Abstract 2651: Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma
Authors: Wallin Jeffrey , Pishvaian Michael J. , Hernandez Genevive , Yadav Mahesh , Jhunjhunwala Suchit , Delamarre Lelia , He Xian , Powderly John , Lieu Christopher , Eckhardt S Gail , Hurwitz Herbert , Hochster Howard S. , Murphy Janet , Leveque Vincent , Cha Edward , Funke Roel , Waterkamp Daniel , Hegde Priti , Bendell Johanna 
Published: July 2016

Genetic and epigenetic alterations can distinguish cancer cells from their normal counterparts, allowing tumors to be recognized as foreign by the immune system. The immune system's ability to detect and destroy these abnormal cells is the foundation of cancer immunotherapy. In order for this to occur immune cells must traffic and persist in the tumors. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and tumor-infiltrating immune cells, plays an important part in blocking immune-mediated tumor cell destruction by binding B7.1 (CD80) and programmed death-1 (PD-1), which is a negative regulator of T-lymphocyte activation. PD-L1 blockade has previously been shown to increase CD8+ T cell infiltration and PD-L1 protein levels, as well as the expression levels of immune genes in tumors. Vascular endothelial growth factor A (VEGF-A) is a secreted factor that specifically acts on endothelial cells to stimulate angiogenesis and has also been shown to exert immunosuppressive effects. Although some cytotoxic agents have been proposed to induce immunogenic cell death, the effects of chemotherapy and anti-angiogenic therapy on the tumor immune milieu have not been extensively studied. This study was designed to evaluate the safety, activity and biomarkers of combined FOLFOX treatment combined with PD-L1 and VEGF-A inhibition in 1L colorectal (CRC) patients using the humanized antibodies atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF-A), respectively. RECIST (v1.1) responses by the cutoff date of 09/01/2015 were observed in 52% (95% CI 30.6-73.2) of the patients (n = 23) with a median progression free survival of 14.1 months (95% CI 8.7-17.1) and a median duration of response of 11.4 months (95% CI 7.6-15.9). No unexpected toxicities were observed. We found that CD8+ T cells and PD-L1 expression by IHC were increased in tumors following administration of FOLFOX alone as well as after combined administration of FOLFOX, atezolizumab and bevacizumab. Elevations in cytotoxic T-cell signatures (e.g. CD8A, IFNγ, GZMB, EOMES) with treatment were also noted in several of the patient tumors. Patients with elevations in tumor-infiltrating CD8+ T cells consistent with increased expression of cytotoxic T-cell signatures and PD-L1 exhibited sustained responses or prolonged disease control. These data suggest that the combination of FOLFOX, atezolizumab, and bevacizumab promote immune-related activity in CRC potentially resulting in enhanced efficacy.

Citation Format: Jeffrey Wallin, Michael J. Pishvaian, Genevive Hernandez, Mahesh Yadav, Suchit Jhunjhunwala, Lelia Delamarre, Xian He, John Powderly, Christopher Lieu, S Gail Eckhardt, Herbert Hurwitz, Howard S. Hochster, Janet Murphy, Vincent Leveque, Edward Cha, Roel Funke, Daniel Waterkamp, Priti Hegde, Johanna Bendell. Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2651.