TY - JOUR
T1 - Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma
AU - Katz, Matthew H.G.
AU - Petroni, Gina R.
AU - Bauer, Todd
AU - Reilley, Matthew J.
AU - Wolpin, Brian M.
AU - Stucky, Chee Chee
AU - Bekaii-Saab, Tanios S.
AU - Elias, Rawad
AU - Merchant, Nipun
AU - Costa, Andressa Dias
AU - Lenehan, Patrick
AU - Cardot-Ruffino, Victoire
AU - Rodig, Scott
AU - Pfaff, Kathleen
AU - Dougan, Stephanie K.
AU - Nowak, Jonathan Andrew
AU - Varadhachary, Gauri R.
AU - Slingluff, Craig L.
AU - Rahma, Osama
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2023.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Background Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC. Methods Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination. Results Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8+ T-cell densities in Arms A and B were 67.4 (IQR: 39.2–141.8) and 37.9 (IQR: 22.9–173.4) cells/mm2, respectively. Arms showed no noticeable differences in density of CD8+Ki67+, CD4+, or CD4+FOXP3+ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively. Conclusions Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8+ TILs was observed.
AB - Background Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC. Methods Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination. Results Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8+ T-cell densities in Arms A and B were 67.4 (IQR: 39.2–141.8) and 37.9 (IQR: 22.9–173.4) cells/mm2, respectively. Arms showed no noticeable differences in density of CD8+Ki67+, CD4+, or CD4+FOXP3+ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively. Conclusions Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8+ TILs was observed.
UR - http://www.scopus.com/inward/record.url?scp=85178329798&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85178329798&partnerID=8YFLogxK
U2 - 10.1136/jitc-2023-007586
DO - 10.1136/jitc-2023-007586
M3 - Article
C2 - 38040420
AN - SCOPUS:85178329798
SN - 2051-1426
VL - 11
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 12
M1 - e007586
ER -