Expert Discusses Emerging Treatments, Immunotherapy Potential in pNETs

Pamela L. Kunz, MD

Several recent studies have shown promise for the treatment of pancreatic NETs (pNETs). In the phase II CALGB-80701, which investigated the addition of bevacizumab (Avastin) to a treatment paradigm of everolimus and octreotide (Sandostatin) LAR in patients with locally advanced or metastatic pNETs, bevacizumab extended progression-free survival (PFS) by more than 3 months compared with everolimus and octreotide LAR alone.

Response rate was also higher in the bevacizumab arm, with a 31% response to everolimus plus bevacizumab versus a 12% response in the control arm. Toxicity, however, was significantly higher in the bevacizumab arm.¹

Bevacizumab also showed promising results as a single-agent in pNETs in a phase II multicenter prospective trial. In this study, partial response (PR) rate was 9% (2/22) and the 6-month PFS was 95% (20/22). The Kaplan-Meier 12-month PFS was 54% (95% CI, 34-85%) and the median PFS was 13.6 months (95% CI, 10.6-NA).²

Advancements were also made for the treatment of patients with carcinoid syndrome. In the phase III TELESTAR trial, telotristat etiprate resulted in a more than 30% reduction in daily bowel moments in 44% and 42% of patients treated with telotristat etiprate at 250 and 500 mg, respectively, compared with 20% of patients in the placebo arm (P <.04).

OncLive: What are your thoughts on the findings from the phase II CALGB-80701 study of everolimus plus bevacizumab in pNETs?

Can you discuss the phase II trial of bevacizumab in progressive pNETs?

What do you think the impact of the phase III TELESTAR trial is?

In an interview with OncLive, Pamela L. Kunz, MD, assistant professor of Medicine (Oncology) at Stanford University Medical Center, discusses these studies as well as other ongoing trials investigating the potential of immunotherapies in NETs.Kunz: Dr Matthew Kulke led this study. Everolimus, as a single agent, is already FDA approved in pNETs; there has been some thought that angiogenesis inhibitors could also provide some benefit. This study met its primary endpoint of PFS benefit in the combination arm over everolimus alone. Also, there was a response and tumor shrinkage, which I think was a surprise, since everolimus monotherapy does not have a very high response rate. This was just a phase II study. I think a phase III study looking at angiogenesis inhibitors in combination with an mTOR inhibitor is important; however, bevacizumab is ending its patent life and I think this study will not happen using bevacizumab, but we are hoping that it will be done with another angiogenesis inhibitor.This was a single-agent bevacizumab study that similarly showed some encouraging PFS data. I think these results, in combination with Dr Kulke’s study, are encouraging regarding the use of angiogenesis inhibitors. Just to draw a parallel, we know that sunitinib is approved in pNETs, which is a tyrosine kinase inhibitor (TKI) that targets VEGF. We are drawing data from a number of trials that suggest that angiogenesis inhibition in pNETs is important. It is still to be determined which agents—there are certainly newer monoclonal antibodies that target angiogenesis inhibition, such as TKIs&mdash;so I think some future trials will likely include angiogenesis inhibitions. It is an important class of agent for NETs.Telotristat etiprate is an oral inhibitor of TPH, which is the rate-limiting enzyme in the synthesis of serotonin. It is the first agent in decades that is available for patients with carcinoid syndrome, which is mediated by serotonin release. It is a really exciting option to have for refractory patients with carcinoid syndrome. There has been a lot of discussion regarding what patients we would consider using this. In the clinical trial, it was tested in the refractory setting. Therefore, patients had to not have a lot of control already on asomatostatin analog. It showed pretty dramatic reduction in urinary 5-HIAA and really good symptom improvement.

Is there potential for the use of immunotherapies in NETs?

There was a companion study looking at quality of life improvement in these patients and that is remarkably consistent with the quantitative data that was presented. There is also some thought that this could prevent the long-term side effects of the serotonin release, such as carcinoid heart disease. However, there will need to be studies that look at this specifically. I am very excited that this will be an option for patients.NETs of all primary sites are generally thought to have a low mutation load compared to some of the other cancers where immunotherapy has been effective. Because of this, there is some thought of, “Is it even worth thinking about for NETs?” Combination therapies could overcome the fact that these cancers have a low mutation load. Some practitioners believe that the mutation load itself may not even be predictive of response. Some combinations that may be of interest for the treatment of NETs would be dual checkpoint inhibition with two immunotherapies or checkpoint inhibitors with radiation. Vaccine and immunotherapy combinations are also an option.

There are a few studies in development, none of which are open yet, that are looking at immunotherapies in NETs, both at Stanford University Medical Center and University of Pennsylvania. We have a trial that is not yet open, but will be combining intratumoral ipilimumab and an anti—PD-L1 agent. This is really just an exploratory phase I/II trial that is looking at safety and early efficacy. It’s still early, but we hope to start looking at this in clinical trials.

What I think is interesting is that, initially, it was thought that PD-L1 expression was required to be a predicative biomarker for immunotherapy, and now it is recognized that it may not be absolutely necessary.

References

1. Hobday TJ, Yin J, Pettinger A, et al. Multicenter prospective phase II trial of bevacizumab (bev) for progressive pancreatic neuroendocrine tumor (PNET). J Clin Oncol. 33, 2015 (suppl; abstr 4096).
2. Kulke MH, Niedzwiecki D, NR, et al. Randomized phase II study of everolimus vs everolimus plus bevacizumab in patients with locally advanced or metastatic pancreatic neuroendocrine tumors (CalGB 80701/Alliance). J Clin Oncol. 33, 2015 (suppl; abstr 4005).