Tumor Burden and Clinical Benefit Assessment in Immunotherapy Clinical Trials

Clinical Trials, Drug Discovery and Development, Life Sciences, Pharmaceutical, Pharmaceutical Regulation ,
  • Monday, September 19, 2016

In a clinical trial, the treating investigator is responsible for deciding whether a trial participant continues on study. An important determinant on treatment decisions in solid metastatic tumors is the time course of lesion evolution as assessed by imaging using criteria such as the Response Evaluation Criteria in Solid Tumors (RECIST). According to RECIST, progressive disease (PD) is defined as a substantial increase in measurable or non-measurable disease or in the appearance of unequivocal new disease. Progressive disease suggests that a treatment is ineffective and therefore should be discontinued. RECIST has become the standard tumor assessment criterion for cytotoxic drugs and is accepted by regulatory agencies for evaluation of best overall response and time to progression as efficacy endpoints.

Immunotherapies may have a delayed efficacy profile resulting in initial PD followed by response, called pseudo-progression. Current imaging methods cannot distinguish between pseudo-progression and true progression. Most protocols suggest continuing immunotherapy beyond the first RECIST PD for patients without serious adverse events or clinical signs of progression. At the next imaging time point a modified set of radiographic response criteria, the so called immune related Response Criteria (irRC), are applied to check for confirmation of PD. Treatment will be discontinued in case of confirmed irRC PD or if the patient is “no longer clinically benefiting.”

With immunotherapy, deciding on whether to continue treatment may become subjective and idiosyncratic. For large international trials where experience levels and treatment standards vary, a large degree of assessment heterogeneity can be introduced. In order to mitigate the concern, a central review committee can be established that takes into account clinical benefit, adverse events, and imaging results.

Numbers extracted from KEYNote-001 (Evaluation of Immune-Related Response Criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab, Hodi et al. JCO 2016) illustrate the relevance of pseudo-progression. A RECIST PD occurred in 44% of patients. One third of the initial RECIST progressors were pseudo-progressors who mostly continued on treatment and had an improved overall survival compared to the remaining progressors.

This webinar will give an overview of endpoint assessment as it relates to RECIST, irRC, and clinical benefit in the setting of cancer immunotherapy. Recommendations on when and how to apply each criterion will be reviewed as will case histories illustrating the clinical decision-making needed to determine if a patient should continue treatment.


Klaus Noever, MD, Senior Director of Medical Affairs, WorldCare Clinical, LLC

Dr. Klaus Noever joined WorldCare Clinical from BioClinica where he had been for more than 15 years and served as VP of Business Development and Medical Director in Europe. Dr. Noever obtained his MD from University of Erlangen and worked as a physician at the University hospitals of Bochum (radiology) and Erlangen (cardiology) in Germany.Dr. Klaus Noever has extensive experience with medical imaging having served as a medical imaging consultant for clinical drug development across a range of therapeutic areas including oncology, skeletal diseases, CNS and cardiovascular diseases. Prior to joining BioClinica, Dr. Noever has held positions in clinical R&D at Schwarz Pharma, Boehringer Ingelheim and Siemens Medical Systems.

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Ryan J. Sullivan, MD, Assistant in Medicine, MGH Cancer Center, Massachusetts General Hospital, and Assistant Professor, Medicine, Harvard Medical School

Ryan J. Sullivan, MD is a clinical and translational investigator whose main areas of interest are the development of novel molecular therapeutic agents for malignant melanoma, the translation of promising preclinical finding into early stage clinical trials, and the development of predictive biomarkers for these investigational, as well as standard, treatment approaches. He is an Assistant in Medicine and member of the Center for Melanoma and Teermer Center for Targeted Therapy at Massachusetts General Hospital (MGH), a member of the Melanoma Program at Dana-Farber/Harvard Cancer Center (DF/HCC), and an Assistant Professor in Medicine at Harvard Medical School. Dr. Sullivan is certified in Medical Oncology by the American Board of Internal Medicine.

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WorldCare Clinical is a global imaging CRO that employs scientific expertise, innovative technology, and operational excellence to maximize the precision and accuracy of a blinded independent central review of Phase I – IV clinical trial data. The company has worked with thousands of sites in more than 60 countries. WCC’s robust technology platform processes over 250 million images annually (CT, MRI, X-Ray, Echo, US, PET). Originally founded in 1992 by the Massachusetts General Hospital (MGH) Department of Radiology, WorldCare continues to maintain a strategic relationship with the Harvard Hospital System as well as other leading academic institutions.

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