Sulindac Plus Erlotinib Reduce Duodenal Polyp Burden in FAP

Treatment with sulindac plus erlotinib may combat duodenal polyp development in patients with an inherited disorder associated with a high lifetime risk of colorectal cancer

medwireNews: Preliminary trial results suggest that patients with familial adenomatous polyposis (FAP) might be able to reduce their duodenal polyp burden using a combination of sulindac and erlotinib .

Polyp burden, defined as the sum of the diameter of polyps, in the 10 cm distal to the first segment of duodenum was reduced by a median of 8.5 mm, or 37.9%, in the 46 patients who were randomly assigned to receive 6 months of treatment with the nonsteroidal anti-inflammatory drug sulindac 150 mg twice daily plus the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib 75 mg once daily.

By comparison, polyp burden in the 46 placebo-treated patients increased by a median 8.0 mm over 6 months, translating to a 30.6% increase; the between group difference was a significant –19.0 mm.

Patients given the combined therapy also had a median 2.8 reduction in their median number of duodenal polyps over 6 months, compared with a median 4.3 increase in controls. Again, the between group difference was significant, at –8.0.

And these patterns were true when considering both patients with classic and attenuated FAP, and when looking at only patients with a confirmedgermline APC mutation.

“Our study suggests the possibility of an effective chemoprevention strategy for duodenal neoplasia in patients with FAP and supports the need for future longer-term studies to establish clinically meaningful outcomes”, the investigators write in a preliminary communication published in JAMA.

Deborah Neklason, from the University of Utah in Salt Lake City, USA, and co-authors add that the trial was halted by an external data and safety monitoring board when the second preplanned interim analysis demonstrated superiority with the combined treatment.

They report that the chemopreventive effect was stronger in patients with a high polyp burden at baseline, defined as a sum of diameters greater than 21 mm, than those with a lower burden, with a significant between-group difference of –36.6 mm.

However, there were some patients in both the active and placebo treatment groups who had no change in their polyp burden over 6 months.

Analysis of polyp lysates demonstrated detectable phosphorylated EGFR in six of seven placebo-treated polyps versus no or minimal EGFR in the seven polyps taken from patients given the combined treatment.

“These data indicate that the sulindac-erlotinib treatment effectively limited activation of EGFR”, the authors suggest.

Only two patients given sulindac plus erlotinib experienced grade 3 adverse events and there were no cases of grade 4 but the combined treatment was associated with a significantly higher rate of grade 2 or 3 side effects, at 46% versus 13%. Acneiform-like rash was the most common adverse event, with grade 1–3 symptoms affecting 87% versus 20% of those in the placebo group.

“Although the dosing of sulindac was based on prior chemoprevention studies, the dosing of erlotinib was estimated from cancer treatment and lung cancer chemotherapy trials”, the researchers write.

Acknowledging that dose modifications of erlotinib due to intolerance were common in the trial and did not seem to affect efficacy, the team emphasizes that “[d]ose-ranging studies will be needed to determine if lower and/or less-frequent dosing of erlotinib could diminish these adverse effects, but retain efficacy.”

Nevertheless, they caution: “The incomplete efficacy of sulindac and erlotinib in some participants necessitates continued endoscopic surveillance and surgery for advanced duodenal neoplasia at the dosing levels and duration of our study.”


Samadder NJ, Neklason DW, Boucher KM, et al. Effect of sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis. A randomized clinical trial. JAMA2016; 315: 1266–1275. doi:10.1001/jama.2016.2522

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