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

Abstract

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.

• Authors: Jason M Redman, Yo-Ting Tsai, Benjamin A Weinberg, Renee N Donahue, Shruti Gandhy, Margaret E Gatti-Mays, Houssein Abdul Sater, Marijo Bilusic, Lisa M Cordes, Seth M Steinberg, Jennifer L Marte, Caroline Jochems, Sunnie S Kim, John L Marshall, Sheri McMahon, Erica Redmond, Jeffrey Schlom, James L Gulley, Julius Strauss
• Journal: The oncologist (Oncologist) Vol. 27 Issue 3 Pg. 198-209 (03 11 2022) ISSN: 1549-490X [Electronic] England
• PMID: 35274710 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Oxford University Press 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Chemical References

• Antibodies, Monoclonal, Humanized
• Vaccines
• Bevacizumab
• avelumab

Topics

• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Bevacizumab (therapeutic use)
• Colorectal Neoplasms (drug therapy, pathology)
• Humans
• Immunotherapy
• Vaccines (therapeutic use)