Esophagus to Small Intestine
Phase 2 trial of weekly erlotinib dosing to reduce duodenal polyp burden associated with familial adenomatous polyposis
Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. The combination of sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate.
Objective: To evaluate if a once-weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in 8 academic cancer centers.
Exposures: Participants self-administered 350 mg of erlotinib by mouth, 1 time per week for 6 months.
Main outcomes and measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean percent change defined as the primary efficacy outcome of interest. Rate of grade 2–3 AEs was evaluated as a coprimary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy).
Results: 46 participants (mean age, 44.1 years [range, 18–68]; women, 22 [48%]) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean percent change of -29.6% (95% confidence interval [CI]: -39.6% to -19.7%; p < 0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI: -38.7% to -15.2%; p < 0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; interquartile range, -47.4–0.0%; p = 0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only 2 experiencing grade 3 toxicity at least possibly related to intervention.
Conclusion: In this single-arm, multicenter trial of participants with familial adenomatous polyposis (FAP), erlotinib 1 time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower gastrointestinal (GI) polyp burden, after 6 months of intervention. While adverse events were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer-preventive agent for FAP-associated GI polyposis.