Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial

Altorki, Nasser K.; McGraw, Timothy E.; Borczuk, Alain C.; Saxena, Ashish; Port, Jeffrey L.; Stiles, Brendon M.; Lee, Benjamin E.; Sanfilippo, Nicholas J; Scheff, Ronald; Pua, Bradley B.; Gruden, James F.; Christos, Paul J.; Spinelli, C; Gakuria, Joyce; Uppal, Manik; Binder, Bhavneet; Elemento, Olivier; Ballman, Karla V.; Formenti, Silvia C.

doi:10.1016/s1470-2045(21)00149-2

Cited by 227 publications

(170 citation statements)

References 35 publications

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“…A further treatment setting under evaluation is neo-adjuvant treatment of patients with early-stage disease. A recent phase II study of Durvalumab and SBRT therapy in NSCLC (NCT02904954) showed a significant increase in major pathological response rates with combination therapy when compared to single agent Durvalumab (53.3% and 6.7% respectively), validating the strategy for a larger trial (121). This setting has also been evaluated in breast cancer.…”

Section: Antonia Et Al Reported a Pronounced Benefit In Pfs Withmentioning

confidence: 93%

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

et al. 2021

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Cancer patients with low or absent pre-existing anti-tumour immunity (“cold” tumours) respond poorly to treatment with immune checkpoint inhibitors (ICPI). In order to render these patients susceptible to ICPI, initiation of de novo tumour-targeted immune responses is required. This involves triggering of inflammatory signalling, innate immune activation including recruitment and stimulation of dendritic cells (DCs), and ultimately priming of tumour-specific T cells. The ability of tumour localised therapies to trigger these pathways and act as in situ tumour vaccines is being increasingly explored, with the aspiration of developing combination strategies with ICPI that could generate long-lasting responses. In this effort, it is crucial to consider how therapy-induced changes in the tumour microenvironment (TME) act both as immune stimulants but also, in some cases, exacerbate immune resistance mechanisms. Increasingly refined immune monitoring in pre-clinical studies and analysis of on-treatment biopsies from clinical trials have provided insight into therapy-induced biomarkers of response, as well as actionable targets for optimal synergy between localised therapies and ICB. Here, we review studies on the immunomodulatory effects of novel and experimental localised therapies, as well as the re-evaluation of established therapies, such as radiotherapy, as immune adjuvants with a focus on ICPI combinations.

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Section: Antonia Et Al Reported a Pronounced Benefit In Pfs Withmentioning

confidence: 93%

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

et al. 2021

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“…Hence, multiple clinical trials were launched on the combination of ICIs and fractionated radiotherapy intending to enhance both a local and a systemic anti-tumoral immune response. Such clinical trials were performed in NSCLC ( 97 ) and in head and neck squamous cell carcinoma ( 98 ), where they showed great promise as the treatment was reported to be safe, well-tolerated and to induce a major response in 53.3% and 86% of patients under the combination in each tumor respectively. Complementing these clinical trials with preclinical humanized mice studies would lead to a better understanding of the underlying molecular mechanisms and could help select optimal treatment doses and schedule, which would significantly accelerate the research processes leading to faster translation strategies.…”

Section: Future Directionsmentioning

confidence: 99%

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

et al. 2021

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Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”.

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“…Unfortunately the study did not find improvement in response, PFS, or OS between the two arms and there was no evidence of an abscopal effect with the addition of SBRT to Nivolumab in unselected patients with metastatic HNSCC ( 291 ). Interestingly however, in the neoadjuvant setting in early stage resectable NSCLC, concurrent SBRT and Durvalumab was safe and associated with significantly better pathological response compared to neoadjuvant Durvalumab alone demonstrating a robust evidence of abscopal immune-modulatory effect of radiation ( 292 ). These contrasting results could probably be attributed to the hypothesis that immunotherapy is generally more effective with less disease burden and therefore the abscopal effect could be captured in that setting ( 293 ).…”

Section: Radiation-targeted Therapy Combinations In the Clinic: Stories Of Success And Failurementioning

confidence: 99%

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

et al. 2021

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In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ‘‘one size fits all’’ paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.

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Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial

Cited by 227 publications

References 35 publications

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

Humanized Mice as a Valuable Pre-Clinical Model for Cancer Immunotherapy Research

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

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