CDER-Approved NDA for LUTATHERA® (lutetium Lu 177 dotatate)
On January 26, 2018, the FDA granted approval to Advanced Accelerator Applications USA, Inc. (AAA)’s LUTATHERA® (lutetium Lu 177 dotatate) for “treatment of adult patients with somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) including foregut, midgut, and hindgut, neuroendocrine tumors.” Key findings from the FDA’s Multi-Discipline Review:
While a randomized controlled trial (Netter-1 AAA-III-01) provided the primary safety and efficacy evidence, a single-arm study based on an expanded access program, called the Erasmus Medical Center (EMC) trial, “provided supportive data on safety” and “support for the indication for the treatment of patients with GEP-NETs other than those arising in the midgut.”
The primary objective of the EMC trial was to assess the safety and activity of 177Lu-DOTA0-Tyr3-Octreotate. Data from the EMC trial was submitted to provide supportive evidence of the safety of 177Lu-DOTA0 -Tyr3-Octreotate, to confirm the efficacy findings of the NETTER-1 trial in the subset of patients with midgut neuroendocrine tumors, and to provide evidence to extend the proposed indication to include patients with pancreatic neuroendocrine tumors.
What was done
The EMC trial, which was conducted in Rotterdam, the Netherlands, is an investigator-sponsored, open-label, single-arm, single-institution, expanded access study of 1,214 patients with SSTR positive neuroendocrine (NEC) tumors. To expand on this —
- There was no pre-specified statistical analysis plan.
- The study population was heterogeneous with respect to the primary tumor site. Most patients had GEP-NETs of the foregut, midgut, hindgut, digestive tract, bronchus, and pancreatic neuroendocrine tumors (pNET). Other NETs that were included in the trial: medullary thyroid cancer, pheochromocytoma, paraganglioma, neuroblastoma, and Merkel cell carcinoma. Non-NET SSTR positive tumors melanoma, non-differentiated thyroid cancers, non-small cell lung cancer, breast cancer, lymphoma, and malignant meningioma were also treated.
- The major efficacy outcome was investigator-assessed overall response rate (ORR). This response assessment changed during the study, with patients treated later being evaluated by response evaluation criteria in solid tumors (RECIST), which is accepted for regulatory purposes.
In a pre-NDA meeting, the FDA wrote that “the adequacy of the data from the EMC study to support the broader indication cannot be determined until the data is reviewed at the time of the NDA submission.” Ultimately, the EMC trial:
- Provided supportive data on safety; and,
- Supported the indication for the treatment of patients with GEP-NETs other than those arising in the midgut.
Note the review priority: Priority. The FDA wrote that “this population of patients represents an unmet medical need, as available treatment options offer few true benefits.”