estimated to be about 2 years. That is the longest median PFS of all our approved systemic treatments. In addition, there is about an 18% response rate, and many of our systemic agents like SSAs and biologics do not yield tumor shrinkage. I think this will play an important role for most patients with NETs. When I’m meeting with a patient for the first time and we’re starting to talk about selection of therapies, I talk about having a toolbox.

We have many tools in our toolbox, 1 of which is SSAs, 1 of which is PRRT, etc. I tell them they will likely get all these therapies in their lifetime. It’s just a matter of selecting when. Our colleagues in Europe for a long time had PRRT available and were using it earlier in the disease course—for example, right after progression on SSAs, so they were using it in the second-line setting. Now that we’ve had this available in the United States for a couple of years, there is some comfort level with having moved that up some in the order of treatments.

I am using it a little earlier, very often right after progression on SSA. I also tell patients that with PRRT, at least right now, it’s likely not the correct first treatment and not the correct last treatment but somewhere in the middle. When patients get very ill, PRRT can be a really tough treatment to tolerate, so I don’t want to wait too long and miss a window where I can use that treatment for patients.

Transcript Edited for Clarity