Demystifying the New iRECIST Guidelines for Immunotherapy Clinical Trials

Joe Pierro, MD|

Immune-based therapies are a major advancement in cancer patient care.However, compared to chemotherapy ─ the most common form of cancer treatment1 ─ immunotherapies have been found to produce unusual response patterns, including a delay in the appearance of measurable clinical activity. One of the most alarming features of immunotherapy is the potential for an increase in tumor size, also known as pseudoprogression, before shrinkage.2 This is of utmost concern to clinicians and patients alike because tumor progression endpoints are used for treatment decisions and inaccurate assessments could lead to delayed or misinformed treatment.So the question becomes:How should clinicians assess the progression of tumor size and the response to novel immunotherapeutic drugs in clinical trials?The answer is thought to be in the new standardized response criteria, iRECIST,3 published March 2017 in Lancet Oncology.

RECIST Guidelines:From the Beginning

The original consensus guideline, ’Response Evaluation Criteria in Solid Tumors, (RECIST)’ was first published in 2000 as a follow-up to earlier World Health Organization (WHO) solid-tumor evaluation and treatment guidelines.The RECIST guidelines were developed by a group of clinicians, academics, and pharmaceutical company and regulatory agency representatives using information from large clinical trial databases (6,500+ cancer patients), simulation studies, and literature reviews.This RECIST working group developed and published a set of peer-reviewed guidelines intended to standardize how clinicians determine tumor changes after a patient is exposed to novel therapeutics in a clinical trial.4

Updated Guidelines:RECIST 1.1

After the first RECIST publication, clinicians raised concerns about the multiple variations of the guidelines used across clinical trials worldwide.This prompted the RECIST working group to develop an updated version of the guidelines (RECIST 1.1) in 2009.5

The main changes of RECIST 1.1 from the original guidelines included:

  • Number of lesions to be assessed
  • Assessment of pathological lymph nodes
  • Confirmation of response
  • Clarification of disease progression

Newest Standardized Guidelines for Immunotherapy Clinical Trials:iRECIST

Since the publication of RECIST 1.1, there have been subsequent recommendations to include even more detailed information for assessment guidelines in immunotherapy response patterns. Specifically, irRC, a modified version of the original WHO criteria, involved the inclusion of the measurements of new targets into disease assessments6.  Another version of the guidelines, irRECIST, incorporated RECIST and RECIST 1.1 recommendations for tumor assessment and were published by different groups and sometimes in abstract form.7,8,9 Neither of these updated criteria was consistently applied, leading to concerns about the comparability of data and results across trials, difficulty with pooling databases, and poor clarity regarding whether new lesions were measured.

Moreover, and of most concern, were the inaccuracies in how RECIST 1.1 defined tumor progression and how endpoints were assessed in immunotherapeutic trials.  In some cases, using RECIST 1.1 in immunotherapy trials would lead clinicians to declare that the tumor was growing larger at too early a time point, when the immunotherapy treatment effect was not yet fully evident. Inaccurate diagnosis could unnecessarily pull the patient out of the clinical trial.  Altogether, this led the RECIST working group to reconvene and create a new data warehouse, termed iRECIST.

iRECIST is considered the most up-to-date tumor response criteria and is now undergoing the process of validation.The new guidelines provide:

  • Clear definitions to standardize solid tumor measurement and change in tumor size measurements
  • Specific response criteria for the delayed responses that occur after pseudoprogression, or increase of tumor burden, after therapy
  • Guidelines that establish the minimum amount of data to be collected, enabling the development of a data warehouse to validate iRECIST
  • Definition of optimal timing and frequency of response assessment metrics
  • Requirement that clinicians record the reason why it was not possible to confirm progression when subjects continue in the trial


The table 10,11 below outlines the differences between the two guidelines (NB:iRECIST does not include treatment guidelines):


Definitions of measurable, non-measureable diseases X X
Definitions of T and NT lesions X X
Measurement and management of nodal disease X X
Calculation of the sum-of-measurement (SOM) X X
Definitions of CR, PR, and SD, and their duration X X
Confirmation of CR and PR X X
Definition of progression in T and NT X X
Management of new lesions X
Time point response after RECIST 1.1 progression X
Confirmation of progression required X
Collection of reason why progression cannot be confirmed X
Inclusion and recording of clinical status X


Abbreviation Legend
T = target
NT = non-target
CR = complete responses
PR = partial responses
SD = stable disease


What These Changes Mean to Immunotherapeutic Clinical Trials

On a day-to-day basis, the new iRECIST guidelines will not change the activities of clinicians or clinical trial sponsors.What will change is the way in which the clinical trial data are read by central radiologists and oncologists.This will require updating the read system software programming to reflect the new tumor response criteria.  Once updated, the software providers will train core lab personnel on how the new criteria should be used and provide release notes, which will subsequently lead to updated SOPs.This process of implementing updated software can take several months, but the precise amount of time will vary depending on the complexity of the updated/new criteria and individual core labs.

As we have previously seen, there will likely be some modifications made to these criteria once they have been used in real life situations, and thus updated read systems will be necessary.

The potential of cancer cell-directed immune therapy, compared to one-size-fits-all toxic chemotherapy techniques, is thought to be a game-changer in cancer care.But in order to successfully advance some of these candidates to market, clinicians must eliminate ambiguity and be able to consistently determine whether a patient is getting worse, improving, or staying the same.The new iRECIST standardization criteria guidelines are designed to do just that.

Employ quantitative and objective image analysis with a technology-driven imaging solution that’s more accurate and verifiable than subjective and time-consuming scoring systems.




  1. Bendandi M. Idiotype vaccines for lymphoma:proof-of-principles and clinical trial failures. Nat Reviews Cancer 2009;9(9):675–681.
  2. RECIST Committee.The components of progression as explanatory variables for overall survival in the Response Evaluation Criteriain Solid Tumours1 database.Eur J Cancer.2014 Jul; 50(10):1847-53. 
  3. RECIST Working Group, EG et al. iRECIST:guidelines for response criteria for use in trials testing immunotherapeutics.Lancet 2017; 18(3):e143-e152.
  4. Therasse P, et al.New guidelines to evaluate the response to treatment in solid tumors.J Natl Cancer Inst 2000; 92:205–216.
  5. Verweij, J et al., New response evaluation criteria in solid tumours:Revised RECIST guideline (version 1.1).European Journal of Cancer 45 (2009) 228 – 247.
  6. Wolchok JD, et al.Guidelines for the evaluation of immune therapy activity in solid tumors:immune-related response criteria.Clin Cancer Res 2009; 15:7412–20.
  7. Bohnsack O, Ludajic K, Hoos A. Adaptation of the immune-related response criteria:irRECIST.Ann Oncol 2014; 25 (suppl 4):iv361–iv372.
  8. Hodi FS, Hwu WJ, Kefford R, et al.Evaluation of immune-related response criteria and RECIST v1·1 in patients with advanced melanoma treated with pembrolizumab.J Clin Oncol 2016;
  9. Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors.J Clin Oncol 2015; 33:3541–43.
  10. RECIST Committee.The components of progression as explanatory variables for overall survival in the Response Evaluation Criteriain Solid Tumours1 database.Eur J Cancer.2014 Jul; 50(10):1847-53. 
  11. RECIST Working Group, EG et al. iRECIST:Guidelines for response criteria for use in trials testing immunotherapeutics.Lancet 2017;18(3):e143-e152.    
  12. Bendandi M. Idiotype vaccines for lymphoma:proof-of-principles and clinical trial failures. Nat Reviews Cancer 2009; 9(9):675–681.