A Randomized Phase II Trial of mFOLFOX6+Bevacizumab Alone or with AdCEA Vaccine plus Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer

This article presents the findings of a randomized phase II clinical trial comparing FOLFOX-based standard of care to FOLFOX-based standard of care plus avelumab plus AdCEA vaccine. Prospective studies of effects of FOLFOX plus bevacizumab on circulating cascade antigen-specific T cells, peripheral blood immune cell subset frequencies, serum cytokines, and soluble factors are also reported. Background FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. Methods Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. Results Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. Conclusions SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell-mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.

Automated summary

This study compared the effectiveness of the standard of care with and without the addition of Avelumab and AdCEA vaccine in the treatment of metastatic colorectal cancer. The results showed that while the combination treatment generated a multifunctional immune response, it did not improve progression-free survival. Additional agents may be required to enhance the clinical benefit.