Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial

Schoenfeld, Jonathan D.; Giobbie‐Hurder, Anita; Ranasinghe, Srinika; Kao, Katrina Z.; Lako, Ana; Tsuji, Junko; Liu, Yang; Brennick, Ryan; Gentzler, Ryan D.; Lee, Carrie; Hubbard, Joleen M.; Arnold, Susanne M.; Abbruzzese, James L.; Jabbour, Salma K.; Uboha, Nataliya Volodymyrivna; Stephans, Kevin L.; Johnson, Jennifer M.; Park, Haeseong; Villaruz, Liza C.; Sharon, Elad; Streicher, Howard; Ahmed, Mansoor M.; Lyon, Hayley; Cibuskis, Carrie; Lennon, Niall J.; Jhaveri, Aashna; Yang, Lin; Altreuter, Jennifer; Gunasti, Lauren; Weirather, Jason L.; Mak, Raymond H.; Awad, Mark M.; Rodig, Scott J.; Chen, Helen X; Wu, Catherine J.; Monjazeb, Arta M.; Hodi, F. Stephen

doi:10.1016/s1470-2045(21)00658-6

Cited by 154 publications

(105 citation statements)

References 28 publications

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“…A small number of these mAbs have been developed for clinical use as immune checkpoint inhibitors (ICIs). However, despite durable clinical responses for subsets of melanoma, lung and bladder cancer patients, regimens of approved ICIs remain largely ineffective and difficult to predict as a monotherapy 9–11 . Additionally, high levels of permanent and irreversible immune‐related toxicity occur in a large subset of patients 12 .…”

Section: Introductionmentioning

confidence: 99%

“…However, despite durable clinical responses for subsets of melanoma, lung and bladder cancer patients, regimens of approved ICIs remain largely ineffective and difficult to predict as a monotherapy. 9 , 10 , 11 Additionally, high levels of permanent and irreversible immune‐related toxicity occur in a large subset of patients. 12 Clinical biomarkers and/or bench‐to‐bedside in vitro prediction tools to direct the use of many ICIs are currently lacking.…”

Section: Introductionmentioning

confidence: 99%

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Modelling the tumor immune microenvironment for precision immunotherapy

et al. 2022

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The complexity of the cellular and acellular players within the tumor microenvironment (TME) allows for significant variation in TME constitution and role in anticancer treatment response. Spatial alterations in populations of tumor cells and adjacent non‐malignant cells, including endothelial cells, fibroblasts and tissue‐infiltrating immune cells, often have a major role in determining disease progression and treatment response in cancer. Many current standard systemic antineoplastic treatments target the cancer cells and could be further refined to directly target commonly dysregulated cell populations of the TME. Recent developments in immuno‐oncology and bioengineering have created an attractive potential to model these complexities at the level of the individual patient. These developments, along with the increasing momentum in precision medicine research and application, have catalysed exciting new discoveries in understanding drug–TME interactions, target identification, and improved efficacy of therapies. While rapid progress has been made, there are still many challenges to overcome in the development of accurate in vitro, in vivo and ex vivo models incorporating the cellular interactions that take place in the TME. In this review, we describe how advances in immuno‐oncology and patient‐derived models, such as patient‐derived organoids and explant cultures, have enhanced the landscape of personalised immunotherapy prediction and treatment of solid organ malignancies. We describe and compare different immunological targets and perspectives on two‐dimensional and three‐dimensional modelling approaches that may be used to better rationalise immunotherapy use, ultimately providing a knowledge base for the integration of the autologous TME into these predictive models.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modelling the tumor immune microenvironment for precision immunotherapy

et al. 2022

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“…In order to improve the response rates of immunotherapy, a growing number of studies are evaluating different treatment combinations or strategies, one of which is the combination of systemic immunotherapy and local radiotherapy. [1][2][3][4][5][6][7] Indeed, there is substantial evidence that radiotherapy induces immune stimulation with the release of tumor antigens and proinflammatory cytokines at the local and systemic levels and thus, may act synergistically with immunotherapy in the systemic control of advanced metastatic cancers. 1 8-12 Radiotherapy activates immune response by triggering immunogenic cell death (with extracellular release of release of high-mobility group box 1 protein and adenosine-5′-triphosphate, and cell surface translocation of calreticulin) and production of type I interferon (IFN) via the activation of the cGAS-STING pathway, leading to dendritic cells and cytotoxic T cells activation, which may eventually lead to an outof-field 'abscopal' response.…”

Section: Introductionmentioning

confidence: 99%

“…However, a randomized phase 2 trial was not able to identify a benefit of low-dose or high-dose radiation therapy with durvalumab (anti-PD-L1)+tremelimumab (anti-CTLA4) in advanced immunotherapy-pretreated NSCLC patients. 4 Irradiation modalities to optimize the achievement of a systemic antitumor immune response are then subject to numerous studies. 10 21-23 Fine tuning delivered dose and fractionation (dose per session) may be crucial for Open access achieving an out-of-field abscopal response.…”

Section: Introductionmentioning

confidence: 99%

Imaging approaches and radiomics: toward a new era of ultraprecision radioimmunotherapy?

Sun

Henry

Laville

et al. 2022

J Immunother Cancer

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Strong rationale and a growing number of preclinical and clinical studies support combining radiotherapy and immunotherapy to improve patient outcomes. However, several critical questions remain, such as the identification of patients who will benefit from immunotherapy and the identification of the best modalities of treatment to optimize patient response. Imaging biomarkers and radiomics have recently emerged as promising tools for the non-invasive assessment of the whole disease of the patient, allowing comprehensive analysis of the tumor microenvironment, the spatial heterogeneity of the disease and its temporal changes. This review presents the potential applications of medical imaging and the challenges to address, in order to help clinicians choose the optimal modalities of both radiotherapy and immunotherapy, to predict patient’s outcomes and to assess response to these promising combinations.

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“…Despite these promising preliminary findings, the contribution of LDI was not confirmed in a recently published phase 2 randomized clinical trial. 4 Indeed, Schoenfeld et al presented the results of a randomized phase 2 clinical trial, in which two different radiotherapy (RT) regimens known to enhance immune responses in preclinical models 5 6 were tested in non-small-cell lung carcinoma (NSCLC) patients with innate or acquired resistance to previous PD-1 or PD-L1 inhibitors in combination with dual ICB including durvalumab, an anti-PD-L1 antibody, and tremelimumab, an anti-CTLA-4 antibody. We congratulate the authors for incorporating these preclinical concepts into a well-designed, randomized phase 2 trial.…”

mentioning

confidence: 99%

Low-dose irradiation for reversing immunotherapy resistance: how to translate?

Olza

Bourhis

Coukos

et al. 2022

J Immunother Cancer

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The use of low-dose irradiation (LDI) for mobilizing innate and adaptive immunity is gaining interest among the scientific community. Recent evidence suggests that LDI can reprogramme the tumor microenvironment, induce inflammation and turn cold tumors susceptible to immunecheckpoint blockade therapy. Translating immuno-radiation preclinical findings in the clinic is more challenging than expected. We propose therapeutic strategies for combining LDI with immunotherapy, and emphasize the importance of pursuing clinical research to determine optimal radiation dosage, fractionation, volumes, and sequencing to stimulate immune-mediated tumor responses.

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Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial

Cited by 154 publications

References 28 publications

Modelling the tumor immune microenvironment for precision immunotherapy

Modelling the tumor immune microenvironment for precision immunotherapy

Imaging approaches and radiomics: toward a new era of ultraprecision radioimmunotherapy?

Low-dose irradiation for reversing immunotherapy resistance: how to translate?

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