SAN FRANCISCO — Nine years after conceiving of a novel treatment regimen for neuroendocrine tumors in his laboratory at Columbia University in New York City, Robert Fine, MD, finally got a moment in the limelight with his brainchild.
At a press conference held in advance of the 2014 Gastrointestinal Cancers Symposium (GICS), Dr. Fine reported that the chemotherapy combination of capecitabine plus temozolomide either stalled disease progression or shrank tumors in 97% of patients whose disease had worsened after standard high-dose octreotide (Sandostatin, Novartis).
"These are absolutely remarkable results," said Dr. Fine in an interview with Medscape Medical News. "I was shocked by them."
The results with the combination, known as CAPTEM, are unprecedented, even though the number of evaluable patients was small. All 28 were treated at the Columbia-Presbyterian Medical Center, Dr. Fine noted.
CAPTEM is the first treatment to demonstrate efficacy in a wide variety of neuroendocrine tumors, including carcinoid tumors, which are "notoriously difficult to treat," he said.
Of the 12 patients with carcinoid tumors, 5 (41%) had tumor shrinkage. This is "unusual," he said, because the typical response rate to chemotherapy in these patients is less than 3%.
CAPTEM was also effective in pituitary tumors, another difficult-to-treat neuroendocrine tumor subtype known to be resistant to chemotherapy. Of the 3 patients with pituitary tumors — all resistant to every form of earlier treatment (radiation therapy, chemotherapy, and surgery) — 2 experienced complete remission with CAPTEM and 1 experienced a 75% reduction in tumor size.
The 2 complete remissions are especially dramatic cases. Both "were end-stage and on respirators because of spinal cord compression [from the tumor]; they both had complete responses, got off the machine, and are still tumor-free close to 4 years out and on continual treatment," he told reporters.
The combination was also effective in the 11 pancreatic neuroendocrine tumors (stable disease, 55%; partial response, 36%) and 2 medullary thyroid tumors (stable disease, 100%) in the cohort.
For the 28 study patients at the time of analysis, median progression-free survival was more than 22 months. The overall survival data are still maturing, but median progression-free survival is more than 29 months at this point, and 16 patients remain alive and on therapy.
Overall, 43% of this phase 2 study cohort responded to CAPTEM, and 54% experienced stable disease.
Dr. Fine said that these results compare favorably with octreotide, which has a response rate of about 6% in the various neuroendocrine tumor types and about 30% to 40% in stable disease.
Tyrosine kinase inhibitors (TKIs), a drug class for neuroendocrine tumors that includes sunitinib (Sutent, Pfizer), have response rates of less than 10% and stable disease rates of about 60%. Notably, clinical trials with TKIs have been conducted exclusively in patients with pancreatic neuroendocrine tumors (which account for about 35% of neuroendocrine tumors), and have not included patients with the more treatment-resistant carcinoids (about 55% of all neuroendocrine tumors), Dr. Fine noted.
"The duration of response with CAPTEM is very, very long," Dr. Fine reported. The longest responder in the CAPTEM cohort is now at 8 years.
CAPTEM was also "extraordinarily nontoxic" compared with other chemotherapies for these patients. The most common grade 3/4 toxicities are lymphopenia (35%), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).
"This study is of interest even though it is small and not randomized.... The CAPTEM combination resulted in tumor responses in neuroendocrine tumors that are typically resistant to chemotherapy," said Smitha S. Krishnamurthi, MD, associate professor of medicine at Case Western Reserve University in Cleveland, who moderated the press briefing during which the results were presented.
Now the Subject of a Cooperative Group Trial
Given the impressive efficacy of CAPTEM, clinicians might wonder why they have never heard of it.
Dr. Fine explained that every year since 2005, he has had either a poster or abstract about CAPTEM at the annual meeting of the American Society of Clinical Oncology (ASCO). However, he has never been in the press program or given an oral presentation.
CAPTEM is comprised of 2 generic oral chemotherapies, he noted. There is no pharmaceutical or biotech company to champion it or fund research. And given the disparities in Medicare reimbursement for oral and intravenous chemotherapy, clinicians are unlikely to clamor for news about the combination, he suggested.
Neuroendocrine tumors are also relatively uncommon; there are only about 10,000 new cases a year in the United States.
The sum of the parts has added up to low profile for CAPTEM. Nevertheless, these results "speak for themselves," said Dr. Fine.
Temozolomide, which is also known by its brand name, Temodar, is a cytotoxic alkylating agent indicated for use in patients with brain tumors and metastatic melanoma.
Capecitabine, a prodrug that is converted to 5-fluorouracil (5-FU) in the body, slows tumor growth and is used in a variety of cancer types, including those of the breast and colon.
Dr. Fine explained that the combination works well because 5-FU chemotherapy depletes thymidine stores, which improves the "cell kill" of temozolomide.
He and his team tested various combinations of the drugs in the laboratory before they arrived at the protocol used in the study. Patients received daily capecitabine 1500 mg/m² for 2 weeks and daily temozolomide 150 to 200 mg on days 10 to 14, with the next 2 weeks off, in a 28-day cycle. All of the study patients had well- or moderately differentiated tumors. These account for most cases of neuroendocrine tumors and are typically resistant to treatment.
Although GICS, which is sponsored by ASCO and 3 other organizations, provides an impressive stage for CAPTEM, the combination is likely to have more time in the spotlight, Dr. Fine explained. He is planning to publish these data from this phase 2 study, and CAPTEM is currently the subject of an Eastern Cooperative Oncology Group randomized trial comparing temozolomide with or without capecitabine in patients with advanced pancreatic neuroendocrinetumors.
Dr. Fine and Dr. Krishnamurthi have disclosed no relevant financial relationships.
2014 Gastrointestinal Cancers Symposium (GICS): Abstract 179. To be presented January 17, 2014.
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