Updated Data Confirm Survival, QoL Benefit With Lutathera in GI NETs

Jonathan Strosberg, MD

Lutathera (lutetium Lu 177 dotatate) continued to demonstrate a statistically meaningful progression-free survival (PFS) and quality-of-life (QoL) benefit in patients with midgut neuroendocrine tumors (NETs), according to updated data of the NETTER-1 trial presented at the 2018 ASCO Annual Meeting.

At the time the data were presented, the median overall survival (OS) for patients treated with Lutathera was not reached. Those treated with high-dose octreotide demonstrated a median OS of 27.4 months.

The NETTER-1 study, led by Jonathan R. Strosberg, MD, compared Lutathera with high-dose octreotide for patients with grade 1 or 2 metastatic midgut NETs. Response data from the phase III trial led to an FDA approval of Lutathera in January 2018 for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic NETs.

Updated PFS data showed 30 events in the Lutathera arm compared with 78 events for the patients treated with octreotide (HR, 0.21; 95% CI, 0.14-0.33; P <.0001). Time to decline was significantly longer in the Lutathera arm versus the octreotide arm for global health status (HR, 0.406; P = .0006), physical functioning (HR, 0.518; P = .0147), role functioning (HR, 0.580; P = .0298), and fatigue (HR, 0.621; P = .0297).

OncLive: Please provide some background to the NETTER-1 study and the updated findings.

In an interview with OncLive, Strosberg, associate professor, section head, Neuroendocrine Tumor Program, Moffitt Cancer Center, discussed the latest NETTER-1 update and the potential impact of Lutathera in patients with gastroenteropancreatic NETs.Strosberg: This was a phase III randomized clinical trial of Lutathera versus high-dose octreotide in patients with progressive midgut NETs. It was actually the first randomized trial of its kind. It led to an FDA approval of Lutathera in midgut and other NETs.

The primary endpoint [analysis] of the study, which was published in the New England Journal of Medicine, [was] from [a data cutoff date of] July 2015. [These newer data are from] an updated analysis that was requested by regulatory authorities a year later. We now have updated OS and PFS data. We also used that time point to calculate a QoL analysis.

At the time of initial analysis, the median OS had not been reached in either arm. However, there was a roughly 60% improvement in OS if you look at the hazard ratio. With this updated analysis, we can say that the median OS has been crossed with the control arm of the study, octreotide, which was roughly 27 months. It still has not been reached with Lutathera, but the hazard ratio has been preserved. An OS analysis is expected to be performed in several years.

With respect to PFS, it was 8.4 months with high-dose octreotide. That has not changed. With Lutathera, there was 1 event that crossed the midline, leading to a median PFS of roughly 28 to 29 months. Again, this was based on 1 event. There was an 80% reduction in risk of progression or death.

Was any part of these data particularly unexpected?

How tolerable is Lutathera?

Now that it is FDA approved, how do you see this impacting the landscape?

Is there anything you would like to add?

Looking at QoL, we look at many different domains. There is a questionnaire specific to NETs. We performed an analysis of that, and we found a very clinically and statistically significant improvement in time to deterioration of QoL. The most important aspect is global health. There was a great improvement of that with Lutathera. The median time to decline improved from about 6 months to approximately 30 months. In all the key and relevant domains, we saw improvements with Lutathera.First, it was nice to see the data we reported with the initial analysis still held up a year later. It was more mature data with a larger number of events. This is the first takeaway message. With respect to QoL, I don't think we expected to see such an improvement. I would say, in some cases, the results were probably a little bit better than what we initially expected. Beyond the trial, we have been treating patients with the commercial drug. Because the drug just came out, and we have patients using it who are highly symptomatic, we're seeing good responses in a few patients. It's nice to see clinical experience match what we see in clinical trials. The drug is rolling out slowly because it is a highly specialized radiopharmaceutical. It will probably be mostly used in academic centers for now. We are trying to ramp it up as quickly as possible. There is a long waiting list of patients who are hoping to use it. We hope to treat at least 6 patients a week with it [in our clinic]. There's a lot of excitement about it. It's important for institutions that administer this drug to have very good collaboration with the nuclear medicine departments and the medical oncology departments. It's a multidisciplinary approach to cancer treatment. All of the correct protocols need to be acknowledged.

Strosberg J, Wolin E, Chasen B, et all. First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. J Clin Oncol. 2018;36(suppl; abstr 4099).