Strosberg Discusses QoL Analysis and Next Steps With Lutathera in Midgut NETS

Jonathan Strosberg, MD

The phase III NETTER-1 trial compared Lutathera plus best supportive care, including octreotide long-acting repeatable (LAR), with octreotide LAR alone in patients with advanced, progressive, somatostatin receptor-positive midgut neuroendocrine tumors (NETS).

“It was a positive study that met its primary endpoint of improvement in progression-free survival (PFS) in a statistically significant and clinically meaningful fashion,” explained NETTER-1 lead study author Jonathan Strosberg, MD, in an interview with OncLive.

The NETTER-1 researchers also assessed the impact of the Lutathera on patient quality of life during the trial, using the EORTC C30 and GINET21 questionnaires.

Quality of life was much higher in the Lutathera arm than the high-dose octreotide arm. The median global health status improved 28% with Lutathera versus 15% with octreotide and worsened in 18% versus 26%, respectively.

OncLive: Can you give an overview of the NETTER-1 study?

At the 2017 Gastrointestinal Cancers Symposium, Strosberg, medical oncologist, Department of Gastrointestinal Oncology, section head, Neuroendocrine Division, chair, Gastrointestinal Department Research Program, Moffitt Cancer Center, discussed the overall findings of the NETTER-1 trial along with the quality of life analysis in patients with midgut NETs.Strosberg: Peptide receptor radiotherapy has been around for over a decade, primarily in Europe, where various institutions have been offering treatment with radiolabeled metastatic analogs for well-differentiated NETs.

Results of the NETTER-1 study were published in The New England Journal of Medicine. The study was the first randomized, perspective study of radiolabeled a metastatic analog, specifically Lutathera, compared to high-dose octreotide in patients with progressive midgut neuroendocrine tumors.

Where do you predict this therapy going in the future?

It was a positive study that met its primary endpoint of improvement in PFS in a statistically significant and clinically meaningful fashion. There was a 79% improvement in PFS on the study, which will hopefully lead to registration of the drug sometime in 2017.The first step may be approval in midgut NETs based on the NETTER-1 study, but we're also hoping that data from Erasmus Hospital in the Netherlands with hundreds of patients will lead to approval in a broader group of NETs.

Regardless, I think that there is room for phase III clinical studies of Lutathera in non-midgut NETs, such as pancreatic, bronchial, or colorectal NETs. Looking at a broad group of NETs and potentially comparing to another standard of care, such as everolimus (Afinitor), would be a first step.

What were the quality-of-life findings in patients with midgut NETs in the NETTER?

There's interest in combination studies, such as combinations with radiosensitizing chemotherapy drugs or immunotherapy drugs, based on the theoretical potential of radiotherapy to enhance immunosensitivity. There are several new directions this can go.This was part of the phase III NETTER-1 study. Patients were provided with quality-of-life questionnaires to complete every 12 weeks. It was both a general cancer EORTC C30 questionnaire survey as well as a specific gastrointestinal neuroendocrine tumor questionnaire (GINET21) consisting of 21 questions and pertaining to neuroendocrine specific symptoms.

This is a preliminary analysis where we focused on global health quality of life, which is an important quality of life endpoint in any cancer. It asks how patients will rate their quality of life on a 7-point scale.

We also looked at other NET specific symptoms, such as diarrhea, flushing, and pain. What we found with perspective global health quality of life was, on average, more patients on the Lutathera arm of the study had improvement in their quality of life compared to high-dose octreotide. Fewer patients had declined in their quality of life and this was statistically significant at certain time points during the study.

Similarly, with diarrhea more patients in the investigational arm experienced improvement of quality of life on average, whereas fewer experienced worsening. To some extent that was seen with pain, although it was not statistically significant. With respect to flushing, which is often seen in midgut NETs, there were similar improvements in quality of life in both arms of the study.

What are the next steps with this quality of life assessment?

Is there anything else you would like to add?

Overall, it's very encouraging. Usually when we look at a new agent in quality of life, we hope that the quality of life is not diminished as a result of the introduction of a new agent. Here, it seems like the quality of life is improved, which is very encouraging. We are going to be doing more analysis of time to deterioration and quality of life.The next steps with the quality of life analysis is to do a more thorough analysis looking at all the metrics and the quality of life questionnaires and looking specifically at time to deterioration and quality of life. We've started doing that but we haven't completed that project yet. The preliminary analysis of overall survival was encouraging. On the NETTER-1 study, there were nearly twice as many deaths on the high-dose octreotide control arm of the study versus the investigational arm. We're looking forward to being able to present mature analysis of overall survival in the next few years.

References

1. Strosberg JR, Wolin EM, Chasen B, et al. Quality-of-life findings in patients with midgut neuroendocrine tumors: results of the NETTER-1 phase III trial. J Clin Oncol. 2017;35 (suppl 4S; abstr 348).
2. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi:10.1056/NEJMoa1607427.