Sulindac/erlotinib combo reduces polyp burden in FAP patients

Last Updated: 2016-03-22

By Megan Brooks

NEW YORK (Reuters Health) - Treatment with the cyclooxygenase inhibitor sulindac in combination with the TKI inhibitor erlotinib reduced duodenal polyp burden and polyp number in patients with familial adenomatous polyposis (FAP) in a double-blind, placebo-controlled trial.

"We were surprised at how dramatic the response was. We stopped the study early because it was determined that we had a clear answer that it worked. One other surprise was that the polyps did not only stop progressing in participants on study drugs, they actually got smaller or even went away in some participants," Dr. Deborah Neklason, of the Huntsman Cancer Institute, University of Utah in Salt Lake City, told Reuters Health by email.

Patients with FAP are at high risk of duodenal polyps and cancer, with duodenal adenomas eventually seen in more than half of patients and duodenal adenocarcinoma occurring in up to 12%.

"Following colectomy, duodenal adenocarcinoma is the leading cause of cancer death in these patients, and prevention of duodenal adenocarcinomas by endoscopic surveillance with polyp resection, duodenectomy, Whipple surgical procedure, and ampullectomy are often challenging and suboptimal," the authors note in their March 22 JAMA paper.

Several studies have shown that sulindac significantly inhibits colorectal adenomatous polyps in patients with FAP, while nonsteroidal anti-inflammatory drugs (NSAIDs) have much less efficacy in duodenal adenomas.

Dr. Neklason and colleagues tested the effect of six months of treatment with sulindac (150 mg twice daily) plus erlotinib (75 mg daily) versus placebo on duodenal adenoma regression in 92 FAP patients. Their mean age was 41 years and 56 were women. The researchers mapped the total number and diameter of polyps in the proximal duodenum at baseline and six months.

The external data and safety monitoring board stopped the trial at the second preplanned interim analysis when it was found that the sulindac/erlotinib combination met the prespecified stopping rule for superiority.

The sulindac/erlotinib group experienced an 8.5-mm median decrease in polyp burden from baseline, while the placebo group experienced an 8-mm median increase from baseline in polyp burden (between-group difference, 19.0 mm, p<0.001).

As for percentage change in polyp burden from baseline, there was a 38% decrease with sulindac/erlotinib and a 31% increase with placebo (between-group difference, 71.2%, p<0.001).

Total duodenal polyp count dropped by 2.8 polyps in the sulindac/erlotinib group and rose by 4.3 polyps in the placebo group (p<0.001).

"Subgroup analyses confirmed similar findings in participants with classic or attenuated FAP and a genetic diagnosis," the authors report.

However, adverse events may "limit" the use of this treatment at the doses studied, they note. There was a "high rate" of grade 1 and 2 adverse events, most notably acne-like rash seen in 87% of those on the drug combination and oral mucositis seen in 39%.

"Another study is planned to evaluate efficacy of different dosing (once per week and/or lower doses) to make the drugs more tolerable and to extend the study to 12 months instead of just six months to see if a better response will come of longer treatment," Dr. Neklason told Reuters Health.

There are several other questions that need answers as well, she said.

"The most important question is if treating patients with these drugs changes the clinical management of these patients? Does it delay or stop surgery? Does it prevent duodenal cancer? This would require a long-term study and require patients with more advanced disease," Dr. Neklason said.

Also, "What is the durability of the response? Once you take someone off the drugs, do polyps come back? How long until polyps come back? This would allow you to possibly put someone on drug for six months, stop for a period of time, then resume if polyps became problematic."

In ongoing molecular studies, Dr. Neklason and colleagues are examining the effect of the drugs on the tissues. "What pathways are most affected? Cell growth? Cell death? Cell differentiation? Signaling to adjacent tissues? Our hope in understanding this is that it will inform us more broadly of how precancerous tissues of the gut (small intestine and colon) respond to cancer prevention. This is because the patients under study have an inherited mutation in the APC gene and 80% of all colon cancers arise when mutations in this gene occur. In this era of precision medicine - we like to think of this as precision prevention," Dr. Neklason said.

The study had no commercial funding. Three authors had disclosures, which are listed with the original article.

SOURCE: http://bit.ly/1XK8hnO

JAMA 2016.