To compare tumor best overall response (BOR) by RECIST 1.1 and iRECIST, to explore the incidence of pseudoprogression in melanoma treated with pembrolizumab, and to assess the impact of pseudoprogression on overall survival (OS).
A total of 221 patients with locally advanced/unresectable melanoma who received pembrolizumab as part of KEYNOTE-002 trial were included in this study. Radiological assessment of imaging was centrally reviewed to assess tumor response. Incidence of discordance in BOR between RECIST 1.1 and iRECIST as well as rate of pseudoprogression were measured. OS of patients with pseudoprogression was compared with that of those with uncontrolled disease.
Of the 221 patients in this cohort, 136 patients developed PD as per RECIST v1.1 and 78 patients with PD continued treatment and imaging beyond initial RECIST 1.1-defined PD. Among the 78 patients who continued therapy and imaging post-progression, RECIST 1.1 and iRECIST were discordant in 10 patients (12.8%) and pseudoprogression was encountered in 14 patients (17.9%). OS of patients with pseudoprogression was longer than that of patients with uncontrolled disease/true progression (29.9 months versus 8.0 months, p value < 0.001).
Effectiveness of immunotherapy in clinical trials depends on the criterion used to assess tumor response (RECIST 1.1 vs iRECIST) with iRECIST being more appropriate to detect pseudoprogression and potentially prevent premature termination of effective therapy. Pseudoprogression was associated with improved OS in comparison with that of patients with uncontrolled disease.
• Discordance between iRECIST and RECIST 1.1 was found in 12.8% of unresectable melanoma patients on pembrolizumab who continued therapy beyond initial RECIST 1.1-defined progression.
• Pseudoprogression, captured with iRECIST, occurred in 17.9% and was significantly associated with improved overall survival in comparison with uncontrolled disease.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Best overall response
Immune-confirmed progressive disease
Immune- Response Evaluation Criteria in Solid Tumors, proposed in 2017
Immune-unconfirmed progressive disease
Programmed cell death protein 1
Programmed cell death protein 1 ligand
Progression free survival
- RECIST 1.1:
Response Evaluation Criteria in Solid Tumors, updated in 2009
Sharpe AH, Pauken KE (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18:153–167
Ribas A, Puzanov I, Dummer R et al (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16:908–918
Eggermont AMM, Blank CU, Mandala M et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801
Topalian SL, Sznol M, McDermott DF et al (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030
Robert C, Ribas A, Schachter J et al (2019) Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 20:1239–1251
Robert C, Ribas A, Hamid O et al (2018) Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol 36:1668–1674
Hodi FS, Hwu WJ, Kefford R et al (2016) Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 34:1510–1517
Queirolo P, Spagnolo F (2017) Atypical responses in patients with advanced melanoma, lung cancer, renal-cell carcinoma and other solid tumors treated with anti-PD-1 drugs: a systematic review. Cancer Treat Rev 59:71–78
Wolchok JD, Hoos A, O'Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420
Beaver JA, Hazarika M, Mulkey F et al (2018) Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis. Lancet Oncol 19:229–239
Chiou VL, Burotto M (2015) Pseudoprogression and immune-related response in solid tumors. J Clin Oncol 33:3541–3543
Seymour L, Bogaerts J, Perrone A et al (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18:e143–ee52
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Ferte C, Marabelle A (2017) iRECIST: a clarification of tumour response assessment in the immunotherapy era. Eur J Cancer 77:165–167
Tazdait M, Mezquita L, Lahmar J et al (2018) Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: comparison of RECIST 1.1, irRECIST and iRECIST criteria. Eur J Cancer 88:38–47
Beer L, Hochmair M, Haug AR et al (2019) Comparison of RECIST, iRECIST, and PERCIST for the evaluation of response to PD-1/PD-L1 blockade therapy in patients with non-small cell lung cancer. Clin Nucl Med 44:535–543
Yang H, Schwartz LH, Zhao B (2016) A response assessment platform for development and validation of imaging biomarkers in oncology. Tomography 2:406–410
Zhao B, Lee SM, Lee HJ et al (2014) Variability in assessing treatment response: metastatic colorectal cancer as a paradigm. Clin Cancer Res 20:3560–3568
Pignon JC, Jegede O, Shukla SA et al (2019) irRECIST for the evaluation of candidate biomarkers of response to nivolumab in metastatic clear cell renal cell carcinoma: analysis of a phase II prospective clinical trial. Clin Cancer Res 25:2174–2184
Bohnsack O, Hoos A, Ludajic K (2014) Adaptation and modification of the immune related response criteria (IRRC): IrRECIST. J Clin Oncol 32
Johnson K, Gomez A, Burton J et al (2019) Directional inconsistency between Response Evaluation Criteria in Solid Tumors (RECIST) time to progression and response speed and depth. Eur J Cancer 109:196–203
Kurra V, Sullivan R, Gainor JF et al (2016) Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes. J Clin Oncol 34:6580
Mulkey F, Theoret MR, Keegan P, Pazdur R, Sridhara R (2020) Comparison of iRECIST versus RECIST V.1.1 in patients treated with an anti-PD-1 or PD-L1 antibody: pooled FDA analysis. J Immunother Cancer. https://doi.org/10.1136/jitc-2019-000146
Dercle L, Connors DE, Tang Y et al (2018) Vol-PACT: a foundation for the NIH public-private partnership that supports sharing of clinical trial data for the development of improved imaging biomarkers in oncology. JCO Clin Cancer Inform 2:1–12
The authors would like to thank other members of the Vol-PACT team (especially Mithat Gonen, PhD, and Chaya Moskowitz, PhD) for their feedback and suggestions during the preparation of the manuscript.
This study has (through multi-institutional collaboration as a project of the Foundation for the National Institute of Health (FNIH) Biomarkers Consortium, Advanced Metrics and Modeling with Volumetric CT for Precision Analysis of Clinical Trial Results (Vol-PACT)) received funding support provided to the FNIH by Amgen, Inc.; Boehringer Ingelheim; Merck KGaA, Darmstadt, Germany; Genentech, Inc.; Merck Sharp & Dohme Corp.; Regeneron Pharmaceuticals, Inc., and Takeda Pharmaceuticals International, Inc.
The scientific guarantor of this publication:
Lawrence H. Schwartz, MD
Conflict of interest
The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.
Statistics and biometry
One of the authors, Laurent Dercle, MD, PhD, has significant statistical expertise.
No complex statistical methods were necessary for this paper.
Written informed consent was not required for this study because the study is a retrospective analysis of imaging that had already been collected during KEYNOTE-002 clinical trial.
Institutional Review Board approval was obtained for the KEYNOTE-002 clinical trial.
Institutional Review Board approval was not required for this retrospective study of the de-identified imaging data which was collected during KEYNOTE-002 clinical trial.
Study subjects or cohorts overlap
Some study subjects or cohorts have been previously reported in the original publication of KEYNOTE-002 clinical trial manuscript in Lancet Oncology: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext
• Randomized controlled trial (only the immunotherapy arm)
• Multicenter study
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
About this article
Cite this article
Ahmed, F.S., Dercle, L., Goldmacher, G.V. et al. Comparing RECIST 1.1 and iRECIST in advanced melanoma patients treated with pembrolizumab in a phase II clinical trial. Eur Radiol 31, 1853–1862 (2021). https://doi.org/10.1007/s00330-020-07249-y