Optimal Sequencing Strategy for NETs

Pamela Kunz, MD: To determine the optimal sequencing of therapies, we think about both treatment characteristics and patient characteristics. As I mentioned before, we’re very fortunate to have a number of treatment options available. However, we don’t have high-level evidence or clinical trials that tell us how to select these therapies and in what order. In the past few years, somatostatin analogues [SSAs] have come out as a preferred first-line therapy for grade 1 and 2 NETs [neuroendocrine tumors].

I think that is for a couple of reasons. First, their toxicity or adverse-effect profile is very favorable. Adverse effects for SSAs like octreotide or lanreotide can include some mild gastrointestinal upset and occasionally some fatigue. For patients who still have a gall bladder, it can predispose them to developmental gallstones. But in general, they are well tolerated and don’t cause what patients often associate with chemotherapy adverse effects. Many of our patients with newly diagnosed metastatic NETs are actually asymptomatic at the time of diagnosis, so I tell patients I don’t want the fix to be worse than the problem.

That’s another reason why SSAs can be a great first-line choice. In addition, SSAs can control their disease by preventing new spots and further growth. I’m also clear with patients when I’m talking with them that SSAs are unlikely to shrink their cancer. Just talking about goals of therapies very clearly with patients as you’re choosing them is very important. What is the goal of treatment for you? I explain that, and that’s OK. For patients with NETs, achieving tumor control for many years, preventing growth, and preventing new spots is still considered a success as long as patients are feeling well.

In terms of thinking then about second- and third-line therapies, that really depends on those treatment characteristics and the patient characteristics we talked about before. For example, if I have a patient who has a preexisting lung condition, we know that everolimus can have a low risk of causing pneumonitis. This may not be an absolute contraindication to selecting everolimus, but it may weigh into my decision. I’ll pose another question and then answer it, which is, What is the situation when SSAs would not be first-line therapy? There is a subset of patients, particularly patients with pancreatic NETs, who have bulky disease, symptoms from tumor bulk, and perhaps have a slightly higher Ki-67 or a grade 2 tumor who are really in need of tumor shrinkage.

As I mentioned before, SSAs do not yield tumor shrinkage. In this case, I might choose something like the combination of temozolomide and capecitabine. These are 2 oral chemotherapy agents that have been proven recently in a large, randomized study called E2211. This was a study that I led that randomized temozolomide capecitabine versus temozolomide alone and that yielded about a 30% response rate or shrinkage rate. That’s just in pancreatic NETs and has not been proven yet in small-bowel or lung NETs.

Transcript Edited for Clarity