TY - JOUR
T1 - Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer
T2 - clinical and immunologic analyses from the randomized phase 2 PRINCE trial
AU - Padrón, Lacey J.
AU - Maurer, Deena M.
AU - O’Hara, Mark H.
AU - O’Reilly, Eileen M.
AU - Wolff, Robert A.
AU - Wainberg, Zev A.
AU - Ko, Andrew H.
AU - Fisher, George
AU - Rahma, Osama
AU - Lyman, Jaclyn P.
AU - Cabanski, Christopher R.
AU - Yu, Jia Xin
AU - Pfeiffer, Shannon M.
AU - Spasic, Marko
AU - Xu, Jingying
AU - Gherardini, Pier Federico
AU - Karakunnel, Joyson
AU - Mick, Rosemarie
AU - Alanio, Cécile
AU - Byrne, Katelyn T.
AU - Hollmann, Travis J.
AU - Moore, Jonni S.
AU - Jones, Derek D.
AU - Tognetti, Marco
AU - Chen, Richard O.
AU - Yang, Xiaodong
AU - Salvador, Lisa
AU - Wherry, E. John
AU - Dugan, Ute
AU - O’Donnell-Tormey, Jill
AU - Butterfield, Lisa H.
AU - Hubbard-Lucey, Vanessa M.
AU - Ibrahim, Ramy
AU - Fairchild, Justin
AU - Bucktrout, Samantha
AU - LaVallee, Theresa M.
AU - Vonderheide, Robert H.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6
Y1 - 2022/6
N2 - Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
AB - Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC (NCT03214250). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
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UR - http://www.scopus.com/inward/citedby.url?scp=85131291377&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-01829-9
DO - 10.1038/s41591-022-01829-9
M3 - Article
C2 - 35662283
AN - SCOPUS:85131291377
SN - 1078-8956
VL - 28
SP - 1167
EP - 1177
JO - Nature medicine
JF - Nature medicine
IS - 6
ER -