Skip to main content

Advertisement

SpringerLink
Log in

Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors’ (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients’ survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.

Methods

This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan–Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.

Results

A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2–3 (HR 2.57, 95%CI 1.44–4.57; P < 0.01), LDH ≥ 618 IU/L (HR 2.20, 95% CI 1.47–3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35–3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36–0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41–0.76; P < 0.01).

Conclusion

GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients’ OS rates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CI:

Confidence interval

CT:

Computed tomography

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

ECOG:

Eastern Cooperative Oncology Group

FDA:

Food and Drug Administration

FDG PET:

Fluorodeoxyglucose positron emission tomography

GI:

Gastrointestinal

HQROL:

Health-related quality of life

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

iCPD:

Confirmed progressive disease

iCR:

Immune complete response

IDC:

Immune-mediated diarrhea and colitis

imRECIST:

Immune-modified response evaluation criteria in solid tumors

iPR:

Immune partial response

IQR:

Interquartile range

irAE:

Immune-related adverse event

iRECIST:

Immune-related response evaluation criteria in solid tumors

iSD:

Immune stable disease

iUPD:

Immune unconfirmed progressive disease

LDH:

Lactate dehydrogenase

OS:

Overall survival

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed death-ligand 1

PFS:

Progression free survival

SD:

Standard deviation

References

  1. Abu-Sbeih H et al (2018) Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma. J Immunother Cancer 6(Suppl 1):P537

    Google Scholar 

  2. Ribas A et al (2016) Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315(15):1600–1609

    Article  CAS  PubMed  Google Scholar 

  3. Wolchok JD et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14):1345–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Friedman CF, Proverbs-Singh TA, Postow MA (2016) Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol 2(10):1346–1353

    Article  PubMed  Google Scholar 

  5. Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Herbst RS et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Puzanov I et al (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5(1):95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Haanen J et al (2017) Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl_4):iv119–iv142

    Article  CAS  PubMed  Google Scholar 

  9. Abu-Sbeih H et al (2018) Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer 6(1):95

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang Y et al (2018) Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis 24(8):1695–1705

    Article  PubMed  Google Scholar 

  11. Wang DY et al (2017) Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. Oncoimmunology 6(10):e1344805

    Article  PubMed  PubMed Central  Google Scholar 

  12. Freeman-Keller M et al (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22(4):886–894

    Article  CAS  PubMed  Google Scholar 

  13. Weber JS et al (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35(7):785–792

    Article  CAS  PubMed  Google Scholar 

  14. Downey SG et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13(22 Pt 1):6681–6688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beck KE et al (2006) Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 24(15):2283–2289

    Article  CAS  PubMed  Google Scholar 

  16. Wang Y et al (2018) Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer 6(1):37

    Article  PubMed  PubMed Central  Google Scholar 

  17. Oken MM et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655

    Article  CAS  PubMed  Google Scholar 

  18. Wolchok JD et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15(23):7412–7420

    Article  CAS  PubMed  Google Scholar 

  19. Nishino M et al (2013) Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 19(14):3936–3943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nishino M et al (2014) Optimizing immune-related tumor response assessment: does reducing the number of lesions impact response assessment in melanoma patients treated with ipilimumab? J Immunother Cancer 2:17

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hodi FS et al (2018) Immune-modified response evaluation criteria in solid tumors (imRECIST). Refining guidelines to assess the clinical benefit of cancer immunotherapy. J Clin Oncol 36(9):850–858

    Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  24. Cox DR (1972) Regression models and life-tables. J R Stat Soc 34(2):187–220

    Google Scholar 

  25. Therneau TM, Grambsch PM (2000) Modeling survival data: extending the Cox model. Statistics for Biology and Health

  26. Balch CM et al (2001) Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19(16):3622–3634

    Article  CAS  PubMed  Google Scholar 

  27. Tas F (2012) Metastatic behavior in melanoma: timing, pattern, survival, and influencing factors. J Oncol 2012:647–684

    Article  Google Scholar 

  28. Balch CM et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206

    Article  PubMed  PubMed Central  Google Scholar 

  29. Weber JS, Kahler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30(21):2691–2697

    Article  CAS  PubMed  Google Scholar 

  30. Hua C et al (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152(1):45–51

    Article  PubMed  Google Scholar 

  31. Gogas H et al (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354(7):709–718

    Article  CAS  PubMed  Google Scholar 

  32. Horvat TZ et al (2015) Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 33(28):3193–3198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schadendorf D et al (2017) Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol 35(34):3807–3814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nordlund JJ et al (1983) Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol 9(5):689–696

    Article  CAS  PubMed  Google Scholar 

  35. Neemann K, Freifeld A (2017) Clostridium difficile-associated diarrhea in the oncology patient. J Oncol Pract 13(1):25–30

    Article  PubMed  Google Scholar 

  36. Nesher L, Rolston KV (2013) Neutropenic enterocolitis, a growing concern in the era of widespread use of aggressive chemotherapy. Clin Infect Dis 56(5):711–717

    Article  PubMed  Google Scholar 

  37. Castilla-Llorente C et al (2014) Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transpl 49(7):966–971

    Article  CAS  Google Scholar 

  38. Roychowdhury DF, Hayden A, Liepa AM (2003) Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer. J Clin Oncol 21(4):673–678

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Medical editing of this paper was provided by the Department of Scientific Publications at MD Anderson Cancer Center.

Funding

This study was not supported by any funding.

Author information

Author notes

  1. Adi Diab and Yinghong Wang contributed equally.

Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Hamzah Abu-Sbeih, Faisal S. Ali & Yinghong Wang

  2. Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Wei Qiao

  3. Department of Nuclear Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Yang Lu

  4. Department of Melanoma Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA

    Sapna Patel & Adi Diab

Authors
  1. Hamzah Abu-Sbeih
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faisal S. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sapna Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adi Diab
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yinghong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HA-S: conceptualization, data curation, writing-original draft, methodology. FSA: writing-original draft, data curation. WQ: formal analysis, software, review and editing, methodology. YL: conceptualization, writing-review and editing, data curation. SP: conceptualization, writing-review and editing. AD: conceptualization, writing-review and editing, project administration, methodology. YW: conceptualization, writing-review and editing, project administration, methodology.

Corresponding author

Correspondence to Yinghong Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

This retrospective, single-center study was approved by the Institutional Review Board at MD Anderson Cancer Center. Approval number: PA18-0472.

Informed consent

This study was granted waiver of consent.

Additional information

Note on previous publication

This paper was partially published as a poster abstract at the Society for Immunotherapy of Cancer (SITC) 2018 conference (Washington, D.C., USA, 7–11 November 2018). Abstract number: P537 [1].

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 268 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abu-Sbeih, H., Ali, F.S., Qiao, W. et al. Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma. Cancer Immunol Immunother 68, 553–561 (2019). https://doi.org/10.1007/s00262-019-02303-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-019-02303-1

Keywords

Search

Navigation