January 19, 2009 (San Francisco, California) — RAD001 (everolimus, Novartis) may be beneficial to patients with metastatic pancreatic neuroendocrine tumors, either as monotherapy or combined with octreotide (Sandostatin LAR, Novartis). The majority of patients experienced disease stabilization or some degree of tumor shrinkage following therapy, according to the results of a phase 2 trial presented here at the 2009 Gastrointestinal Cancers Symposium.
"Progression-free survival at 6 months was more than double the rate of historical controls," said lead author James Yao, MD, associate professor at the University of Texas MD Anderson Cancer Center, in Houston. "Durable objective responses and stable disease were observed in both arms of the study."
Pancreatic neuroendocrine tumors are generally believed to be rare, with a reported incidence of 0.12 to 0.32 per 100,000 people. However, the true incidence might be higher, according to Dr. Yao.
There is no established treatment for pancreatic neuroendocrine tumor for patients who fail chemotherapy. But even with chemotherapy, outcomes are poor in advanced disease. The median survival is 2.2 years for patients receiving streptozotocin–doxorubicin chemotherapy, and median overall survival for patients with distant disease is about 23 months from the time of diagnosis. In patients with progressive disease at study entry, the estimated 6-month progression-free survival was 28%.
"Novel therapeutic approaches are needed in this patient population," said Dr. Yao.
RAD001 is an oral inhibitor of the mammalian target of rapamycin (mTOR), and has exhibited broad antitumor activity in both preclinical and clinical trials, although all these oncology applications are still investigational. However, the product is already marketed in Europe and Australia (but not in the United States) as Certican for the prevention of organ rejection in heart- and kidney-transplant patients.
A recent phase 2 trial that investigated patients with low to intermediate neuroendocrine tumors showed that RAD001 was well tolerated at doses of 5 and 10 mg, and showed promising antitumor activity, explained Dr. Yao.
RAD001 might also act synergistically with octreotide to inhibit cellular growth and sectretory activity of malignant cells, he added. Octreotide has been used to control symptoms in patients with neuroendocrine tumors, and some data indicate that it affects tumor growth.
Increase in Progression-Free Survival Observed
In this phase 2 study, Dr. Yao and colleagues evaluated the response rate and progression-free survival in patients with metastatic pancreatic neuroendocrine tumors who had progressed during or after receiving chemotherapy. Study participants were stratified according to previous and ongoing use of depot octreotide therapy. Patients in stratum 1 (n = 115) received RAD001 10 mg daily alone, whereas those in stratum 2 (n = 45) received RAD001 and depot octreotide.
Tumor assessment with triphasic computed tomography or magnetic resonance imaging was performed at baseline and every 3 months, and the images were evaluated by central radiology using RECIST.
The response rate, as measured by central radiology, was 7.8% in stratum 1 and 4.4% in stratum 2. Progression-free survival at 6 months was 65.4% in stratum 1 and 70.6% in stratum 2, and median progression-free survival was 9.3 months in stratum 1 and 12.9 months in stratum 2. At 15 months, survival was 52.6% in stratum 1 and 90.3% in stratum 2.
These results represent the data as of January 15, 2008, and at the time of data cut, 37.4% of patients in stratum 1 and 46.7% in stratum 2 remained on treatment.
Response Assessment by Central Review (CR) and Investigator Assessment (IA)
| CR: RAD001 | CR: RAD001 + octreotide | IA: RAD001 | IA: RAD001 + octreotide | |
| CR/PR, n (%) | 9 (7.8) | 2 (4.4) | 8 (7.0) | 4(8.9) |
| SD, n (%) | 79 (68.7) | 35 (7.8) | 76 (66.1) | 32 (71.1) |
| Clinical benefit (PR + SD), n (%) | 88 (76.5) | 37 (82.2) | 84 (73.0) | 36 (80.0) |
| Progressive disease, n (%) | 16 (13.9) | 1 (2.2) | 21 (8.3) | 5 (1.1) |
| Unknown, n (%) | 11 (9.6) | 7 (15.6) | 10 (8.7) | 4 (8.9) |
| Median response duration (months) | 10.8 | N/A | 10.15 | N/A |
The researchers also reported results for a subgroup of patients who had an abnormal chromogranin A (CgA). In stratum 1, 75 of 115 (65%) patients had an abnormal CgA and at least 1 postbaseline assessment. Of this group, a response (decrease by at least 50% or normalization) was noted in 37 patients (49.3%). In stratum 2, 25 of 45 (55%) patients had an abnormal baseline CgA and at least 1 baseline assessment, response was noted in 14 (56%) patients at any postbaseline point.
Treatment with RAD001 was well tolerated, and most adverse events were mild to moderate. The most common grade 3 adverse events with a suspected relation to the therapy were asthenia, fatigue, and thrombocytopenia. Only 4% of patients experienced grade 4 effects, and grade 1/2 pneumonitis occurred in 4% of patients. There were no major differences in safety between the 2 study groups.
The higher rates of stable disease and progression-free survival observed in stratum 2 could be due to the addition of octreotide, he pointed out. "But, in conclusion, progression-free survival and overall survival in strata 1 and 2 support the efficacy of RAD001. A phase 3 study is ongoing."
Strengths and Potential Limitations
The study has both strengths and potential limitations, commented Lillian L. Siu, MD, from Department of Medical Oncology and Hematology at Princess Margaret Hospital, in Toronto, Ontario. "It is a large multicenter study of patients with a rare disease. It has a homogenous patient population by history and disease status."
But Dr. Siu, who served as a discussant at the presentation of the study, questioned whether such a large single-group phase 2 study was needed. Could they have conducted a randomized trial instead, she wondered.
"The final results will have to come from a phase 3 trial, which is underway," she said. "The study demonstrated promising activity in patients with pancreatic neuroendocrine tumors with mTOR inhibition. We applaud the authors for conducting these trials in rare tumors."
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