Eflornithine Plus Sulindac Has Limited Impact on Disease Progression in Familial Polyposis

The incidence of disease progression in patients with familial adenomatous polyposis (FAP) was not significantly lower when patients were treated with eflornithine (Vaniqa) plus sulindac (CPP-1X/sul) compared with either drug alone, according to the findings from the randomized, double-blind phase 3 FAP-310 study.¹

“The results of the phase 3 trial demonstrate CPP-1X/sul may be a potential pharmaco-preventive option for FAP patients in delaying surgical procedures,” said Alfred Cohen, MD, chief medical officer, Cancer Prevention Pharmaceuticals, Inc, developer of the drug; and co-author of the article, in a statement.² “These surgeries are life-altering and we are encouraged by this positive data for pre-colectomy FAP patients.”

Almost all patients with FAP, a rare genetic disorder, will progress to colorectal cancer if left untreated. The current standard of care is surgery, and no other drugs are approved for the treatment of these patients. This was the largest prospective controlled study ever performed in patients with FAP, as well as the only clinical event-driven trial conducted.

Overall, 171 patients were randomized to receive either the CPP-1X/sul combination (n = 56), eflornithine (n = 57), or sulindac (n = 58). The primary end point of the study was delaying time to the first occurrence of any FAP-related event, and secondary end point was improvement in investigator lower gastrointestinal (GI) assessment.¹

Eighteen patients (32%) in the combination arm had disease progression, 22 (38%) in the sulindac arm, and 23 (40%) in the eflornithine arm. The mean time to the first disease progression event in the intention-to-treat (IIT) population was 32.3 months (95% CI, 31.8-32.8) with the combination, 23.6 months (95% CI, 23.2-23.9) with sulindac, and 21.8 months (95% CI, 21.4-22.2) with eflornithine; the hazard ratios (HRs) were 0.71 (95% CI, 0.39-1.32; P =.29) and 0.66 (95% CI, 0.36-1.24) for the combination arm versus sulindac and eflornithine, respectively.

Neither upper nor lower GI cancer developed in any patient on the study. Twelve patients had progression of lower GI polyposis. Fourteen patients with duodenal polyposis progression underwent duodenal surgery. Thirty patients had disease progression in the duodenum involved progression in Spigelman stage and in duodenal endoscopic excisional intervention in 19 patients; 8 of the 30 patients underwent intervention for progression or had an additional FAP-related event. Disease progression was not severe enough for intervention in the remaining 22 patients.

In terms of the secondary end point among patients in the 3 surgical subgroups, disease progression occurred in 2 patients (17%) out of 12 in the combination arm, 6 (46%) of 13 in the sulindac arm, and 5 (42%) of 12 in the eflornithine arm. The estimated mean times to first event of disease progression was 39.3 months (95% CI, 37.1-41.6) in the combination group, 25.2 (95% CI, 24.2-26.1) in the sulindac group, and 19.7 (95% CI, 18.2-21.1) in the eflornithine group. The HRs for the combination compared with the sulindac and eflornithine arms, respectively, were 0.30 (95% CI, 0.07-1.32) and 0.20 (95% CI, 0.03-1.32). No polyposis-related events, nor surgical procedures, in the lower GI tract occurred in the combination arm.

Among 34 patients with rectal or ileal pouch polyposis after colectomy, disease progression was observed in 4 (36%) of 11 in the combination arm, 2 (18%) of 11 in the sulindac arm, and 5 (42%) of 12 in the eflornithine arm. The estimated mean times to first event of disease progression was 20.9 months (95% CI, 19.8-22.0) in the combination arm, 27.5 months (95% CI, 25.3-29.6) in the sulindac arm, and 15.7 months (95% CI, 14.9-16.6) in the eflornithine arm, and the HRs for the combination with either single agent were 2.03 (95% CI, 0.43- 9.62) and 0.84 (95% CI, 0.24-2.90), respectively.

Among 100 patients with duodenal polyposis, disease progression was observed in 12 (36%) of 33 in the combination arm, 14 (41%) of 34 in the sulindac arm, and 13 (39%) off 33 in the eflornithine arm. The estimated mean times to first disease progression event were 23.6 months (95% CI, 23.0-24.2) with the combination, 21.1 months (95% CI, 20.5-21.8) with sulindac, and 21.7 months (95% CI, 21.0-22.3) with eflornithine. The HRs were 0.73 (95% CI, 0.34-1.52) and 0.76 (95% CI, 0.35-1.64) for the combination compared with sulindac and eflornithine alone, respectively.

Treatment-related adverse events (TRAEs) were observed in 68% of the patients in the combination arm, 74% in the sulindac arm, and 55% in the eflornithine arm, and most events were mild to moderate in severity and usually resolved with minimal intervention.

The most common TRAEs among all patients were nausea (15%), headache (11%), diarrhea (7%), vomiting (7%), rectal hemorrhage (7%), abdominal pain (7%), flatulence (6%), dyspepsia (5%), and decreased appetite (5%). More patients in the combination arm experienced rash, upper abdominal pain, and erosive gastritis.

Serious TRAEs included acute pancreatitis, nephritis, and psychosis–paranoia, each in 1 patient from the combination arm; severe nausea, deep-vein thrombosis, worsening of depression, and spontaneous abortion, each in 1 patient from the sulindac arm; and stroke in 1 patient from the eflornithine arm. Treatment discontinuation due to AE occurred in 9 patients (16%) from the combination arm 6 (10%) in the sulindac arm and 5 (9%) in the eflornithine arm.

Based on these findings, Cancer Prevention Pharmaceuticals, plans to pursue regulatory approval of CPP-1X/sul from the FDA, as well as a Marketing Authorization Application with the European Medicines Agency, in order to delay or prevent surgical procedures in patients with an intact colon, retained rectum, or surgical pouch.²

A New Drug Application was submitted to the FDA in June 2020, seeking accelerated approval of the combination for the treatment of adult patients with FAP.

_References

_{1. Burke CA, Dekker E, Lynch P, et al. Eflornithine plus sulindac for prevention of progression in familial adenomatous polyposis. N Engl J Med. 2020; 383; 1028-39. doi: 10.1056/NEJMoa1916063}

_{2. Cancer prevention pharmaceutical announces NEJM publication of landmark phase 3 clinical trial for treatment of familial adenomatous polyposis. News Release. Cancer Prevention Pharmaeticals, Inc. September 11, 2020. Accessed September 17, 2020.}