Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study

Nie, Caiyun; Lv, Haiyan; Chen, Beibei; Xu, Weifeng; Wang, Jianzheng; Liu, Yingjun; Wang, Saiqi; Zhao, Jing; He, Yakun; Chen, Xiaobing

doi:10.3389/fonc.2022.917353

Cited by 10 publications

(6 citation statements)

References 30 publications

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“…In retrospective analyses, ICIs alone or in combination with other agents were reported to have improved outcomes in patients without LM for both MSI-H-dMMR and MSS-pMMR groups and in both first-line or refractory settings. [17][18][19][20] In the recently reported LEAP-017 study, 10 pembrolizumab and lenvatinib produced improved OS, PFS, and difference in overall response rate in patients without LM compared with investigators' choice of regorafenib or trifluridine and tiparicil. In addition to ICIs, the presence of LM may confer resistance to other immune-modulating agents.…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports of the lack of efficacy of ICIs in patients with LM and advanced colorectal cancer are from single-arm phases 1 and 2 studies 7,16,21 or retrospective case series with a limited number of patients. [17][18][19][20] The current analysis was based on a randomized phase 2 study with a control arm of BSC. Our findings are consistent with those from the recently reported randomized phase 3 LEAP-017 study.…”

Section: Discussionmentioning

confidence: 99%

“…In a follow-up study, the combination of regorafenib, ipilimumab, and nivolumab appeared to be more active in patients without LM. In retrospective analyses, ICIs alone or in combination with other agents were reported to have improved outcomes in patients without LM for both MSI-H–dMMR and MSS-pMMR groups and in both first-line or refractory settings . In the recently reported LEAP-017 study, pembrolizumab and lenvatinib produced improved OS, PFS, and difference in overall response rate in patients without LM compared with investigators’ choice of regorafenib or trifluridine and tiparicil.…”

Section: Discussionmentioning

confidence: 99%

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Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Chen,

Loree,

Titmuss

et al. 2023

JAMA Netw Open

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ImportanceImmune 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).ObjectiveTo investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer.Design, Setting, and ParticipantsIn 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.InterventionDurvalumab plus tremelimumab or best supportive care.Main Outcomes and MeasuresHazard 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).ResultsOf 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 RelevanceIn 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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Chen,

Loree,

Titmuss

et al. 2023

JAMA Netw Open

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“…The 2021 ASCO Meeting Abstract revealed that the objective response rate (ORR) was 27.3% and the PFS was 6.9 months in the fruquintinib 5-mg group, though it was a phase Ib/II study of the fruquintinib and sintilimab combination for advanced CRC ( 7 ). Caiyun Nie suggested that patients with MSS mCRC without liver metastasis responded well to the fruquintinib plus sintilimab regimen (ORR: 21.4%) ( 8 ). We recommend the combination of fruquitinib and sintilimab for the patient based on recent clinical trials, and our center has received several successful treatment cases.…”

Section: Discussionmentioning

confidence: 99%

Case report: Bullous pemphigoid associated with sintilimab therapy for pMMR/MSS colorectal cancer

et al. 2023

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Immunotherapy has become a very effective treatment for many cancers. It has a unique set of immune system-related adverse effects, collectively known as immune-related adverse events (irAEs). Skin toxicities are the most common irAEs, of which bullous pemphigoid, although rare, is potentially life-threatening and affects patients’ survival. In this article, we report the treatment of bullous pemphigoid caused by programmed cell death protein-1 (PD-1) in a case of proficient mismatch repair (pMMR)/microsatellite stable (MSS) colorectal cancer. No significant adverse effects were observed in the patient after methylprednisone was tapered to 4 mg twice a day. No new skin lesions occurred recently in the patient and the original skin lesions healed. In particular, the patient’s immunotherapy was not stopped and the best outcome was a partial remission of the disease, lasting for more than 8 months.

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“…Another retrospective study aimed to evaluate the efficacy and safety of combining regorafenib or fruquintinib with sintilimab in patients with MSS mCRC. Subgroup analysis revealed that NLM patients responded more positively to this combined regimen than LM patients (ORR: 21.4% vs. 9.1%) and achieved improved OS (26 vs. 10.0 months, P=0.016) ( 28 ). Organ sites have exhibited differential responses, with lymph node and LM among the most and least responsive, respectively ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

Efficacy, safety, and predictors of fruquintinib plus anti-programmed death receptor-1 (PD-1) antibody in refractory microsatellite stable metastatic colorectal cancer in a real-world setting: a retrospective cohort study

Yang,

Yin,

et al. 2023

J Gastrointest Oncol

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Background Patients with microsatellite stable (MSS) advanced colorectal cancer (CRC) have few alternatives for salvage therapy and a large unmet clinical need. Preclinical studies demonstrate that fruquintinib combined with anti-programmed death protein 1 (PD-1) has a synergistic anti-tumor effect. But a few phase 2 clinical studies show inconsistent efficacy of this combination therapy in CRC. The aim of this study was to investigate the efficacy, safety, and predictors of fruquintinib plus PD-1 antibodies in refractory MSS metastatic CRC (mCRC) in a real-world setting. Methods We performed a retrospective single-center analysis to assess the outcomes of patients with MSS mCRC who were treated with fruquintinib plus anti-PD-1 antibodies subsequent to the failure of standard therapies at the Hunan Cancer Hospital. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity were reviewed and evaluated. The primary endpoint was OS. The impact on OS and PFS was examined using the Cox regression model. Results Between 1 January 2019 and 30 June 2022, we enrolled 70 eligible patients. The median follow-up was 17.2 months (range, 5.3–32.9 months). The median OS (mOS) and median PFS (mPFS) were 19.48 and 5.5 months respectively. The ORR was 11.43% and the DCR was 84.29%. Multivariate Cox regression analysis reveals liver metastasis (LM) without local treatment was a risk factor for OS [hazard ratio (HR) =5.31, P=0.0184], whereas that with local treatment (HR =2.19, P=0.263) was not. The most common adverse events were hand-foot syndrome (37.14%), hypertension (34.29%), mucositis oral (32.86%). No serious adverse effects or adverse effect-related deaths were reported. There were no instances of severe adverse effects or deaths related to adverse effects reported. Conclusions Our study indicates that the combination of fruquintinib and anti-PD-1 antibodies can improve the OS and PFS with a tolerable toxicity profile for Chinese patients with refractory MSS mCRC. LM without local therapy is a negative prognostic factor for OS, but those with local treatment can significantly prolong survival. We require additional well-structured, prospective, and extensive studies to confirm and validate these findings.

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Microsatellite stable metastatic colorectal cancer without liver metastasis may be preferred population for regorafenib or fruquintinib plus sintilimab as third-line or above therapy:A real-world study

Cited by 10 publications

References 30 publications

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Case report: Bullous pemphigoid associated with sintilimab therapy for pMMR/MSS colorectal cancer

Efficacy, safety, and predictors of fruquintinib plus anti-programmed death receptor-1 (PD-1) antibody in refractory microsatellite stable metastatic colorectal cancer in a real-world setting: a retrospective cohort study

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