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

Abstract

Objectives

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).

Methods

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.

Results

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).

Conclusions

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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Abbreviations

BOR:

Best overall response

CR:

Complete response

iCPD:

Immune-confirmed progressive disease

iCR:

Immune-complete response

iPR:

Immune-partial response

iRECIST:

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

iSD:

Immune-stable disease

iUPD:

Immune-unconfirmed progressive disease

OS:

Overall survival

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed cell death protein 1 ligand

PFS:

Progression free survival

PR:

Partial response

RECIST 1.1:

Response Evaluation Criteria in Solid Tumors, updated in 2009

SD:

Stable disease

References

  1. 1.

    Sharpe AH, Pauken KE (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18:153–167

    CAS  Article  Google Scholar 

  2. 2.

    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

    CAS  Article  Google Scholar 

  3. 3.

    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

    CAS  Article  Google Scholar 

  4. 4.

    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

    CAS  Article  Google Scholar 

  5. 5.

    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

    CAS  Article  Google Scholar 

  6. 6.

    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

    CAS  Article  Google Scholar 

  7. 7.

    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

    CAS  Article  Google Scholar 

  8. 8.

    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

    CAS  Article  Google Scholar 

  9. 9.

    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

    CAS  Article  Google Scholar 

  10. 10.

    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

    CAS  Article  Google Scholar 

  11. 11.

    Chiou VL, Burotto M (2015) Pseudoprogression and immune-related response in solid tumors. J Clin Oncol 33:3541–3543

    CAS  Article  Google Scholar 

  12. 12.

    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

    Article  Google Scholar 

  13. 13.

    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

    CAS  Article  Google Scholar 

  14. 14.

    Ferte C, Marabelle A (2017) iRECIST: a clarification of tumour response assessment in the immunotherapy era. Eur J Cancer 77:165–167

    Article  Google Scholar 

  15. 15.

    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

    CAS  Article  Google Scholar 

  16. 16.

    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

    Article  Google Scholar 

  17. 17.

    Yang H, Schwartz LH, Zhao B (2016) A response assessment platform for development and validation of imaging biomarkers in oncology. Tomography 2:406–410

  18. 18.

    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

    CAS  Article  Google Scholar 

  19. 19.

    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

    CAS  Article  Google Scholar 

  20. 20.

    Bohnsack O, Hoos A, Ludajic K (2014) Adaptation and modification of the immune related response criteria (IRRC): IrRECIST. J Clin Oncol 32

  21. 21.

    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

    Article  Google Scholar 

  22. 22.

    Kurra V, Sullivan R, Gainor JF et al (2016) Pseudoprogression in cancer immunotherapy: rates, time course and patient outcomes. J Clin Oncol 34:6580

    Article  Google Scholar 

  23. 23.

    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

  24. 24.

    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

    Article  Google Scholar 

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Acknowledgments

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.

Funding

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.

Author information

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Authors

Corresponding author

Correspondence to Firas S. Ahmed.

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Guarantor

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: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00083-2/fulltext

Methodology

• 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). https://doi.org/10.1007/s00330-020-07249-y

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Keywords

  • RECIST
  • Melanoma
  • Immunotherapy