Immuno-oncology Trial Endpoints: Capturing Clinically Meaningful Activity

Self Cite

The development of immunotherapy is an important breakthrough for the treatment of cancer, with anti-tumor efficacy observed in a wide variety of tumors. To optimize immunotherapy use, approaches must be developed to identify which patients are likely to achieve benefit. To minimize therapeutic toxicities and costs, understanding the ideal choice and sequencing of the numerous immuno-oncology agents available for individual patients is thus critical, but fraught with challenges. The immune tumor microenvironment (TME) is a unique aspect of the response to immuno-oncology agents and measurement of single biomarkers does not adequately capture these complex interactions. Therefore, multiple potential biomarkers are likely needed. Current candidates in this area include PD-L1 expression, CD8+ tumor infiltrating lymphocytes, tumor mutation load and neoantigen burden, immune related gene signatures and multiplex immunohistochemical assays that examine the pharmacodynamic and spatial interactions of the TME. The most fruitful investigations are likely to use several techniques to predict response and interrogate mechanisms of resistance. Immuno-oncology biomarker research must employ validated assays to ask focused research questions utilizing clinically annotated tissue collections and biomarker focused clinical trial designs to investigate specific endpoints. Real time input from patients and their advocates into biomarker discovery is necessary to ensure that the investigations pursued will improve both clinical outcomes and quality of life. We herein provide a framework of recommendations to guide the search for immuno-oncology biomarkers of value.

Section: Biomarker Selection Must Incorporate Patient Perspective Andmentioning

confidence: 91%

The Challenge for Development of Valuable Immuno-oncology Biomarkers

Mehnert

Monjazeb

Beerthuijzen

et al. 2017

Self Cite

“…Furthermore, immunotherapies have the potential to induce not only sustained, long-term benefits, but also lingering adverse effects. With these features in consideration, three articles in this CCR Focus examine conventional elements of clinical trials – endpoints, biomarkers and combination strategies – in the context of immunotherapy to highlight where standard principles prevail and where innovations are needed (1–3). The limitations and challenges encountered thus far in the design, implementation, and integration of immunotherapy clinical trials are discussed in the final article of this series (4).…”

Section: Introductionmentioning

confidence: 99%

“…hazard ratios of 0.5–0.6). In this CCR Focus , Anagnostou et al (1). examine the challenges of utilizing the traditional endpoints of ORR, PFS and OS in immuno-oncology clinical trials.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies

Siu

Ivy

Dixon

et al. 2017

Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era.

“…As discussed by Anagnostou and colleagues in this series, the determination of clinically meaningful efficacy endpoints in immunotherapy trials is contentious, owing to atypical immune response patterns (101–103). Delayed anti-tumor effect can lead to late separation of survival curves in randomized trials, affecting study duration and statistical power in detecting differences in the overall treatment effect (104).…”

Section: Goals and Challenges Of Immunotherapy Combinationsmentioning

confidence: 99%

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

Day

Monjazeb

Sharon

et al. 2017

Self Cite

Not until the turn of this century has immunotherapy become a fundamental component of cancer treatment. While monotherapy with immune modulators such as immune checkpoint inhibitors provides a subset of patients with durable clinical benefit and possible cure, combination therapy offers the potential for anti-tumor activity in a greater number of patients. The field of immunology has provided us with a plethora of potential molecules and pathways to target. This abundance makes it impractical to empirically test all possible combinations efficiently. We recommend that potential immunotherapy combinations be chosen based on sound rationale and available data to address the mechanisms of primary and acquired immune resistance. Novel trial designs may increase the proportion of patients receiving potentially efficacious treatments and, at the same time, better define the balance of clinical activity and safety. We believe that implementing a strategic approach in the early development of immunotherapy combinations will expedite the delivery of more effective therapies with improved safety and durable outcomes.