Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

El-Khoueiry, Anthony B.; Sangro, Bruno; Yau, Thomas; Crocenzi, Todd S.; Kudo, Masatoshi; Hsu, Chiun; Kim, Tae You; Choo, Su Pin; Trojan, Jörg; Welling, Theodore H.; Meyer, Tim; Kang, Yoon Koo; Park, Yeon Hee; Chopra, Akhil; Anderson, Jeffrey; Cruz, Christine Marie Dela; Lang, Lixin; Neely, Jaclyn; Tang, Hao; Dastani, Homa; Melero, Ignacio

doi:10.1016/s0140-6736(17)31046-2

Cited by 3,566 publications

(3,604 citation statements)

References 28 publications

Supporting

Mentioning

3,318

Contrasting

Unclassified

Order By: Relevance

“…17-21 Targeting the PD-1/PD-L1 inhibitory pathway has resulted in objective responses in 17%-28% of advanced melanoma patients, 12%-27% of renal cell cancer patients, 10%-18% of non-small cell lung cancer patients and 20% of advanced hepatocellular carcinoma patients. 22-25 In contrast, CRC patients hardly respond to PD-1 and PD-L1 blocking antibodies, 23-26 except for the minority of patients who are with mismatch repair (MMR)-deficient CRC. 27 , 28 A defective MMR enzyme system occurs in 10%-20% of CRC tumors and results in microsatellite instability, which is used as a molecular marker of MMR-deficiency.…”

Section: Introductionmentioning

confidence: 99%

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

View full text Add to dashboard Cite

Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

show abstract

Section: Introductionmentioning

confidence: 99%

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Across dose escalation and expansion phases (262 patients), grade 3/4 treatment-related adverse events occurred in 20%. The ORR was 20% (95% CI: 15-26) in 214 patients treated in the dose expansion phase with a median duration of response of 9.9 months and a disease control rate of 64% (95% CI: 58-71) [35].…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…For instance, MET activation was confirmed as one of the alternative escape routes found by tumoral cells during exposition to antiangiogenic drugs [58]. As for immunotherapy, tumor PD-L1 expression was regarded as a possible biomarker but preliminary experiences with nivolumab seem not to confirm this hypothesis [35].…”

Section: The Quest For Biomarkersmentioning

confidence: 99%

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial

et al. 2017

View full text Add to dashboard Cite

The search for systemic therapies for hepatocellular carcinoma has been characterized by difficulties and failures. Despite recent progresses, many issues are still to be settled. In particular, the development of drugs inhibiting different neoplastic pathways remains a priority for patients intolerant or resistant to antiangiogenic drugs. This task may be daunting, as previous failures extensively demonstrated. We aimed to identify the future perspective of postsorafenib trials analyzing the strengths and the critical points of past and currently undergoing studies, in the light of the most recent evidences in the field. We identified various points (including stratification, biomarkers, end points, radiologic criteria of response, treatment beyond radiologic progression) that should be considered by future trials to reduce the risks of failure.P P P P P P P P P P T cell PD-1

show abstract

“…[8][9][10][11][12][13][14] Also, its use in the treatment of hepatocellular cancer is under an expedited review by FDA. [15] The first CTLA-4 inhibitor in the market was ipilimumab and one of the most widely used PD-1 inhibitor is nivolumab. Both have been used with great success in the treatment of metastatic melanoma with improved survival at 5 years.…”

Section: Metastatic Malignancies and Immune Modulationmentioning

confidence: 99%

Urgent need to define Pretreatment predictors of immune check point inhibitors related endocrinopathies: A case report and review of literature

Sehgal

Childress

2017

Journal of Translational Internal Medicine

View full text Add to dashboard Cite

Immune check point inhibitors have revolutionized the treatment of metastatic malignancies. They are a promising area in oncology and more drugs are likely to be available in the coming years. Along with the promise of better response oncologically, there is an increased incidence of endocrinopathies related to autoimmunity. This case report illustrates the dramatic development of hypothyroidism in a patient with underlying subclinical hyperthyroidism. It also suggests the potential pretreatment predictors of endocrinopathies related to these immune check point inhibitors.

show abstract

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

Abstract: Bristol-Myers Squibb.

Cited by 3,566 publications

References 28 publications

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial

Urgent need to define Pretreatment predictors of immune check point inhibitors related endocrinopathies: A case report and review of literature

Contact Info

Product

Resources

About