Article Text

Download PDFPDF

343 Multiomic biomarker signatures identify subsets of patients who may benefit from either nivolumab or sotigalimab in combination with chemotherapy in metastatic pancreatic cancer
  1. Deena Maurer1,
  2. Jia Xin Yu1,
  3. Kamil Sklodowski2,
  4. Marco Tognetti2,
  5. Lukas Reiter2,
  6. Roland Bruderer2,
  7. Jakob Vowinckel2,
  8. Shannon Pfeiffer1,
  9. Mark O’Hara3,
  10. Eileen O’Reilly4,
  11. Robert Wolff5,
  12. Zev Wainberg6,
  13. Andrew Ko7,
  14. Osama Rahm8,
  15. George Fisher9,
  16. Jaclyn Lyman1,
  17. Christopher Cabanski1,
  18. Pier Federico Gherardini1,
  19. Jill O’Donnell-Tormey10,
  20. Theresa LaVallee1,
  21. Robert Vonderheide3 and
  22. Lacey Kitch1
  1. 1Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
  2. 2Biognosys, Schileren, Switzerland
  3. 3Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA, USA
  4. 4Memorial Sloan Kettering Cancer Center, New York, NY, USA
  5. 5University of Texas MD Anderson Cancer, Houston, TX, USA
  6. 6University of California, Los Angeles, Santa Monica, CA, USA
  7. 7University of California, San Francisco, San Francisco, CA, USA
  8. 8Dana-Farber Cancer Institute, Boston, MA, USA
  9. 9Stanford University School of Medicine, Stanford, CA, USA
  10. 10Cancer Research Institute, New York, NY, USA


Background Gemcitabine/nab-Paclitaxel (GnP) is a standard of care regimen for first-line metastatic pancreatic ductal adenocarcinoma (PDAC) and has a 1-year overall survival (OS) rate of approximately 35%. There is an urgent need for novel therapeutics and precision medicine approaches in PDAC. PRINCE, a randomized phase 2 trial, reported an increased 1-year OS relative to historical data, for patients treated with nivolumab (nivo)/GnP (57.3%, p = 0.007, n=34) and sotigalimab (sotiga) (APX005M; CD40 agonist)/GnP (48.1%, p = 0.062, n= 36).

Methods To investigate immune modulatory and pharmacodynamic (PD) effects of nivo or sotiga in combination with GnP we used several orthogonal minimally invasive, blood-based biomarker technologies. Immune population profiles were evaluated by CyTOF and features of T cell phenotype and function by multicolor flow cytometry. Soluble proteins were evaluated with predefined panels using the Olink platform (Immuno-oncology (IO) and Immune Response) along with an unbiased mass spectrometry proteomic approach (Biognosys) that identified circulating soluble proteins of significance.

Results Relative to baseline, patients who received nivo/GnP had numerically increased frequencies of proliferating, activated CD8+ and CD4+ effector memory T cells in circulation across multiple timepoints. These patients also had significantly increased levels of soluble proteins associated with type II interferon responses and immune cell migration and T cell activation, as well as significantly decreased levels of immunomodulatory proteins.Patients who received sotiga/GnP had increased expression of the co-stimulatory molecule CD86 on conventional dendritic cells. These patients also had significantly increased concentrations of soluble proteins associated with mature antigen presenting cells, and the activation of helper CD4+ T cells, B cells, and monocytes. Significant increases in soluble proteins associated with type-1 cell-mediated effector immunity and decreases in immunosuppressive factors were observed in both arms. Significant proteins were defined as p ≤ 0.05, log2 expression fold change ≥ 0.5 (Olink) and Sparse PLS discriminant analysis was used with zero as a threshold (Biognosys).

Conclusions This study is a first to use multiomic minimally invasive biomarker approaches in PDAC to demonstrate PD effects and immune modulation with immunotherapy/chemotherapy combinations. Orthogonal assays demonstrate that nivo/GnP and sotiga/GnP elicit unique immune responses and the observed effects are consistent with their distinct mechanisms of action. These data suggest that multiomic biomarker signatures may identify subsets of patients who may benefit from an immunotherapy/chemo approach in PDAC. Moreover, results from these analyses will support early phase clinical study development decisions.

Acknowledgements We extend our gratitude to the patients, their families, the clinical investigators, and their site staff members who are making this trial possible. We would also like to thank Sultan Nawabi at Parker Institute for Cancer Immunotherapy (PICI) for operations leadership of the trial. We thank Bristol Myers Squibb (BMS) and Apexigen for collaboration and study drugs. The study was funded by Cancer Research Institute, BMS and PICI.

Trial Registration NCT03214250

Ethics Approval This study was approved by University of Pennsylvania Institutional Review Board; Federalwide assurance #00004028.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.