Lutathera Fills Unmet Need in NETs, Role of Radiation Expands Across GI Cancers

Derek R. McHaffie, MD

The peptide receptor radionuclide therapy Lutathera (lutetium Lu 177 dotatate) has addressed what was previously a significant unmet need in the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), said Derek R. McHaffie, MD. Now, investigators are exploring different radiotherapy techniques to improve outcomes in those with oligometastatic gastrointestinal (GI) cancers.

In the phase III NETTER-1 trial, investigators compared the use of Lutathera with high-dose octreotide LAR (Sandostatin) in patients with metastatic or locally advanced, inoperable, well-differentiated midgut NETs who progressed during treatment with standard-dose octreotide LAR. Initial data, which demonstrated a 79% reduction in the risk of progression or death with Lutathera, led to the FDA’s decision in January 2018 to approve the therapy for patients with somatostatin receptor—positive GEP-NETs.¹

Updated progression-free survival data presented at the 2018 ASCO Annual Meeting showed 30 events in the Lutathera arm compared with 78 events in the octreotide LAR arm. Lutathera also appeared to be much better tolerated in terms of global health status, fatigue, and physical functioning.²

“In our own practice, what we've seen is a lot of demand for this therapy,” said McHaffie, a radiation oncologist at Levine Cancer Institute. “Patients who did not have many other options and were metastatic have been reaching out from long distances to receive treatment.”

Beyond radionuclide therapy, stereotactic radiotherapy is making headway in the GI cancers space. This approach, which directs high doses of radiation on tumor cells while sparing normal tissue, has the potential to be a game changer in the treatment of those with oligometastatic disease, said McHaffie.

“There has also been a broad shift in GI cancers toward the use of more neoadjuvant therapies,” added McHaffie. “We’re thinking about how to incorporate treatments with proven survival advantages into surgery. That's probably a big theme in our world, as we also decide where radiation fits into that.”

OncLive: How has Lutathera impacted the treatment landscape for patients with NETs?

What are some challenges with Lutathera?

Beyond radionuclide therapy, what advances have been made with radiation in GI cancers?

What sets stereotactic radiation apart from other methods?

Are there any ongoing trials exploring the use of radiation in GI cancers that you are particularly excited about?

In an interview at the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, McHaffie discussed the role of radiation therapy in the treatment of GI cancers and the impact of radionuclide therapy in patients with NETs.McHaffie: This was a significant unmet need in a disease that lacked effective systemic therapies. To have the phase III NETTER-1 trial published and show such promising and striking results compared with the control arm [was a big accomplishment.] The use of radiation isotopes for targeted therapy is something that various investigators around the world have been working on for many years. It was encouraging to finally see this [work pay off] in a significant way.Lutathera requires a lot of coordination, radiation safety personnel, and medical oncologists making sure that patients receive the needed octreotide on schedule. We also have to make sure we take the proper radiation safety precautions because the patients are radioactive after treatment. A team approach is definitely required.The most exciting thing has been the emergence of stereotactic radiation therapy for those with oligometastatic disease. Even within the last year, there have been impressive data on incorporating this therapy with frontline chemotherapy for patients with limited disease sites. There is more yet to be learned, but this could potentially be a gamechanger for the way we will treat patients with oligometastatic disease moving forward.Stereotactic radiation is the incorporation of some of our newer techniques. These include advanced immobilization, motion management, and primarily, respiratory management. This approach incorporates a much higher dose per fraction with a limited number of fractions; generally, it is about 3 to 5 fractions given over 1 week to 1.5 weeks. There is also a real emphasis on image guidance for treatment. Along with this comes a reduction in margins, so we are able to shrink the size of our field and target volumes, which are associated with toxicity. Stereotactic radiation facilitates these higher ablative doses of radiation.At Levine Cancer Institute, we have been actively participating in the ALLIANCE trial in patients with rectal cancer, looking at total neoadjuvant therapy. Specifically, it is conventional neoadjuvant concurrent chemoradiation with moving FOLFOX upfront before surgery. This trial, and the newer addition incorporating PD-1 inhibitors, has some real potential to affect local control as well as distant metastases.

References

1. 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.
2. Strosberg JR, Wolin EM, Chasen BA, et al. 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 15; abstr 4099). doi: 10.1200/JCO.2018.36.15_suppl.4099.