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Purpose:Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response.Patients and Methods:Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level.Results:Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs.Conclusions:In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Purpose: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Patients and Methods: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Results: Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. Conclusions: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Background: Small bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic SBA beyond first-line FOLFOX/CAPOX. Later-line therapy has been extrapolated from colorectal cancer (CRC) studies, though SBA is biologically distinct with higher rates microsatellite instability (MSI-H) and intratumoral T-lymphocyte infiltration. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Methods: Previously treated advanced SBA patients received pembrolizumab 200 mg IV q3 weeks until disease progression (PD), toxicity, or to 35 dose maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary survival and safety endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Findings: 40 patients were treated for median duration of 4 cycles (range 1-35). MSI status was available for 36 patients (90%). All 40 patients are off study treatment due to: PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AE, 5%). Three confirmed partial responses (PR) (8%; 95% CI: 2-20) did not meet pre-defined success criteria. Median overall survival (OS) 7 . 1 mo (95% CI: 5 . 1-17 . 1) and median progression free survival (PFS) 2 . 8 mo (95% CI: 2 . 7-4 . 2) were similar across primary tumor sites. One confirmed PR was seen in 32 MSS/MSI-low patients (3%). MSS response correlated with high tumor mutation burden (TMB). Two of four MSI-H patients had a confirmed PR (50%) and remain alive without progression. 25 patients (63%) had grade ≥ 3 AEs, 11 pts (28%) had grade 4/5 AEs. Interpretation: In the largest study of SBA to date, and the first using immunotherapy, pembrolizumab did not achieve the hypothesized response rate; however, we did identify responses in certain biomarker-selected cohorts. Trial Registration: RU021502I (ACCRU), MISP #52192 (Merck), NCT02949219 (clinicaltrials.gov). Funding Statement: Primary study funding and investigational product was provided by the Merck Investigator Studies Program (MISP), and additional site-specific funding provided by the Kavanagh Family Foundation (MDACC) and Kevin T. Doner Memorial Fund (MDACC). Declaration of Interests: None to declare Ethics Approval Statement: Ethics board review and human research protections monitoring were performed at each institution. The trial was conducted according to ICH GCP.