Treatment Options Expanding for Neuroendocrine Tumors


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Christoph Zielinsky, MD

James Yao, MD

While few treatment options were available up to now for patients with advanced midgut gastrointestinal tumors, 177Lu-DOTATATE appears to be a major advance in this population.

—Philippe Ruszniewski, MD
Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract.

—James Yao, MD

Patients with advanced neuroendocrine tumors have two promising new treatment options, according to studies that earned spots in the Presidential Session of the 2015 European Cancer Congress, held recently in Vienna, Austria.

The phase III studies evaluated the mTOR inhibitor everolimus (Afinitor) in the RADIANT-4 trial and the radiopharmaceutical agent 177Lu-DOTATATE in the European NETTER-1 trial.1,2 Everolimus was studied in patients with advanced nonfunctional gastrointestinal and lung neuroendocrine tumors, whereas the evaluation of 177Lu-DOTATATE was limited to midgut neuroendocrine tumors.

Everolimus is approved by the U.S. Food and Drug Administration for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin, whereas 177Lu-DOTATATE has been used outside of the United States and has not been formally evaluated. Investigators reported promising results with each of these approaches. In the studies, both treatments significantly prolonged progression-free survival and gave hints that an overall survival benefit could emerge.

“We truly have just heard two practice-changing presentations,” said press briefing moderator Christoph Zielinsky, MD, of the Medical University of Vienna.

NETTER-1 Trial

Patients with advanced midgut neuroendocrine tumors have few therapeutic options after progression on first-line somatostatin analog therapy, according to Philippe Ruszniewski, MD, Professor of Gastroenterology at the University of Paris VII, Beaujon Hospital, who presented the results of NETTER-1.1

He explained that 177Lu-DOTATATE belongs to a therapeutic category known as peptide receptor radionuclide therapy. It consists of a lutetium radionuclide chelated to a peptide that targets somatostatin receptors, which are overexpressed in about 80% of neuroendocrine tumors. Upon binding to the receptors, cytotoxic high-energy electrons are released into cancer cells.

The NETTER-1 study evaluated 177Lu-DOTATATE in 229 patients with somatostatin receptor–positive well-differentiated midgut neuroendocrine tumors (functioning or not) that had progressed on octreotide LAR (30 mg). Three-quarters of the patients had the ileum as the primary tumor site, and 84% had liver metastases.

Patients were recruited from 36 sites in Europe and the United States. They received four administrations of 177Lu-DOTATATE (7.4 GBq) every 8 weeks plus octreotide LAR (30 mg), whereas the control arm received octreotide LAR at 60 mg every 4 weeks. Patients were followed for 5 years.

The primary endpoint, progression-free survival, was convincingly met by the radiopharmaceutical, according to Dr. Ruszniewski. There were 67 clinical events in the control arm and only 23 in the 177Lu-DOTATATE arm (hazard ratio [HR] = 0.209; P < .0001), resulting in a median progression-free survival of 8.4 months with octreotide LAR and a median that has not yet been reached with 177Lu-DOTATATE. 

“The interim analysis also suggests increased overall survival, but that remains to be confirmed by the final analysis,” said Dr. Ruszniewski.

Thus far, 13 patients in the 177Lu-DOTATATE arm have died, compared with 22 in the octreotide LAR group (P < .0186). However, the difference did not meet the prespecified level of statistical significance for this analysis.

Response rates were also increased with 177Lu-DOTATATE, from 3% with octreotide LAR alone to 19% with the combination (P < .0004). Serious adverse events were reported for 26% in the experimental arm and 24% in the control arm, with 9% and 1%, respectively, considered related to treatment.

“While few treatment options were available up to now for patients with advanced midgut gastrointestinal tumors, 177Lu-DOTATATE appears to be a major advance in this population,” Dr. Ruszniewski commented.

RADIANT-4 Trial

RADIANT-4 demonstrated a statistically significant 52% reduction in the risk of progression or death with everolimus among patients with a variety of neuroendocrine tumors, after progression on a somatostatin analog, according to James Yao, MD, Chairman in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.

Patients with anatomically diverse neuroendocrine tumors had nearly a threefold increase in median progression-free survival with everolimus: 11.0 vs 3.9 months with placebo (P < .00001).

“Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract,” Dr. Yao said.

RADIANT-4 examined everolimus at 10 mg daily vs placebo in 302 patients with progressive, well-differentiated nonfunctional, advanced neuroendocrine tumors of gastrointestinal or lung origin (about 25% were midgut). Patients had stopped somatostatin analogs for 4 weeks before enrollment and had no active carcinoid symptoms.

The primary endpoint was progression-free survival, which was reduced by 52% with everolimus (P < .00001) and by 61% according to investigator assessment (P < .00001). “Local radiology review confirmed the significant progression-free survival benefit—a change of 8.5 months. The curves were durable and remained separated for more than 18 months,” he said.

The benefit was observed in all sites of origin. Hazard ratios were most impressive in patients with the worst prognosis—ie, those whose tumors originated in the lung, stomach, rectum, and colon (HR = 0.43) and among patients with a liver tumor burden > 25% (HR = 0.18). While the response rates were just 2% with everolimus and 1% with placebo, the disease control rates were 82.4% and 64.9%, respectively.

A preliminary analysis of overall survival showed a 36% improvement with everolimus (P = .037), although this did not meet the prespecified statistical criteria for significance at this planned interim analysis. Additional overall survival analyses are planned as the data matures. The safety profile was consistent with the known safety profile for everolimus.

How to Position These Treatments?

Since both agents delayed disease progression, an obvious next step would be to compare them in a randomized trial, said Dr. Zielinsky, though he and Dr. Yao agreed that a head-to-head comparison would be unlikely.

“Now we have two options that are better than the classical or global standards, but we don’t know which of the two is better,” Dr. Zielinsky said, suggesting they will work as “cascade treatments.” Dr. Yao agreed that in advanced neuroendocrine tumors, most patients should survive long enough to need both treatment options. He also emphasized that the study outcomes in the two populations should not be viewed in comparison. “We should wait for the data to mature,” he said.  ■

Disclosure: Dr. Ruszniewski has served as an advisor to Advanced Accelerator Applications and has received honoraria and research funding from Advanced Accelerator Applications, Ipsen, and Novartis. Dr. Yao has served in a consulting or advisory role for Advanced Accelerator Applications, Ipsen, Lexicon, and Novartis.

References

1. Strosberg J, Wolin E, Chasen B, et al: 177Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours. 2015 European Cancer Congress. Abstract 6LBA. Presented September 27, 2015.

2. Yao J, Fazio N, Singh S, et al: Everolimus in advanced non-functional neuroendocrine tumours of lung or gastrointestinal origin. 2015 European Cancer Congress. Abstract 5LBA. Presented September 27, 2015.


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