Pembrolizumab Fails to Achieve Goal Response Rate in Patients With Advanced Small Bowel Adenocarcinoma

Barcelona, Spain—Pembrolizumab did not achieve the goal response rate in pretreated patients with advanced small bowel adenocarcinoma but could control disease in patients with microsatellite stable (MSS) tumors.

“Small bowel adenocarcinoma is a rare malignancy seen in only about 6-7 persons per million population annually. This incidence has, however, been rising over the past several years across the US and Europe,” Katrina S. Pedersen, MS, MD, Washington University School of Medicine, St. Louis, Missouri, stated during her presentation at the ESMO 21st World Congress on Gastrointestinal Cancer.

The lack of a standard of care for patients with this disease beyond first-line FOLFOX/CAPOX, led Dr Pederson and colleagues to conduct a clinical trial of 40 previously treated patients (median age, 63 years) with the disease.

“At this point, I think we all know very well in this room that pembrolizumab is an anti-PD-1 immune checkpoint inhibitor. Of prospectively predictive biomarkers, MSI-high status has been most associated with response in advanced colorectal cancer, however, in MSS-advanced colorectal cancer, anti-PD1 therapy has not produced responses,” Dr Pedersen explained.

PD-L1 expression has been validated as a predictive biomarker in advanced upper-GI malignancies, and half of tumors in small bowel adenocarcinoma are PD-L1 positive, thus they hypothesized that pembrolizumab would be an active agent in this disease.

A total of 40 patients were enrolled in the trial from May 2017 to September 2018 and received pembrolizumab 200 mg until disease progression or toxicity occurred.

The primary end point was confirmed overall response rate (ORR) per RECIST v1.1 criteria; tumor responses were assessed every 12 weeks. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety outcomes. Dr Pederson noted that if ≥7 of 35 patients had a confirmed response, then pembrolizumab would be considered adequately effective for further study.

There were primary tumors distributed in the duodenum, jejunum, and ileum (60%, 25%, and 15%, respectively); and MSI status was available for 22 (55%) patients.

A total of 32 patients are no longer in the trial because of progressive disease (n=25; 78%), death (n=5; 16%), and adverse events (n=2; 6%). These 32 patients underwent therapy for a median of 4 cycles, with 3 confirmed partial responses (8%; 95% CI, 2-20%).

According to Dr Pedersen, the study did not meet its primary endpoint.

The median OS (6.9 months; 95% CI, 5.1 to not reached) and median PFS (2.8 months; 95% CI, 2.7-5.1) were similar across the 3 primary tumor sites.

Of 18 patients with MSS tumors, 1 (6%) had a confirmed partial response and disease control rate of 50%. Among 2 patients with MSI-low disease, 1 patient with stable disease had the best response. Both patients with MSI-high disease had partial responses and lived progression-free.

There were 23 (58%) patients with adverse events grade >3, and 9 (23%) with adverse events grade 4/5. All 5 grade 5 adverse events were considered to be most likely secondary to disease progression, except for 1 grade 5 sepsis which was deemed to be possibly related to therapy.

“This is the largest trial ever completed in small bowel adenocarcinoma to date. This is the first prospective immunotherapy trial also conducted in this population,” said Dr Pederson.

“While the primary end point was not met in regard to overall response rate, we do consider the MSI-high efficacy to be confirmed at a rate somewhat similar to that seen with anti-PD-1 monotherapy in advanced colorectal cancer,” she concluded.—Hina Khaliq

Pedersen K, Foster N, Overman M, et al. ZEBRA: an ACCRU/IRCI multicenter phase 2 study of pembrolizumab in patients with advanced small bowel adenocarcinoma (SBA). Presented at: the ESMO 21st World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain. Abstract O-007.