1. Simoneaux, Richard

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Patients who have had progression of midgut neuroendocrine tumors (NET) while on standard somatostatin analog therapy have limited treatments available. To address this shortcoming, a study was undertaken to evaluate the efficacy and safety of lutetium-177 (177Lu)-dotatate/177Lu-DOTA0-Tyr3-octreotate in patients having advanced somatostatin receptor-positive midgut NET that have had progression (N Engl J Med 2017;376:125-135).

neuroendocrine tumor... - Click to enlarge in new windowneuroendocrine tumors. neuroendocrine tumors

NETs were first described in 1907 by Siegfried Oberndorfer, a German pathologist, who referred to them as "karzinoide." These tumors can occur in neuroendocrine cells wherever they are located in the body and are characterized by their propensity for excreting hormonal peptides and neurologically active amines. The overproduction of these compounds may then lead to manifestation of the associated hormonal syndromes, such as carcinoid syndrome.


The patients in this study had midgut NETs (located in the jejunoileum or proximal colon). Diagnosis of these midgut tumors is complicated, as the symptoms frequently mirror those of irritable bowel syndrome (IBS). Often, these patients will have a long history of vague gastrointestinal symptoms that may be misdiagnosed as IBS. Patients will persist with these symptoms for years, with a median time to correct diagnosis of 9.2 years. By that time, the NETs have often metastasized, making treatment that much more difficult.


"Many midgut NET patients have carcinoid syndrome associated with excess secretion of serotonin," said Jonathan Strosberg, MD, lead author of the study, and Associate Professor at H. Lee Moffitt Cancer Center, Tampa, Fla.


When asked about the causes for these tumors, Strosberg explained, "Not a lot is known about the genetic drivers for these tumors and their genetic landscapes are poorly understood; additionally, there are no known environmental factors. These tumors typically overexpress the somatostatin receptor, and of these, the majority is subtype 2 receptors."


Because patients with metastatic midgut NETs have a 5-year survival rate of less than 50 percent, there is a dire need to find therapies for those patients who have had progression while using the standard regimen of somatostatin analogs.


NET Therapies

The first line therapy for midgut NET patients involves the use of somatostatin analogs (N Engl J Med 1986;315:663-666). The use of these analogs has the dual effect of reducing tumor growth as well as hormone secretion. "Little is understood about the intracellular signaling pathways which mediate how these compounds exert their effect upon these tumors," Strosberg noted while discussing the mechanism of action for these analogs.


In the early 1990s, the use of radiolabeled somatostatin analogs was initiated for the treatment of well-differentiated advanced NETs. Typically, these compounds consist of two parts: the somatostatin analog and a pendant moiety that chelates the utilized radionuclide. In principle, the radionuclide is selectively delivered to the NETs, which typically have an overexpression of somatostatin receptors.


Initial efficacy studies utilized 111In DPTA0-octreotide in very high dosing levels. Subsequent to that research, more promising candidates for this therapy have been identified, e.g., 90Y-DOTA0-Tyr3-octreotide (90Y-DOTATOC) and this study's investigational compound, 177Lu-DOTA0-Tyr3-octreotate (177Lu-dotatate). The primary differences in these therapies are related to the respective radionuclide characteristics (Eur J Nucl Med Mol Imaging 2012;39(Suppl 1):103-112).


90Y was considered a more suitable radionuclide relative to 111In because of its deeper tissue penetration (12 mm) and maximum [beta]-particle energy of 2.27 MeV; its half-life (64 hours) is comparable to that of 111In (~67 hours). 177Lu, however, has a much longer half-life of 160 hours and is a medium energy [beta]-emitter (maximum energy-0.5 MeV) as well as an emitter of low energy g-rays (208 keV-10% abundance; 113 keV-6% abundance) with a maximum tissue penetrability of 2.2 mm.


This principle of selective radionuclide delivery is also utilized in imaging technology such as 111In DPTA0-octreotide somatostatin receptor scintigraphy and, more recently, 68Ga-dotatate PET/CT visualization. Such technologies can be used to determine if a patient's NETs are appropriate for this form of peptide receptor radionuclide therapy. The FDA gave official approval June 1, 2016, for the kit used to prepare the injectable 68Ga-dotatate radioactive imaging agent.


The use of this last technique has become more popular recently because of its benefits to patients, which include shorter data acquisition times as well as lower radiation exposure. Also, quite often, better visualization of the NETs is obtained using the gallium-based imaging agent


NETTER-1 Trial

The international phase III neuroendocrine tumors therapy (NETTER-1) clinical trial was conducted in eight countries at 41 centers. Patients were considered eligible to participate in this study if they had inoperable locally advanced or metastasized midgut NETs with disease progression, as determined by either CT or MRI using Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1, during treatment (20-30 mg every 3-4 weeks for a minimum of 12 weeks prior to randomization) with octreotide long-acting repeatable (LAR) over a maximum period of 3 years.


Additional requirements included a Karnofsky Performance Status score of 60 on a scale of 0-100 (patient requires some occasional assistance, however is able to manage most of their personal needs). Histologically, only those patients having a Ki67 index score of 20 percent or less were included in the study. This means 20 percent or fewer of the cells tested from the patient showed a positive result for the Ki67 proliferation marker.


In this index, a score of 0-2 percent indicated a low-grade tumor, 3-20 percent intermediate grade, and a high grade was assigned to a score of greater than 20 percent. Because only those patients having tumors with an overexpression of the somatostatin receptor were relevant for these studies, a Krenning scale score of grade 2-4 (4 being the highest level of radiotracer uptake) for planar somatostatin receptor scintigraphy performed within 24 weeks of randomization was required for inclusion.


Patients were excluded from this study if they met one or more of the following criteria:


* a creatinine clearance level of less than 50 mL/min or a creatinine level of 150 [mu]mol/L;


* a hemoglobin count of less than 8g/dL;


* a white blood cell count of less than 2000/mm3;


* a platelet count lower than 75,000/mm3;


* a serum albumin level greater than 3g/dL;


* a bilirubin level greater than 3x the upper limit of normal;


* peptide receptor radionuclide at any point before randomization;


* more than 30 mg octeotride LAR within 12 weeks before randomization; or


* any chemotherapy, surgery, or liver-based transarterial therapy within 12 weeks prior to randomization.



Study Methodology

In the NETTER-1 study, patients were randomized in an approximately 1:1 ratio to either the investigational arm or the control arm. The investigational patients received 7.4GBq (200 mCi) of freshly-prepared 177Lu-dotatate via IV infusion over 30 minutes. These patients were to receive a total of four of these injections every 8 weeks unless one or more of the following occurred:


* extreme toxicity was observed;


* imaging showed centrally-determined disease progression (RECIST criteria);


* the patient was unwilling or unable to adhere to clinical trial protocols;


* the patient withdrew consent; or


* the patient died.



To prevent nephrotoxicity, amino acid solutions (VAMIN-18 or Aminosyn 10%) were administered intravenously beginning half an hour before radionuclide infusion. These patients also received supportive care in the form of intramuscularly injected octreotide LAR (30 mg) administered ~24 hours after each radiopharmaceutical infusion and then monthly after finishing the four radiopharmaceutical injections. The control group received intramuscular injections of 60 mg octreotide LAR every 4 weeks. Both groups were allowed rescue doses of octreotide in the event of carcinoid syndrome related hormonal symptoms (typically flushing or diarrhea).


The primary endpoint of progression-free survival (PFS) for this study was defined as the time from randomization to either centrally-determined disease progression or death by any cause. Secondary endpoints included overall survival, objective response rate, safety, and side effects profile.


In the period from September 2012 to January 2016, 229 patients were randomized at 27 European sites and 14 U.S. sites, and of these, 221 received at least one dose of trial treatment. Of these patients, 110 were randomized to the control group and 111 to the 177Lu-dotatate (investigational) group. Of the patients who underwent randomization, 116 were included in the investigational arm and 113 in the control arm. The investigational arm included 63 men and 53 women, while the control arm included 53 men and 60 women.


The primary tumor site for both groups was the ileum (74% in the investigational arm and 73% in the control arm). The number one site of metastasis was the liver (84% in the investigational arm and 83% in the control arm) followed closely by the lymph nodes (66% in the investigational arm and 58% in the control arm).


Most patients had Krenning scale grade 4 somatostatin receptor scintigraphy scores (61% in the investigational arm and 59% in the control arm). Additionally, urine 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) and serum chromogranin A levels were similar for both groups.


The data cutoff for primary analysis was July 2015 and, at that point, 23 incidents of death or disease progression had been noted in the 177Lu-dotatate group while 68 were noted in the control group.


Adverse Events

For the investigational arm, the compound was generally well-tolerated, as a large majority of these patients were able to receive all four injections of 177Lu-dotatate; however, eight patients did require dose reduction. In the investigational arm, 95 percent of the patients had an adverse event (AE) of any grade, and of these, 86 percent were deemed to be treatment-related. Correspondingly, in the control arm, 86 percent of the patients experienced an AE of any grade, with 31 percent being considered treatment-related.


Premature removal from the trial because of post-treatment AEs occurred for 6 percent of the 177Lu-dotatate patients and 9 percent of those in the control group. In the investigational arm, gastrointestinal AEs were the most common, and of these, nausea (59%; any grade) and vomiting (47%; any grade) were the most frequent. However, only 4 percent and 7 percent of the patients having these AEs were of grade 3 or 4, respectively.

177Lu-DOTA0-Tyr3-oct... - Click to enlarge in new window177Lu-DOTA0-Tyr3-octreotate.

The most common hematological AE of any grade was for thrombocytopenia (25%), but of these, only 2 percent were grade 3 or 4. The most frequently noted grade 3 or 4 hematological AE was lymphopenia, which was noted for 9 percent of the investigational patients. In the control group, the most common AEs of any grade were abdominal pain (26%), fatigue/asthenia (25%), and musculoskeletal pain (20%). The most frequently encountered grade 3 or 4 AE was abdominal pain (5%).


Findings, Future Analysis

At month 20, the estimated PFS rate was 65.2 percent (95% CI: 50.0-76.8%) for the investigational arm and 10.8 percent (95% CI: 3.5-23.0%) for the control group. For the 177Lu-dotatate arm, the median PFS had not been reached, while for the control arm, the median PFS was 8.4 months (95% CI: 5.8-9.1 months).


The hazard ratio (HR) for the investigational versus control arms was 0.21 (95% CI; 0.13-0.33; P < 0.001). This corresponded to a 79 percent lower chance of death or disease progression for the investigational arm. Consistently lower HR values were obtained for the 177Lu-dotatate group regardless of baseline prognostic factor (e.g., age, sex, 5-HIAA levels, chromogranin A levels, extrahepatic metastases, etc.).


Survival data showed 14 deaths occurred for the investigational group while 26 occurred in the control group. The HR for death in the investigational versus control arm was 0.40 P = 0.004, and the O'Brien-Fleming significance threshold was 0.000085. Strosberg noted, "the data were not mature enough to provide an accurate assessment of overall survival for either study arm." Among the 201 patients in this study who were evaluable for tumor response, 18 were in the investigational arm and three in the control arm, yielding response rates of 18 percent and 3 percent, respectively (P<0.001).


With respect to objective response rates, Strosberg noted, "The response rate of the 177Lu-dotatate group was significantly higher than the 3 percent response rate obtained for the control group. In other large clinical trials involving this subset of patients, response rates greater than 5 percent have not been observed."


When asked about the next steps for this clinical trial, Strosberg commented, "The final analysis of overall survival will be performed when either 158 deaths have occurred or after 5 years have passed since the last patient was randomized to the study, whichever comes first."


Richard Simoneaux is a contributing writer.