TY - JOUR
T1 - ZEBRA
T2 - A multicenter phase II study of pembrolizumab in patients with advanced small-bowel adenocarcinoma
AU - Pedersen, Katrina S.
AU - Foster, Nathan R.
AU - Overman, Michael J.
AU - Boland, Patrick M.
AU - Kim, Sunnie S.
AU - Arrambide, Kathryn A.
AU - Jaszewski, Brandy L.
AU - Bekaii-Saab, Tanios
AU - Graham, Rondell P.
AU - Welch, Jack
AU - Wilson, Richard H.
AU - McWilliams, Robert R.
N1 - Funding Information:
With the lack of prospective trial data, there is no clearly established therapy beyond the first line for SBA. FOLFIRI efficacy is supported by retrospective data only (8). In the only successful prospective study of second-and later-line patients, nab-paclitaxel was shown to have promising activity, with an overall response rate of 20% [50% disease control rate (DCR)] in 10 patients with refractory SBA (9). This contrasts starkly to the lack of taxane activity in colorectal cancer (9, 10).
Funding Information:
K.S. Pedersen reports grants, nonfinancial support, and other support from ACCRU/Merck during the conduct of the study; grants, personal fees, nonfinancial support, and other support from Array/Pfizer; other support from Beigene; grants and other support from Nouscom; grants from AbbVie, BioLineRx, Boston Biomedical/ Sumitomo Dainippon, BMS, Daiichi Sankyo, Ipsen, MedImmune, Novartis, Pierre Fabre, Rafael, Roche/Genentech, Natera; other support from NCCN outside the submitted work; and Medscape (personal reimbursement for CME videos recorded) and UpToDate (royalties for section entitled diagnosis of small intestinal cancers).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-0159
DO - 10.1158/1078-0432.CCR-21-0159
M3 - Article
C2 - 33883178
AN - SCOPUS:85109190295
SN - 1078-0432
VL - 27
SP - 3641
EP - 3648
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -