Clinical Development and Initial Approval of Novel Immune Checkpoint Inhibitors in Oncology: Insights From a Global Regulatory Perspective

Serrano, Philippe; Hartmann, Markus; Schmitt, Elmar; Franco, Pedro; Amexis, Georgios; Gross, Jan Tomasz; Mayer‐Nicolai, Christine

doi:10.1002/cpt.1123

Cited by 10 publications

(8 citation statements)

References 94 publications

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“…Therapeutically, this is evidenced by a number of recent drug approvals for immunotherapy agents that enhance endogenous antitumor immunity (reviewed by ref. 2) or target tumors directly (reviewed by ref. 3).…”

Section: Introductionmentioning

confidence: 99%

Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response

Sidders

Zhang

Goodwin

et al. 2020

Clinical Cancer Research

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Purpose: There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumor adenosine levels at scale, thus novel, clinically tractable biomarkers are needed.Experimental Design: We generated a gene expression signature for the adenosine signaling using regulatory networks derived from the literature and validated this in patients. We applied the signature to large cohorts of disease from The Cancer Genome Atlas (TCGA) and cohorts of immune checkpoint inhibitor-treated patients.Results: The signature captures baseline adenosine levels in vivo (r 2 ¼ 0.92, P ¼ 0.018), is reduced after small-molecule inhibition of A2AR in mice (r 2 ¼ À0.62, P ¼ 0.001) and humans (reduction in 5 of 7 patients, 70%), and is abrogated after A2AR knockout. Analysis of TCGA confirms a negative association between adenosine and overall survival (OS, HR ¼ 0.6, P < 2.2e -16 ) as well as progressionfree survival (PFS, HR ¼ 0.77, P ¼ 0.0000006). Further, adenosine signaling is associated with reduced OS (HR ¼ 0.47, P < 2.2e -16 ) and PFS (HR ¼ 0.65, P ¼ 0.0000002) in CD8 þ T-cell-infiltrated tumors. Mutation of TGFb superfamily members is associated with enhanced adenosine signaling and worse OS (HR ¼ 0.43, P < 2.2e -16 ). Finally, adenosine signaling is associated with reduced efficacy of anti-PD1 therapy in published cohorts (HR ¼ 0.29, P ¼ 0.00012).Conclusions: These data support the adenosine pathway as a mediator of a successful antitumor immune response, demonstrate the prognostic potential of the signature for immunotherapy, and inform patient selection strategies for adenosine pathway modulators currently in development.

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Section: Introductionmentioning

confidence: 99%

Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response

Sidders

Zhang

Goodwin

et al. 2020

Clinical Cancer Research

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“…The latter of these limitations (known as administrative censoring) plays a key role when establishing the clinical-and cost-effectiveness of interventions. There is a growing trend in accelerated or conditional approvals and breakthrough designations being granted by the Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) meaning it is more often the case that interim analyses are used to inform regulatory submissions, which are subsequently updated as further data are collected [5,6].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of survival extrapolation in immuno-oncology using multiple pre-planned data cuts: learnings to aid in model selection

Bullement¹,

Willis

Amin

et al. 2020

BMC Med Res Methodol

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Background: Due to limited duration of follow up in clinical trials of cancer treatments, estimates of lifetime survival benefits are typically derived using statistical extrapolation methods. To justify the method used, a range of approaches have been proposed including statistical goodness-of-fit tests and comparing estimates against a previous data cut (i.e. interim data collected). In this study, we extend these approaches by presenting a range of extrapolations fitted to four pre-planned data cuts from the JAVELIN Merkel 200 (JM200) trial. By comparing different estimates of survival and goodness-of-fit as JM200 data mature, we undertook an iterative process of fitting and re-fitting survival models to retrospectively identify early indications of likely long-term survival. Methods: Standard and spline-based parametric models were fitted to overall survival data from each JM200 data cut. Goodness-of-fit was determined using an assessment of the estimated hazard function, information theorybased methods and objective comparisons of estimation accuracy. Best-fitting extrapolations were compared to establish which one provided the most accurate estimation, and how statistical goodness-of-fit differed. Results: Spline-based models provided the closest fit to the final JM200 data cut, though all extrapolation methods based on the earliest data cut underestimated the 'true' long-term survival (difference in restricted mean survival time [RMST] at 36 months: − 1.1 to − 0.5 months). Goodness-of-fit scores illustrated that an increasingly flexible model was favored as data matured. Given an early data cut, a more flexible model better aligned with clinical expectations could be reasonably justified using a range of metrics, including RMST and goodness-of-fit scores (which were typically within a 2-point range of the statistically 'best-fitting' model). Conclusions: Survival estimates from the spline-based models are more aligned with clinical expectation and provided a better fit to the JM200 data, despite not exhibiting the definitively 'best' statistical goodness-of-fit. Longer-term data are required to further validate extrapolations, though this study illustrates the importance of clinical plausibility when selecting the most appropriate model. In addition, hazard-based plots and goodness-of-fit tests from multiple data cuts present useful approaches to identify when a more flexible model may be advantageous.

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“…Anti‐CTLA‐4 monoclonal antibody ipilimumab is the first checkpoint inhibitor approved by the US Food and Drug Administration (FDA). It extends the median overall survival to 10.1 months in metastatic melanoma patients . However, patients treated with anti‐CTLA‐4 experienced immune‐related adverse events .…”

Section: Introductionmentioning

confidence: 99%

Strategies of Combination Drug Delivery for Immune Checkpoint Blockades

Ruan

et al. 2018

Adv Healthcare Materials

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The past few years have witnessed vast clinical accomplishments of immune checkpoint blockades (ICB), which block the regulatory receptor expressed on immune cells or tumor cells to prevent the suppression of antitumor cytotoxic T‐cell responses. Despite this, limitations still exist, such as low objective response rate (ORR) and the risk of immune‐related side effects. To address these issues, combination treatment strategies are vastly explored and recommended. This review summarizes recent advances in combination of ICB with therapies that participate in different stages of cancer immune cycle, including tumor antigen release, tumor antigen presentation, T‐cell activation, recognition of cancer cells by T‐cells, and tumor‐killing activity. Challenges and potential opportunities of combination approaches in this field are also discussed.

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Clinical Development and Initial Approval of Novel Immune Checkpoint Inhibitors in Oncology: Insights From a Global Regulatory Perspective

Cited by 10 publications

References 94 publications

Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response

Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response

Evaluation of survival extrapolation in immuno-oncology using multiple pre-planned data cuts: learnings to aid in model selection

Strategies of Combination Drug Delivery for Immune Checkpoint Blockades

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