Somatostatin Analogs in the Treatment of NETs

Transcript:Simron Singh, MD: Jon, tell me a little about therapy. That’s our area of expertise. We talked a little about watch and wait, etcetera. However, somatostatin analogs, remain the mainstay of our treatment. Maybe you can just give our audience a bit of an overview on somatostatin analogs since we use them so much?

Jonathan R. Strosberg, MD: Sure. There are 2 that are primarily used for gastric, pancreatic, and lung NETs [neuroendocrine tumors]. Those are, of course, octreotide [Sandostatin] and lanreotide [Somatuline]. Somatostatin analogs have been around for several decades. I think the first FDA approval was around 1985. Initially, they were used for control of hormonal symptoms, particularly carcinoid syndrome, but it was fairly quickly understood that they also controlled tumor growth. It took several decades to prove that, and the first study that showed that was the PROMID study of midgut NETs, predominantly low grade, where patients were randomized to receive octreotide (30 mg) versus placebo. The trial showed a very significant improvement in time to progression. Median time to progression improved from 6 months on placebo to over 14 months with octreotide, so it was a positive study.

Then came the CLARINET study, which looked at a more diverse group of patients with enteropancreatic NETs. This study evaluated lanreotide given at 120 mg versus placebo with progression-free survival as a primary endpoint. In this particular study, which enrolled patients with extremely slow-growing tumors, the median progression-free survival on placebo was 18 months. This was not reached at the time of publication with lanreotide, and the hazard ratio was roughly 0.5. So both studies showed a very significant prolongation in progression-free survival, which was really the primary endpoint, despite having extremely low objective response rates. So we know that somatostatin analogs not only control hormonal symptoms in the large majority of cases, but also significantly inhibit tumor growth. They’re not going to actually shrink tumors, but they can significantly delay time to progression.

The CLARINET study required somatostatin receptor expression on octreoscan [octreotide scan]. The PROMID study did not, but we know that almost all midgut NETs are somatostatin receptor-positive. So this is primarily a treatment for somatostatin receptor-positive tumors. It’s typically a first-line systemic treatment. The reason it’s used in the first-line setting is because these drugs are exceptionally well tolerated. Patients may experience a little bit of gas and bloating. They have increased risk of gallstones. One thing we find is that patients may experience diarrhea or steatorrhea, which can often be controlled with pancreatic enzymes such as Creon [pancrelipase]. But we’re talking about very low-risk drugs—probably the least risky drugs that are used in the entire oncology sphere. So I would say that we’re typically talking about first-line treatment.

Can you talk a little about how these drugs are similar and how they’re different, and whether you have any preference for one or another? Do patients express a preference for either of the drugs?

Simron Singh, MD: There’s always debate about whether these have a class effect. Can we interchange one for the other? I’m of the opinion that yes, they probably are very similar. We can probably interchange them for one or the other. Octreotide is an IM [intramuscular] injection given once every 4 weeks. Lanreotide is what we call a deep subQ [subcutaneous] drug that is also given once every 4 weeks with standard dosing. There are small differences in the sites, and the size of the needles, etcetera, but I generally find them to be quite similar and don’t really have a specific preference for one or the other. How about you? Do you have a preference for one or the other, in terms of any clinical situations?

Jonathan R. Strosberg, MD: No, I agree that they’re extremely similar. Nurses might have an easier time administering lanreotide because it comes in a prefilled syringe. As far as the patient experience with either of the drugs, I’m not sure that there’s much difference between the 2. Of course, we haven’t had a modern study comparing them, so there’s no comparative evidence. If you look at the hazard ratio for midgut NETs on the CLARINET study, it’s virtually identical to what was seen in the PROMID study. So I think that as far as efficacy, they’re probably extremely similar. They target the same somatostatin receptor subtypes. They primarily target SSTR2 [somatostatin receptor 2]. As far as pathophysiology and the clinical evidence that we have so far, I don’t think we could say that one is better than the other, nor can we say that there’s any advantage to switching from one to another at the time of disease progression.

One thing we touched upon though is changes in dose. A fairly common circumstance is that patients can experience syndrome control for 3 weeks but then may experience an exacerbation for the last week of the 4-week cycle, in which case it makes a lot of sense to give the drug every 3 weeks rather than every 4 weeks. Sometimes we go up on the dose and see benefit. We do that primarily for symptom control. I’m not sure that there’s much evidence that it helps improve tumor control.

Simron Singh, MD: I would say that it’s definitely useful for symptom control. I think there is probably a fair amount of use of the drug as well beyond the dose that we’re used to. For tumor control, I don’t think that’s been studied as of yet. I think it’s an interesting question though because, as you were saying, these drugs are extremely well tolerated. So we want to make sure that we’re using them to their maximum advantage before we move on to potentially more toxic agents.

Transcript edited for clarity.