Safety and Efficacy of Sintilimab and Anlotinib as First Line Treatment for Advanced Hepatocellular Carcinoma (KEEP-G04): A Single-Arm Phase 2 Study

Chen, Xiaofeng; Li, Wei; Wu, Xiaofeng; Zhao, Fengjiao; Wang, Deqiang; Wu, Hao; Gu, Yanhong; Li, Xiao; Qian, Xiaofeng; Hu, Jun; Li, Changxian; Xia, Yongxiang; Rao, Jianhua; Dai, Xinzheng; Shao, Qianwen; Tang, Jie; Li, Xiangcheng; Shu, Yongqian

doi:10.3389/fonc.2022.909035

Cited by 28 publications

(32 citation statements)

References 38 publications

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“…Trial of CheckMate040 has ushered the era of immunotherapy for HCC in the recent years, but phase III CheckMate459 trials of PD-1 inhibitors monotherapy for HCC have all failed to meet the primary endpoints (5). Dual combination regimen, such as lenvatinib plus pembrolizumab, camrelizumab plus apatinib, and sintilimab plus anlotinib, have yielded promising clinical efficiency and safety, but the prognosis for those u-HCC patients is still unsatisfactory with the median OS of 20.1 to 20.4 months (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Hepatic arterial infusion chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: A tertiary medical center experience

et al. 2022

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BackgroundUnresectable hepatocellular carcinoma (u-HCC) still accounts for the majority of newly diagnosed HCC which with poor prognosis. In the era of systemic therapy, combination therapy with programmed cell death protein-1 (PD-1) inhibitors and tyrosine kinase inhibitors (TKIs) has become mainstream. Hepatic arterial infusion chemotherapy (HAIC) as a local treatment has also shown a strong anti-tumor effect. This study aimed to investigate the efficacy and safety of HAIC, PD-1 inhibitors plus TKIs for u-HCC.MethodsThis retrospective study included patients with initially u-HCC between October 2020 to April 2022 who had received at least one cycle of therapy with HAIC, PD-1 inhibitors plus TKIs. The primary outcome included overall response rate (ORR), the disease control rate (DCR), surgical conversion rate, progression-free survival (PFS) and treatment-related adverse events.ResultsA total of 145 patients were included in the study. The median treatment cycle of HAIC and PD-1 inhibitors were 3 and 4, respectively. According to the modified RECIST criteria, the best ORR was 57.2% (83/145), 9 had achieved complete response (CR), DCR was 89.7% (130/145). Median time to achieve CR or PR was 65 days. Surgical conversion rate was 18.6% (27/145), seven patients (7/27,25.9%) achieved pathological complete response (pCR). The median follow-up was 12.5 months (4.5-20 months), and the median PFS was 9.7 months. Subgroup analysis showed that Child-pugh A patients had higher DCR (92.2% vs 79.3%, p=0.041) than Child-pugh B patients, as well as increased successful conversion rate (22.4% vs 3.4%, p=0.019). Patients without vascular invasion and extrahepatic metastases showed higher PR (63.4% vs 43.3%, p<0.05) and ORR (73.2% vs 50.0%, p<0.05) than those with vascular invasion. The ORR (73.2% vs 45.5%, p<0.05) and DCR (95.1% vs 78.8%, p<0.05) were also significantly better than those of patients with extrahepatic metastases. HAIC regimen was not related to efficacy (All p>0.05). The incidence rate of grade 3/4 treatment-related AEs was 17.7% without fatal events.ConclusionThe triple combination therapy of HAIC and PD-1 inhibitors plus TKIs for patients with initially unresectable HCC exhibited satisfactory efficacy with tolerable toxicity.

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Section: Introductionmentioning

confidence: 99%

Hepatic arterial infusion chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: A tertiary medical center experience

et al. 2022

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“…This trial demonstrated the tolerability and efficacy of anlotinib in combination with ICI therapy for cervical cancer [240]. Sintilimab plus anlotinib also demonstrated good treatment efficacy and tolerability in both advanced hepatocellular carcinoma (NCT04052152) and advanced non-small cell lung cancer (NCT03628521) [241,242].…”

Section: Combination Of Normalization Strategiesmentioning

confidence: 84%

Novel strategies for cancer immunotherapy: counter-immunoediting therapy

2023

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The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.

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“…Sintilimab is a PD-1 antibody approved in China for the treatment of NSCLC, Hodgin's lymphoma, hepatocellular carcinoma, and esophageal squamous cell carcinoma (ESCC) (25). Recently, the combination of sintilimab and anlotinib has shown promising antitumor activity and tolerable safety profiles in cervical cancer, endometrial cancer, hepatocellular carcinoma, and biliary tract cancer (26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Case report: Complete response of an anaplastic thyroid carcinoma patient with NRAS Q61R/BRAF D594N mutations to the triplet of dabrafenib, trametinib and PD-1 antibody

Gui

Zhu

et al. 2023

Front. Immunol.

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Anaplastic thyroid carcinoma, BRAF non-V600, NRAS, combination immunotherapy and targeted therapy, case report. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with a mortality rate near 100%. BRAF V600 and NRAS mutations are the most common drivers of ATC. While patients with BRAF V600-mutated ATC can be treated with BRAF-targeted therapy, there is no effective treatment for ATC driven by NRAS or non-V600 BRAF mutations. For patients with untargetable driver mutations, immunotherapy provides an alternative treatment option. Here, we present a metastatic ATC patient with PD-L1 positive (tumor proportion score of 60%) tumor and NRAS Q61R/BRAF D594N mutations, who progressed on PD-1 antibody sintilimab plus angiogenesis inhibitor anlotinib. The class 3 BRAF mutant D594N is sensitive to the inhibition of MEK inhibitor trametinib, and its oncogenic activity also depends on CRAF, which can be inhibited by BRAF inhibitor dabrafenib. For these reasons, the patient received a salvage treatment regime of dabrafenib, trametinib, and sintilimab, which resulted in a complete pathological response. To our best knowledge, this is the first report of successful treatment of ATC patients with concurrent NRAS/BRAF non-V600 mutations with the combination of immunotherapy and targeted therapy. Further investigation is required to decipher the mechanism by which the combination of dabrafenib/trametinib with PD-1 antibody overcomes initial immunotherapy resistance likely mediated by concurrent BRAF and NRAS mutations.

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Safety and Efficacy of Sintilimab and Anlotinib as First Line Treatment for Advanced Hepatocellular Carcinoma (KEEP-G04): A Single-Arm Phase 2 Study

Cited by 28 publications

References 38 publications

Hepatic arterial infusion chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: A tertiary medical center experience

Hepatic arterial infusion chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: A tertiary medical center experience

Novel strategies for cancer immunotherapy: counter-immunoediting therapy

Case report: Complete response of an anaplastic thyroid carcinoma patient with NRAS Q61R/BRAF D594N mutations to the triplet of dabrafenib, trametinib and PD-1 antibody

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