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Efficacy of immunotherapy beyond RECIST progression in advanced melanoma: a real-world evidence

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Abstract

Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST 1.1 defined progression. The clinical concept of treating selected patients (pts) beyond disease progression (PD) is supported by so-called pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond (RECIST) progression (TBP) in advanced melanoma patients. Of 584 subsequent melanoma pts analyzed 77 (13.2%) received TBP. In this cohort, the median time to first PD (TTFP) was 5.29 months (m), while time to second PD (TTSP)—8.02 m. On TBP 23.4% pts achieved an objective response (OR), and next 42.9%—stabilization of the disease (SD). 1st PD was reported most often as the development of a new lesion or increase (> 20%) of the diameter of three or more targets. In about 50% second PD was observed as an increase in the diameter of different targets that in 1st PD. Multimodal treatment resulted in 9.82 m TTSP, while ITH alone—4.93 m (p = 0.128). An oligoprogressive pattern of first PD was associated with longer TTSP (HR 0.55, 95% CI: 0.32–0.94). Median OS after first PD was 28.75 months and correlated with OR during TBP (HR 0.18, 95% CI: 0.004–0.76). Selected clinically fit melanoma patients, despite evidence of first radiographic progression, may benefit from continued treatment with PD-1 checkpoint inhibitors, but the findings should be validated in larger prospective trials. Multidisciplinary treatment should be offered to advanced melanoma patients, including radiosurgery or stereotactic radiotherapy of single loci progressing during immunotherapy.

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Availability of data and materials

Data are available from the corresponding author upon research-based request and DTA.

Abbreviations

CI:

Confidence interval

CR:

Complete response

ECOG:

Eastern cooperative oncology group

FPI:

Focus primaries ignotus

HR:

Hazard ratio

ICIs:

Immune checkpoint inhibitors

irRC:

Immune-related response criteria

NSCLC:

Non-small cell lung cancer patients

OS:

Overall survival

ORR:

Objective response rate

post-PD OS:

Overall survival after first progression

PD:

Progressive disease

PR:

Partial response

psPD:

Pseudoprogression

RCC:

Renal cell carcinoma

RECIST:

Response evaluation criteria in solid tumors

SD:

Stable disease

TBP:

Treatment beyond progression

TNM:

The TNM classification of malignant tumors

TTFP:

Time-to-first progression

TTSP:

Time-to-second progression

References

  1. Blumenthal GM, Theoret MR, Pazdur R (2017) Treatment beyond progression with immune checkpoint inhibitors—known unknowns. JAMA Oncol 3(11):1473–1474

    Article  Google Scholar 

  2. Cybulska-Stopa B et al (2021) First-line treatment of advanced/metastatic melanoma with anti-PD-1 antibodies: multicenter experience in Poland. Immunotherapy 13(4):297–307

    Article  CAS  Google Scholar 

  3. Cybulska-Stopa B et al (2020) Efficacy of ipilimumab after anti-PD-1 therapy in sequential treatment of metastatic melanoma patients—real world evidence. Adv Med Sci 65(2):316–323

    Article  Google Scholar 

  4. Czarnecka AM et al (2019) Treatment sequencing and clinical outcomes in BRAF-positive and BRAF-negative unresectable and metastatic melanoma patients treated with new systemic therapies in routine practice. Target Oncol 14(6):729–742

    Article  Google Scholar 

  5. Daud AI (2018) Revisiting RECIST: the case of treatment beyond progression. Lancet Oncol 19(2):157–159

    Article  Google Scholar 

  6. Ren D et al (2020) Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy. Mol Cancer 19(1):19

    Article  Google Scholar 

  7. George S et al (2016) Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression. JAMA Oncol 2(9):1179–1186

    Article  Google Scholar 

  8. Won SE et al (2020) Impact of pseudoprogression and treatment beyond progression on outcome in patients with non-small cell lung cancer treated with immune checkpoint inhibitors. Oncoimmunology 9(1):1776058

    Article  Google Scholar 

  9. Seymour L et al (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18(3):e143–e152

    Article  Google Scholar 

  10. Di Giacomo AM et al (2009) Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother 58(8):1297–1306

    Article  Google Scholar 

  11. Ma Y et al (2019) How to differentiate pseudoprogression from true progression in cancer patients treated with immunotherapy. Am J Cancer Res 9(8):1546–1553

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Beaver JA 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(2):229–239

    Article  CAS  Google Scholar 

  13. Gandara D (2019) GR02.04 immunotherapy: hyperprogression and treatment beyond progression. J Thorac Oncol 14(10):S85

    Article  Google Scholar 

  14. Eisenhauer EA et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247

    Article  CAS  Google Scholar 

  15. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53(282):457–481

    Article  Google Scholar 

  16. Patel PH et al (2019) The dandelion dilemma revisited for oligoprogression: treat the whole lawn or weed selectively? Clin Oncol (R Coll Radiol) 31(12):824–833

    Article  CAS  Google Scholar 

  17. Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. Biometrics 38(1):29–41

    Article  Google Scholar 

  18. Spagnolo F et al (2021) Treatment beyond progression with anti-PD-1/PD-L1 based regimens in advanced solid tumors: a systematic review. BMC Cancer 21(1):425

    Article  Google Scholar 

  19. Long GV et al (2017) Nivolumab for patients with advanced melanoma treated beyond progression. JAMA Oncol 3(11):1511–1519

    Article  Google Scholar 

  20. Reinhorn D et al (2020) Treatment beyond progression with immune checkpoint inhibitors in non-small-cell lung cancer. Immunotherapy 12(4):235–243

    Article  CAS  Google Scholar 

  21. Ge X et al (2020) Immunotherapy beyond progression in patients with advanced non-small cell lung cancer. Transl Lung Cancer Res 9(6):2391–2400

    Article  CAS  Google Scholar 

  22. Cortesi E et al (2017) Treatment beyond progression in patients with advanced RCC participating in the expanded access programme (EAP). Ann Oncol 28:v316

    Article  Google Scholar 

  23. Enomoto T et al (2019) Nivolumab treatment beyond progression disease in advanced non-small cell lung cancer. Ann Oncol 30:xi28

    Article  Google Scholar 

  24. Xu Y, Li H, Fan Y (2021) Progression patterns, treatment, and prognosis beyond resistance of responders to immunotherapy in advanced non-small cell lung cancer. Front Oncol 11:642883. https://doi.org/10.3389/fonc.2021.642883

    Article  PubMed  PubMed Central  Google Scholar 

  25. Somarouthu B et al (2018) Immune-related tumour response assessment criteria: a comprehensive review. Br J Radiol 91(1084):20170457

    Article  Google Scholar 

  26. Le Lay J et al (2017) irRECIST and iRECIST: the devil is in the details. Ann Oncol 28(7):1676–1678

    Article  Google Scholar 

  27. Hodi FS 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(13):1510–1517

    Article  CAS  Google Scholar 

  28. Haddad R et al (2019) Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: a subgroup analysis of a randomized phase 3 clinical trial. Cancer 125(18):3208–3218

    Article  CAS  Google Scholar 

  29. Escudier B et al (2017) treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol 72(3):368–376

    Article  CAS  Google Scholar 

  30. Gandara DR et al (2018) Atezolizumab treatment beyond progression in advanced NSCLC: results from the randomized, phase III OAK study. J Thorac Oncol 13(12):1906–1918

    Article  CAS  Google Scholar 

  31. Versluis JM et al (2021) The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: a multicentre retrospective analysis. Eur J Cancer 151:72–83

    Article  CAS  Google Scholar 

  32. Vanpouille-Box C et al (2015) In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine 33(51):7415–7422

    Article  Google Scholar 

  33. Kabiljo J et al (2019) Radiotherapy as a backbone for novel concepts in cancer immunotherapy. Cancers (Basel) 12(1):79

    Article  Google Scholar 

  34. Chicas-Sett R et al (2018) Combining radiotherapy and ipilimumab induces clinically relevant radiation-induced abscopal effects in metastatic melanoma patients: a systematic review. Clin Transl Radiat Oncol 9:5–11

    Article  Google Scholar 

  35. Rogers SJ et al (2019) Radiotherapy for melanoma: more than DNA damage. Dermatol Res Pract 2019:9435389

    Article  Google Scholar 

  36. Grapin M et al (2019) Optimized fractionated radiotherapy with anti-PD-L1 and anti-TIGIT: a promising new combination. J Immunother Cancer 7(1):160

    Article  Google Scholar 

Download references

Funding

This work has been supported by Maria Sklodowska-Curie National Research Institute of Oncology statutory funding (Ministry of Education and Science subsidy).

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Authors and Affiliations

  1. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 5 W.K. Roentgena Street, 02-781, Warsaw, Poland

    Anna Małgorzata Czarnecka, Paweł Sobczuk, Paweł Rogala, Tomasz Świtaj, Joanna Placzke, Katarzyna Kozak, Anna Mariuk-Jarema, Mateusz Spałek, Monika Dudzisz-Śledź, Paweł Teterycz, Aneta Borkowska & Piotr Rutkowski

  2. Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland

    Anna Małgorzata Czarnecka

  3. Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland

    Paweł Sobczuk

  4. Departament of Computional Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland

    Paweł Teterycz

Authors
  1. Anna Małgorzata Czarnecka
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  2. Paweł Sobczuk
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  12. Piotr Rutkowski
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Contributions

Conceptualization: Anna M. Czarnecka, Paweł Sobczuk; Methodology: Anna M. Czarnecka, Paweł Sobczuk; Formal analysis, treatment and investigation: Anna M. Czarnecka, Pawel Sobczuk, Tomasz Switaj, Pawel Rogala, Mateusz Spalek, Pawel Teterycz, Monika Dudzisz-Śledź, Joanna Placzke, Katarzyna Kozak, Aneta Borkowska, Piotr Rutkowski; Writing—original draft preparation: Anna M. Czarnecka, Paweł Sobczuk; Writing—review and editing: all authors; Supervision: Anna M. Czarnecka, Piotr Rutkowski.

Corresponding author

Correspondence to Anna Małgorzata Czarnecka.

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Conflict of interest

Paweł Sobczuk received travel grants from MSD, Roche, Novartis, and Pierre Fabre, honoraria for lectures from Swixx BioPharma and BMS; he is a stockholder of CelonPharma and has a non-financial interest as ESMO Officer and Member of the Board of Polish Society of Clinical Oncology. Anna M. Czarnecka, Katarzyna Kozak, Paweł Rogala, and Tomasz Świtaj received travel grants from BMS, MSD, Novartis, and Pierre Fabre, honoraria for lectures from BMS, MSD, Pierre Fabre, Novartis, and Pfizer. Paweł Teterycz, Joanna Placzke, and Anna Mariuk-Jarema received travel grants from MSD and BMS. Monika Dudzisz-Śledź received honoraria for lectures from Pierre Fabre, Merck KGaA, Sanofi Aventis, Novartis, and BMS, honoraria for participation in advisory meetings from Merck KGaA and Novartis, and financial support for participation in conferences from Novartis. Aneta Borkowska declare no conflict of interest. Mateusz Spałek received travel grants from BMS, honoraria for lectures from BMS, Novartis, and Roche, and has non-financial interests include being a member of the Young ESTRO Committee, ESTRO Education Council, and Co-president of the Young Section of the Polish Society of Radiation Oncology. Piotr Rutkowski received honoraria for lectures from BMS, Merck, MSD, Novartis, Pierre Fabre, and Sanofi, honoraria for participation in advisory meetings from Blueprint Medicines, BMS, Merck, MSD, Novartis, Philogen, Pierre Fabre and Sanofi, and his non-financial interests include being an ASCO Officer and Member of Board of Directors Polish Society of Surgical Oncology.

Ethics approval

The study has been approved by the local bioethics committee at Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw.

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Anna Małgorzata Czarnecka and Paweł Sobczuk are equally contributed to the work.

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Czarnecka, A.M., Sobczuk, P., Rogala, P. et al. Efficacy of immunotherapy beyond RECIST progression in advanced melanoma: a real-world evidence. Cancer Immunol Immunother 71, 1949–1958 (2022). https://doi.org/10.1007/s00262-021-03132-x

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