The use of immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment of cancers that are presumed to be immunogenic and are commonly characterized by a high tumor mutation burden (TMB), which conceivably is associated with the expression of neoantigens on the surface of cancers cells as targets for cytotoxic T cells. High TMB can be associated with exogenous carcinogens, such as smoking (eg, non–small cell lung cancer) and ultraviolet light (eg, melanoma), but also with endogenous cellular factors, such as inherited or acquired deficiencies in DNA repair mechanisms, as in mismatch-repair deficient (dMMR), microsatellite instable (MSI-H) colorectal cancer (CRC). Although MSI-H dMMR CRC has long been known to respond well to ICIs in a later-line setting, the phase 3 KEYNOTE-177 trial1 established single-agent treatment as a new standard of care in the first-line setting of these cancers by demonstrating superior progression-free survival and prolonged duration of response compared with chemotherapy. In addition, combinations of ICIs, such as nivolumab plus ipilimumab, have also shown remarkable activity in MSI-H dMMR CRC.
Unfortunately, approximately 95% of metastatic CRCs are classified as mismatch repair proficient (pMMR), microsatellite stable (MSS) and do not exhibit an immunogenic phenotype. Multiple strategies have been explored to make these cancers respond to immunotherapy by combining ICIs with various agents meant to augment an immune response to MSS pMMR CRCs. Some examples include the use of fluoropyrimidine alone or with bevacizumab as maintenance treatment after induction polychemotherapy in metastatic CRC, atezolizumab plus cobimetinib, or durvalumab and tremelimumab in previously treated advanced CRC.2-4 These strategies disappointingly have not demonstrated convincing activity.
A promising immunotherapy approach in MSS, pMMR CRC seemed to emerge with the combination of a programmed cell death receptor 1 antibody with a multikinase inhibitor with anti–vascular endothelial growth factor activity in further studies. The REGONIVO (Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer) trial evaluated the treatment effect of regorafenib and nivolumab in patients with metastatic MSS CRC who experienced disease progression while receiving standard chemotherapy.5 Specifically, patients with liver metastases had a lower response rate (8.3%) than those with lung metastases without any liver involvement (63.6%), suggesting a preferential response in patients without hepatic metastases.5 Since the REGONIVO trial, additional data from the LEAP-005 (LEnvatinib And Pembrolizumab) study emerged,6 which evaluated the efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors.6 Within the CRC cohort, including 32 patients, the objective response rate was 22% with manageable toxic effects.6 This cohort has been expanded to 100 patients, and it is still unknown whether this combination will show any clinical benefit in patients with liver metastases.
The study by Wang and colleagues7 provides further evidence for the differential response to multikinase inhibitor plus ICI combination based on the location of metastases. Patients with lung and lymph node metastases were much more likely to respond than patients with liver metastases, a consistent phenomenon across clinical studies. Specifically, a significant difference in response rates was observed in patients without liver metastases (8 of 41 patients [9.5%]) compared with no response in those patients with liver metastases (0 of 54 patients).7 The authors did not observe any association between TMB and response rate. On multivariate analysis incorporating age, sex, primary tumor location, Eastern Cooperative Oncology Group status, metastatic site, variant status (APC, RAS, BRAFV600E, and TP53), and TMB, the presence of liver metastases at the time of treatment remained the most significant factor associated with worse progression-free survival (hazard ratio, 7.00; 95% CI, 3.18-15.42; P < .001).7
Discrepancies in response rates based on the site of metastatic lesions have been observed in various other tumors. For instance, in a previous study,8 treatment with interleukin-2 (720 000 IU/kg intravenously) showed an overall response of 20% in patients with metastatic renal cell cancer or melanoma. Except for 1 patient with liver metastases who had a complete response, all other responders had lung or lymph node metastases.8 Similar lower efficacy of checkpoint blockade has been found in patients with liver metastases from various primary tumors, including melanoma, non–small cell lung cancer, urothelial cancer, or renal cell cancer.9
Because liver metastases commonly represent the most clinically important site of disease in metastatic CRC, the development of active immunotherapy options in this setting is of utmost importance. It appears that the hepatic microenvironment is immunosuppressive for yet unknown biological reasons, which need to be elucidated. Because CRC liver metastases are routinely targeted for curative resection after neoadjuvant therapy, they provide a unique clinical model to identify pathways of immune resistance and explore the role of the tumor microenvironment and develop novel immune combination therapies. This strategy could finally expand treatment options for MSS, pMMR CRC into the world of immunotherapy.
Published: August 9, 2021. doi:10.1001/jamanetworkopen.2021.19025
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Gholami S et al. JAMA Network Open.
Corresponding Author: Axel Grothey, MD, West Cancer Center and Research Institute, 7945 Wolf River Blvd, Germantown, TN 38138 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Gholami reported receiving personal fees from Natera board outside the submitted work. Dr Grothey reported receiving grants from Bayer, Merck, Pfizer, Boston Biomedicals, Natera, Genentech, Foundation Medicine, Obi Pharmaceuticals, Eisai, and Taiho outside the submitted work. Dr Lenz reported receiving personal fees from Merck, Bayer, Roche, and Pfizer during the conduct of the study. No other disclosures were reported.
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Gholami S, Grothey A, Lenz H. Microsatellite Stable Colorectal Liver Metastases—Understanding the Mechanisms of Immune Resistance. JAMA Netw Open. 2021;4(8):e2119025. doi:10.1001/jamanetworkopen.2021.19025
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