Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial

Abstract

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.

Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma

“…It was suggested based on these corelative findings that a biomarker-selected population might be required to see the benefit of this drug combination. [ 147 ].…”

“…Clearcut determinants of what defines the rare responder to oleclumab/durvalumab or motixafortide/pembrolizumab are not so obvious at this point. Extensive correlative analyses to characterize tumors with improved responses was performed on the recently reported PRINCE study testing the CD40 agonist sotigalimab with durvalumab and GN [ 147 ]. Most of the candidate circulating biomarkers identified were indeed predictive rather than prognostic, as they were associated with only one of the three study treatment regimens.…”

“…Moreover, varying the dosing schedule, treatment duration, and/or drug sequencing can diametrically alter anti-tumor effects, making it too easy to fail even with a well-considered cocktail of complimentary agents [ 304 ]. For instance, the possibly reduced benefit/lack of increased benefit of the dual immunotherapy arm in the PRINCE study as compared to the single immunotherapy arms was attributed to excessive immune stimulation [ 147 ]. The requirement for rational combination increases the complexity of meaningful assessment.…”

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

“…Animal models demonstrate that combining chemotherapy with the targeting of various elements of the immune microenvironment may enhance the treatment efficacy [ 18 , 19 ]. A very recent study demonstrated that a combination of nivolumab (anti-PD-1 agent) and gemcitabine in metastatic pancreatic carcinoma patients improved the 1-year OS rate compared to a historical chemotherapy cohort [ 20 ]. Importantly, the authors emphasized that the assessment of pre-treatment biomarkers, e.g., the circulating T-follicular cells level, may help to choose an optimal, personalized immune therapy regimen [ 20 ].…”

Metastatic ovarian tumor from pancreatic cancer treated with combined immunotherapy: A case report

“…This strategy was approved by the National Medical Products Administration (NMPA) of China in December 2018 for Hodgkin's lymphoma, locally advanced or metastatic esophageal squamous cell carcinoma, hepatocellular carcinoma and nasopharyngeal carcinoma after systemic treatment failure ( 22 ). Preclinical and clinical data have provided supporting rationale for establishing immunotherapy combined with AG as a first-line treatment for metastatic PDAC ( 23 , 24 ). Data supporting the current regimens of an anti-PD-1-based (camrelizumab) combinatory strategy for PC are summarized in Table I .…”