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Randomized Controlled Trial
. 2023 Dec 1;6(12):e2346094.
doi: 10.1001/jamanetworkopen.2023.46094.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial

Eric X Chen  1 , Jonathan M Loree  2 , Emma Titmuss  2 , Derek J Jonker  3 , Hagen F Kennecke  4 , Scott Berry  5 , Felix Couture  6 , Chaudharry E Ahmad  7 , John R Goffin  8 , Petr Kavan  9 , Mohammed Harb  10 , Bruce Colwell  11 , Setareh Samimi  12 , Benoit Samson  13 , Tahir Abbas  14 , Nathalie Aucoin  15 , Francine Aubin  16 , Sheryl Koski  17 , Alice C Wei  18 , Dongsheng Tu  19 , Chris J O'Callaghan  19
Affiliations
Randomized Controlled Trial

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial

Eric X Chen et al. JAMA Netw Open. .

Abstract

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM).

Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer.

Design, setting, and participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments.

Intervention: Durvalumab plus tremelimumab or best supportive care.

Main outcomes and measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR).

Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM.

Conclusions and relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Chen reported receiving personal fees from AstraZeneca outside the submitted work. Dr Loree reported receiving nonfinancial support from AstraZeneca during the conduct of the study; personal fees from Amgen Inc, Bayer AG, Personalis Inc, SAGA Diagnostics, Ipsen Pharma, Novartis AG, and Merck & Co Inc outside the submitted work. Dr Jonker reported receiving funding to institution from Canadian Cancer Trials Group during the conduct of the study. Dr Kavan reported receiving grant funding from the Jewish General Hospital during the conduct of the study. Dr Colwell reported serving on the advisory boards of Janssen Global Services LLC, Merck & Co Inc, Viatris Inc, Amgen Inc, and Fusion Pharmaceuticals Inc and receiving personal fees for an educational project from Merck & Co Inc outside the submitted work. Dr Aucoin reported serving on the advisory boards of Pfizer Inc, Eisai Inc, Taiho Pharmaceutical, Incyte, Novartis AG, and Merck & Co Inc outside the submitted work. Dr Aubin reported receiving funding to institution from Canadian Cancer Trials Group and AstraZeneca during the conduct of the study; personal fees from Merck & Co Inc, Taiho Pharmaceutical, Amgen Inc, Pfizer Inc, Incyte, and GSK PLC and grant funding to institution from Novartis AG and Bristol Myers Squibb outside the submitted work. Dr Wei reported receiving consulting fees from HistoSonics and grant funding for clinical trial from Ipsen Pharma outside the submitted work. Memorial Sloan Kettering Cancer Center has institutional financial interests relative to BionNTech SE, Clarity Pharmaceuticals Ltd, and Episteme Prognostics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
Figure 2.
Figure 2.. Survival by Treatment Groups and Presence of Liver Metastases
Error bars indicate 90% CIs. BSC indicates best supportive care.
Figure 3.
Figure 3.. Subgroup Analysis of Overall Survival (OS) and Progression-Free Survival (PFS) in Multivariable Analysis
BSC indicates best supportive care; HR, hazard ratio; pTMB, plasma tumor mutation burden.
See this image and copyright information in PMC

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