Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC

Chu, Tianqing; Zhong, Runbo; Zhong, Hua; Zhang, Bo; Zhang, Wei; Shi, Chunlei; Qian, Jialin; Zhang, Yanwei; Chang, Qing; Zhang, Xueyan; Dong, Yu; Teng, Jinfang; Gao, Zhiqiang; Qiang, Huiping; Nie, Wei; Zhao, Yiming; Han, Yuchen; Ya, Chen; Han, Baohui

doi:10.1016/j.jtho.2020.11.026

Cited by 166 publications

(180 citation statements)

References 35 publications

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“…Which combination regimen is most effective for brain metastases remains to be answered by more data. Secondly, early phase clinical studies have reported the use time and the dosage of ICIs and antiangiogenic agents (51)(52)(53), and the use of anti-angiogenic agents prior ICIs was seemed to be more beneficial in vitro and vivo experiments (77). However, no studies have analyzed the changes of pharmacokinetic and pharmacodynamic profiles of each agent after combinational use.…”

Section: Discussionmentioning

confidence: 99%

“…No grade 4-5 TRAEs occurred. In addition, Chu et al conducted a phase Ib trial (NCT03628521) to evaluate chemo-free first-line strategy of sintilimab combining anlotinib in treatment-naive and stage IIIB/IV NSCLC patients (52). Twenty-two patients were enrolled in the study and four had baseline brain metastases.…”

Section: Clinical Datamentioning

confidence: 99%

“…As for the combination therapy, the phase Ib trial (NCT03628521) indicated that the patients with TMB ≥10 mutations per megabase showed higher ORR than those with TMB <10 mutations per megabase (85.7% vs. 63.6%) (52). It is worth mentioning that ORR in the patients with positive and negative PD-L1 expression was 69.2% and 75%, respectively (67).…”

Section: Predictive Indicatorsmentioning

confidence: 99%

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Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer

Fang

Zhao

et al. 2021

Front. Oncol.

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Brain metastases remain a critical issue in the management of non-small cell lung cancer (NSCLC) because of the high frequency and poor prognosis, with survival rates often measured in just months. The local treatment approach remains the current standard of care, but management of multiple asymptomatic brain metastases always involves systemic therapy. Given that anti-angiogenic agents and immune checkpoint inhibitors (ICIs) both target the tumor microenvironment (TME), this combination therapy has become a promising strategy in clinical practice. Increasing number of preclinical and clinical studies have shown remarkable anti-tumor activity of the combination therapy, but the efficacy in brain metastases is unclear due to the strict selection criteria adopted in most clinical trials. This review briefly summarizes the potential synergistic anti-tumor effect and clinical development of the combination of anti-angiogenic agents and ICIs in NSCLC brain metastases, and discusses the existing challenges and problems.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Datamentioning

confidence: 99%

Section: Predictive Indicatorsmentioning

confidence: 99%

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Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer

Fang

Zhao

et al. 2021

Front. Oncol.

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“…Regarding no other common mutations like EGFR or ALK genes and patient willing, she turned to anti-PD-1 antibody sintilimab plus anlotinib and achieved a durable PR for at least 12 months. A recent phase 1b study presented good efficacy and safety of sintilimab and anlotinib in untreated NSCLC patients in China without EGFR/ALK/ROS1 mutations (29). Moreover, other clinical studies also demonstrated the synergistic antitumor effects of immune checkpoint inhibitors plus antiangiogenic drugs in a variety of solid tumors (30,31).…”

Section: Discussionmentioning

confidence: 99%

Durable Response to Immunotherapy With Antiangiogenic Drug in Large-Cell Lung Carcinoma With Multiple Fulminant Postoperative Metastases: A Case Report

et al. 2021

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Immunotherapy alone or chemo-immunotherapy has recently been recommended for treating advanced lung carcinoma in patients without driver mutations. However, the efficacy of immunotherapy and molecular mechanism in large-cell lung cancer (LCLC) remains unclear. Here, we reported a rare case of multiple fulminant postoperative body and mouth metastases in LCLC treating with combination immunotherapy. Initially, the patient was diagnosed as early stage LCLC and underwent a radical resection of the right lower lobe. Just one month later, multiple fulminant body and mouth lesions appeared in the right upper arm, right elbow, right waist, and tongue root. Meanwhile, serum neuron specific enolase (NSE) concentration dramatically increased from 12.12 to 30.14 ng/ml. Immumohistochemistry findings demonstrated moderate PD-L1 expressions with tumor proportion score (TPS), while next-generation sequencing indicated moderate tumor mutational burden (TMB) levels and gene mutations in PBRM1 L1230P and TP53 L194R of both foci. Besides, loss of heterozygosity (LOH) at human leukocyte antigen (HLA) class I (HLA-A*02:03, HLA-B*55:02 and HLA-C*12:03) were detected in the right upper arm metastasis, which may facilitate malignant postoperative metastases in this case. Notably, this patient received combination therapy with anti-PD-1 antibody sintilimab plus anlotinib, and achieved a partial response for at least 12 months. Using an integrated computational method, the mutant peptide TEIPENDIPL derived from PBRM1 L1230P was predicted to be a specific neoantigen and could still be presented by HLA-B*40:01. This case suggests that immunotherapy plus antiangiogenic drug may provide an alternative therapeutic option for advanced LCLC patients without common gene mutations.

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“…The phase 3 trial of sintilimab provided a longer 5.3 months of OS than docetaxel in patients with NSCLC whose disease progressed after chemotherapy ( Yang et al, 2020 ). Besides of monotherapy, sintilimab combined with either chemotherapy or anlotinib as the first-line treatment demonstrated encouraging antitumor activities ( Chu et al, 2021 ; Jiang et al, 2021 ) and combined with anlotinib, it showed a longer PFS of 15 months representing a novel chemotherapy-free regimen of NSCLC ( Zhang et al, 2021 ). The addition of sintilimab to chemotherapy also revealed promising efficacy and manageable safety in untreated gastric/gastroesophageal junction (GEJ) adenocarcinoma ( Jiang et al, 2020 ).…”

Section: Clinical Use Efficacy and Safetymentioning

confidence: 99%

Comparisons of Underlying Mechanisms, Clinical Efficacy and Safety Between Anti-PD-1 and Anti-PD-L1 Immunotherapy: The State-of-the-Art Review and Future Perspectives

2021

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Over the past decade, diverse PD-1/PD-L1 blockades have demonstrated significant clinical benefit in across a wide range of tumor and cancer types. With the increasing number of PD-1/PD-L1 blockades available in the market, differences between the clinical performance of each of them started to be reported. Here, we provide a comprehensive historical and biological perspective regarding the underlying mechanism and clinical performance of PD-1/PD-L1 blockades, with an emphasis on the comparisons of their clinical efficacy and safety. The real-world evidence indicated that PD-1 blockade may be more effective than the PD-L1, though no significant differences were found as regards to their safety profiles. Future head-to-head studies are warranted for direct comparison between them. Finally, we summarize the yet to be elucidated questions and future promise of anti-PD-1/PD-L1 immunotherapy, including a need to explore novel biomarkers, novel combinatorial strategies, and their clinical use on chronic infection.

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Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC

Cited by 166 publications

References 35 publications

Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer

Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer

Durable Response to Immunotherapy With Antiangiogenic Drug in Large-Cell Lung Carcinoma With Multiple Fulminant Postoperative Metastases: A Case Report

Comparisons of Underlying Mechanisms, Clinical Efficacy and Safety Between Anti-PD-1 and Anti-PD-L1 Immunotherapy: The State-of-the-Art Review and Future Perspectives

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