The Challenge for Development of Valuable Immuno-oncology Biomarkers

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123

Immuno-oncology (I-O) has required a shift in the established paradigm of toxicity and response assessment in clinical research. The design and interpretation of cancer clinical trials has been primarily driven by conventional toxicity and efficacy patterns observed with chemotherapy and targeted agents, which are insufficient to fully inform clinical trial design and guide therapeutic decisions in I-O. Responses to immune-targeted agents follow nonlinear dose–response and dose–toxicity kinetics mandating the development of novel response evaluation criteria. Biomarker-driven surrogate endpoints may better capture the mechanism of action and biological response to I-O agents and could be incorporated prospectively in early-phase I-O clinical trials. While overall survival remains the gold standard for evaluation of clinical efficacy of I-O agents in late-phase clinical trials, exploration of potential novel surrogate endpoints such as objective response rate and milestone survival is to be encouraged. Patient-reported outcomes should also be assessed to help redefine endpoints for I-O clinical trials and drive more efficient drug development. This paper discusses endpoints used in I-O trials to date and potential optimal endpoints for future early- and late-phase clinical development of I-O therapies.

Section: Traditional Endpointsmentioning

confidence: 99%

Immuno-oncology Trial Endpoints: Capturing Clinically Meaningful Activity

Anagnostou

Yarchoan

Hansen

et al. 2017

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123

“…Predictive biomarkers of response to ICIs need to be further studied and incorporated into trials and are discussed in the series (see accompanying article by Mehnert and colleagues, ref. 58). Also, some have observed that a subset of patients develop "hyperprogression" defined by rapid progression of disease after initiation of ICI therapy (59).…”

Section: Introductionmentioning

confidence: 99%

Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities

Baik

Rubin²,

Forde

et al. 2017

Self Cite

Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials.

“…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%

“…examine the challenges of utilizing the traditional endpoints of ORR, PFS and OS in immuno-oncology clinical trials. Further, as discussed by Mehnert et al (3), selection biomarkers are not yet universally validated to accurately predict response or resistance to immune checkpoint inhibitors. PD-L1 expression on tumor or immune cells by immunohistochemistry has been the most frequently considered, although this biomarker is confounded by the multiple antibodies and disparate scoring criteria that accompany the various PD-1/PD-L1 inhibitors (13).…”

Section: Introductionmentioning

confidence: 99%

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.