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Comparing RECIST 1.1 and iRECIST in advanced melanoma patients treated with pembrolizumab in a phase II clinical trial



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.

Key Points

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.

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Fig. 1
Fig. 2



Best overall response


Complete response


Immune-confirmed progressive disease


Immune-complete response


Immune-partial response


Immune- Response Evaluation Criteria in Solid Tumors, proposed in 2017


Immune-stable disease


Immune-unconfirmed progressive disease


Overall survival


Progressive disease


Programmed cell death protein 1


Programmed cell death protein 1 ligand


Progression free survival


Partial response


Response Evaluation Criteria in Solid Tumors, updated in 2009


Stable disease


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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.

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Corresponding author

Correspondence to Firas S. Ahmed.

Ethics declarations


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.

Informed consent

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.

Ethical approval

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:


• Retrospective

• Randomized controlled trial (only the immunotherapy arm)

• Multicenter study

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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).

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  • Melanoma
  • Immunotherapy