Acquired Immunotherapy Resistance in Gastrointestinal Cancers

Mechanisms of primary resistance and acquired resistance (AR) to immune checkpoint inhibitors (ICI) remain poorly understood. Zhuo et al¹ investigated the patterns of disease relapse in a retrospective, single-center, heterogenous cohort of patients with gastrointestinal (GI) cancers of luminal (89.0%), hepatobiliary (7.5%), and pancreatic (2.4%) origins with predominantly adenocarcinoma histology (70.5%) that developed AR to ICI-based therapies after initial response. The investigators report that of 1124 patients, 373 (33.2%) achieved complete response, partial response, or stable disease longer than 6 months (ie, initial response) with ICI-based therapies, and 46.4% (173 of 373 patients) developed AR to treatment that is defined by radiographic disease progression or death after initial response. The median duration of clinical benefit was 7.3 months (95% CI, 8.1-10.0 months) from the first dose of ICI to AR. The majority of patients (167 of 173 patients [96.5%]) developed AR within 2 years, and oligoprogression (≤2 sites of disease progression) was found to be the most common pattern of disease relapse (70.5%). Compared with patients with polymetastatic progression (>2 sites of disease progression), those with oligoprogression had longer survival.¹ Along with prior studies, these findings shed light on current challenges in the field of immunooncology, which we describe below.

First, assessing treatment response to ICI-based therapies remains an important challenge. Zhuo et al¹ evaluated treatment response radiographically according to Response Evaluation Criteria in Solid Tumors version 1.1. New lesions were identified in 57 of 173 patients (32.9%), and lymph nodes were determined to be the most frequent site (101 of 173 patients [58.4%]) of disease progression. These data at first appear to be within range and consistent with historical findings from patients with melanoma or lung cancer.^2,3 It is also worth noting that despite radiographic progression following initial response, ICI-based therapies were continued in a relatively smaller proportion of patients (12.7%) compared with historical controls (approximately 50%).¹ ICI rechallenge may lead to continued and sustained responses,³ raising the possibility that in immunoresponsive cancers, radiographic disease progression may not best assess resistance to ICI. Atypical responses to ICI have been previously described; changes in size and appearance of cancerous lesions may be secondary to infiltration of immune cells rather than tumor cell growth.⁴ Therefore, continued efforts in the search for clinical tools and end points that appropriately monitor and assess treatment response to ICI-based therapies are critical.⁵

Moreover, the impact of intrinsic tumor characteristics, such as tumor microenvironment, on mechanisms of resistance to ICI needs to be further defined. It is apparent that the level of heterogeneity of the primary GI tumors and their genetic characterization as represented in the Zhuo et al¹ study are associated with different patterns and time courses of AR to ICI. For example, patients with colorectal and small bowel cancers (61 of 68 patients [89.7%]) had significantly higher rates of deficient mismatch repair tumors compared with the other GI tumors in this study. As such, they exhibited lower rates of AR (26.5%) and a longer median duration of response (8.1 months; 95% CI, 7.1-11.4 months). Additionally, the patterns of disease progression were different: the peritoneum was the most common site of disease progression for the lower GI cancers vs the lymph nodes in esophageal or gastric cancer vs the liver in hepatobiliary or pancreatic cancer. These data suggest that responses to ICI may be affected by tumor-specific factors, a conclusion supported by preclinical studies demonstrating that immune cell infiltration is modulated by tumor cell–specific signaling pathways.⁶

Finally, there remains a critical gap in our understanding of how to best treat patients with cancer that are considered refractory to ICI-based therapies. Using data from the Table in the article by Zhuo et al,¹ we calculate that the rates of AR were similar in patients who received ICI alone vs ICI in combination with other systemic therapies (68 of 152 patients [44.7%] vs 105 of 221 patients [47.5%]). Additionally, subsequent systemic and/or local therapies led to similar overall survival (median 26.1 months [95% CI, 12.5-40.0 months]), indicating that a cookie-cutter approach to overcoming AR does not appear to be effective. Resistance to ICI, whether primary or acquired, appears to stem from a variety of proposed mechanisms, ranging from defective antigen presentation to upregulated immunosuppression.⁷ Taken together, individualizing therapeutic strategies according to biomarker-driven research will likely hold the key to success. In conclusion, although current understanding of resistance mechanisms to ICI is incomplete, the critical foundation for future directions in clearing the confusion is being laid out.

Published: March 29, 2022. doi:10.1001/jamanetworkopen.2022.4646

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Zhu M et al. JAMA Network Open.

Corresponding Author: Tanios S. Bekaii-Saab, MD, Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054 (bekaii-saab.tanios@mayo.edu).

Conflict of Interest Disclosures: Dr Bekaii-Saab reported receiving research funding from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS; receiving consulting fees from Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merck, Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina and Foundation Medicine; receiving independent data monitoring comittee/data and safety monitoring board fees from Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan, and 1Globe; serving on scientific advisory boards of Imugene, Immuneering, Xilis, Replimune and Sun Biopharma; receiving royalties from UpToDate; and holding patents WO/2018/183488 and WO/2019/055687. No other disclosures were reported.