Refining the Use of Everolimus for Neuroendocrine Tumors

Reanalysis Shows Greater Effectiveness

Nick Mulcahy

January 17, 2012

January 17, 2012 (San Francisco, California) — In patients with advanced neuroendocrine tumors that originate outside the pancreas, a new set of prognostic factors can help identify which patients are at greatest risk for progression and are more likely to need therapy sooner, say researchers.

The prognostic factors were identified in a reanalysis of the phase 3 multinational study known as RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors), said lead author James Yao, MD, assistant professor and deputy chair of gastrointestinal oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

He spoke at a press conference hosted by the 2012 Gastrointestinal Cancers Symposium, which begins this week.

The significant prognostic factors include elevated levels of the blood biomarker chromogranin A (CgA), neuroendocrine tumors that originate in the lung, bone metastases, and a World Health Organization (WHO) performance status of 1 or more.

There have not been any "great" studies of this rare form of neuroendocrine tumors that have identified prognostic factors, said Dr. Yao. The RADIANT-2 data revealed that the patient population is "quite heterogenous," he said. The newly defined prognostic factors help identify who is "likely to progress in a short time" and "who actually needs treatment."

Dr. Yao said that the reanalysis had another potentially important finding — that everolimus might be more effective in the treatment of these tumors than originally reported.

In RADIANT-2, Dr. Yao and colleagues originally showed that progression-free survival was a median of 5.1 months longer with the combination of everolimus (Afinitor, Novartis) plus the carcinoid syndrome drug octreotide (Sandostatin, Novartis) than with octreotide alone (16.4 vs 11.3 months); the study results were reported last year by Medscape Medical News.

But the phase 3 study was found to have imbalances in its patient randomization, which put more patients with a poor prognosis in the everolimus group.

After adjusting for randomization imbalances, the researchers found in an exploratory analysis that the reduction in the risk for progression in patients treated with everolimus plus octreotide was 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51 to 0.87; = .003). This is an improvement from the 23% risk reduction seen in the first analysis. Everolimus is likely "a little more active than previously thought," said Dr. Yao. A larger study to confirm these results is planned.

It is likely that the original study had randomization imbalances because the prognostic factors needed to stratify patients were not well defined at the start of the study, said Dr. Yao in a press statement.

In short, the researchers are learning as they go.

The subset of patients most likely in need of drug therapy is "all the more meaningful" because of the "limited treatment options" with this disease, said Morton Kahlenberg, MD, from the University of Texas Health Science Center at San Antonio, who moderated the press conference.

Everolimus was approved last year by the US Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors. The targeted therapy sunitinib (Sutent, Pfizer and Merck) was also approved for these tumors last year.

However, it is not known whether everolimus is effective in treating neuroendocrine tumors that do not originate in the pancreas. Currently, there are no approved therapies for the oncologic control of these types of neuroendocrine tumor, said Dr. Yao.

Study Details

In RADIANT-2, Dr. Yao and colleagues sought to assess the effectiveness of the combination of everolimus plus octreotide in patients with low- or intermediate-grade neuroendocrine tumors associated with carcinoid syndrome.

In the study, 429 patients with unresectable locally advanced or distant metastatic neuroendocrine tumors were randomized to receive either oral everolimus 10 mg daily (n = 216) or placebo (n = 213), both in conjunction with intramuscular octreotide LAR (long-acting repeatable) 30 mg every 28 days. Treatment was continued until disease progression, withdrawal from treatment because of adverse effects, or withdrawal of consent.

Of these patients, 357 discontinued study treatment and 1 was lost to follow-up.

The initial analysis of the study found that median progression-free survival was 16.4 months (95% CI, 13.7 to 21.2) in the combination group and 11.3 months (95% CI, 8.4 to 14.6) in the monotherapy group (HR, 0.77; 95% CI, 0.59 to 1.00; P = .026).

In the reanalysis, the investigators identified prognostic factors that predicted both good and poor outcomes in the trial.

They now report that median progression-free survival was significantly longer for patients with nonelevated CgA (27 vs 11 months; < .001) and nonelevated 5-HIAA (17 vs 11 months; < .001). The analyses also indicated the prognostic potential of age (14 vs 12 years; = .01), WHO performance status of 0 vs 1 or more (17 vs 11; = .004), liver involvement (14 vs not reached; = .02), bone metastases (8 vs 15; < .001), and lung as the primary site (11 vs 14; = .06).

A multivariate analysis found that some factors were significantly associated with a greater likelihood of neuroendocrine tumor progression.

This analysis indicated that bone involvement (HR, 1.52; 95% CI, 1.06 to 2.18; = .02) and lung as the primary site (HR, 1.55; 95% CI, 1.01 to 2.36; = .04) were especially strong prognostic factors for progression-free survival, and that baseline CgA (HR, 0.47; 95% CI, 0.34 to 0.65; < .001) and WHO performance status (HR, 0.69; 95% CI, 0.52 to 0.90; = .006) were also significant.

Randomization in the trial also resulted patient group imbalances, especially in baseline CgA (median, 251 ng/mL for everolimus plus octreotide vs 137 ng/mL for octreotide alone), Dr. Yao reported.

Other randomization imbalances also favored the octreotide group, which had more patients with a WHO performance status of 1 or more and more with lung as the primary tumor site.

Dr. Yao reports receiving research funding and honoraria from Novartis, which sponsored the trial. Other authors report receiving research funding and honoraria or being employees of and owning stock in Novartis.

2012 Gastrointestinal Cancers Symposium (GICS): Abstract 157. To be presented January 20, 2012.


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