Skip to main content
Erschienen in: Journal of Cancer Research and Clinical Oncology 2/2019

11.12.2018 | Original Article – Clinical Oncology

Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma

verfasst von: Alice Indini, Lorenza Di Guardo, Carolina Cimminiello, Michele Prisciandaro, Giovanni Randon, Filippo De Braud, Michele Del Vecchio

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 2/2019

Einloggen, um Zugang zu erhalten

Abstract

Background

Therapeutic chances for metastatic melanoma have consistently changed over the last years with the advent of antibodies targeting the programmed cell death protein-1 (PD-1). Onset of immune-related adverse events (irAEs) during treatment can be a source of concern, and the association with survival outcome is yet to be defined.

Patients and methods

Data of consecutive patients treated with anti-PD1 (nivolumab or pembrolizumab) for metastatic melanoma between July 2013 and January 2018 were retrospectively reviewed. Baseline factors, together with onset of irAEs and vitiligo during treatment, were evaluated to identify predictors of progression-free (PFS) and overall (OS) survival. PFS and OS were assessed using Kaplan–Meier and Cox models.

Results

Overall, 173 patients were included in the present analysis, and 102 patients (59%) experienced irAEs. Disease control rate was 51%. Median (interquartile range) PFS and OS were 4.9 (2.6–13.3) and 8.6 (3.5–18.3) months, respectively. At multivariate analysis, irAEs occurrence was independently associated with improved PFS [HR 0.47 (95% CI 0.26, 0.86); p = 0.016], and correlated with better OS [HR 0.39 (95% CI 0.18, 0.81); p = 0.007]. Among various irAEs, the occurrence of vitiligo was associated with a trend toward a non-significant improved OS in comparison with other irAEs (p = 0.061). Median OS was undefined for patients experiencing vitiligo vs. 21.9 months for patients with other irAEs vs. 9.7 months for patients who had no irAEs (p = 0.003).

Conclusions

Our study underlines the association between irAEs and survival outcomes from anti-PD1 therapy. Careful management of treatment-related toxicity can lead to achieve maximum clinical benefit from this therapy.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
Zurück zum Zitat Boasberg PD, Hoon DS, Piro LD et al (2006) Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma. J Invest Dermatol 126:2658–2663CrossRefPubMed Boasberg PD, Hoon DS, Piro LD et al (2006) Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma. J Invest Dermatol 126:2658–2663CrossRefPubMed
Zurück zum Zitat Boudewijns S, Westdorp H, Koornstra RH et al (2016) Immune-related adverse events of dendritic cell vaccination correlate with immunologic and clinical outcome in stage III and IV melanoma patients. J Immunother 39:241–248CrossRefPubMedPubMedCentral Boudewijns S, Westdorp H, Koornstra RH et al (2016) Immune-related adverse events of dendritic cell vaccination correlate with immunologic and clinical outcome in stage III and IV melanoma patients. J Immunother 39:241–248CrossRefPubMedPubMedCentral
Zurück zum Zitat Bouwhuis MG, Ten Hagen TL, Suciu S, Eggermont AM (2011) Autoimmunity and treatment outcome in melanoma. Curr Opin Oncol 23:170–176CrossRefPubMed Bouwhuis MG, Ten Hagen TL, Suciu S, Eggermont AM (2011) Autoimmunity and treatment outcome in melanoma. Curr Opin Oncol 23:170–176CrossRefPubMed
Zurück zum Zitat Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36:1714–1768CrossRefPubMed Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36:1714–1768CrossRefPubMed
Zurück zum Zitat Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 12:6681–6688CrossRef Downey SG, Klapper JA, Smith FO et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 12:6681–6688CrossRef
Zurück zum Zitat Eggermont AMM, Christian UB, Blank MD et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801CrossRefPubMed Eggermont AMM, Christian UB, Blank MD et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801CrossRefPubMed
Zurück zum Zitat Feng Y, Roy A, Masson E et al (2013) Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res 19:3977–3986CrossRefPubMed Feng Y, Roy A, Masson E et al (2013) Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin Cancer Res 19:3977–3986CrossRefPubMed
Zurück zum Zitat Freeman-Keller M, Kim Y, Cronin H (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22:886–894CrossRefPubMed Freeman-Keller M, Kim Y, Cronin H (2016) Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 22:886–894CrossRefPubMed
Zurück zum Zitat Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significante of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718CrossRefPubMed Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significante of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718CrossRefPubMed
Zurück zum Zitat Heidelberger V, Goldwasser F, Kramkimel N et al (2017) Clinical parameters associated with anti-programmed death-1 (PD-1) inhibitors-induced tumor response in melanoma patients. Invest New Drugs 35:842–847CrossRefPubMed Heidelberger V, Goldwasser F, Kramkimel N et al (2017) Clinical parameters associated with anti-programmed death-1 (PD-1) inhibitors-induced tumor response in melanoma patients. Invest New Drugs 35:842–847CrossRefPubMed
Zurück zum Zitat Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedPubMedCentral Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedPubMedCentral
Zurück zum Zitat Hu Y, Smolkin ME, White EJ et al (2014) Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma. Ann Surg Oncol 21:3978–3984CrossRefPubMedPubMedCentral Hu Y, Smolkin ME, White EJ et al (2014) Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma. Ann Surg Oncol 21:3978–3984CrossRefPubMedPubMedCentral
Zurück zum Zitat Hua C, Boussemart L, Mateus C (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:45–51CrossRefPubMed Hua C, Boussemart L, Mateus C (2016) Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol 152:45–51CrossRefPubMed
Zurück zum Zitat Ku G, Yuan J, Page D et al (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting. Cancer 116:1767–1775CrossRefPubMed Ku G, Yuan J, Page D et al (2010) Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting. Cancer 116:1767–1775CrossRefPubMed
Zurück zum Zitat Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefPubMedPubMedCentral Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefPubMedPubMedCentral
Zurück zum Zitat Nakamura Y, Kitano S, Takahashi A et al (2016) Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget 7:77404–77415PubMedPubMedCentral Nakamura Y, Kitano S, Takahashi A et al (2016) Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget 7:77404–77415PubMedPubMedCentral
Zurück zum Zitat Nakamura Y, Tanaka R, Asami Y et al (2017) Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study. J Dermatol 44:117–122CrossRefPubMed Nakamura Y, Tanaka R, Asami Y et al (2017) Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study. J Dermatol 44:117–122CrossRefPubMed
Zurück zum Zitat Nosrati A, Tsai KK, Goldinger SM et al (2017) Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer 116:1141–1147CrossRefPubMedPubMedCentral Nosrati A, Tsai KK, Goldinger SM et al (2017) Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer 116:1141–1147CrossRefPubMedPubMedCentral
Zurück zum Zitat 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 16:908–918CrossRefPubMedPubMedCentral 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 16:908–918CrossRefPubMedPubMedCentral
Zurück zum Zitat Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532CrossRefPubMed Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532CrossRefPubMed
Zurück zum Zitat Teulings HE, Limpens J, Jansen SN et al (2015) Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 33:773–781CrossRefPubMed Teulings HE, Limpens J, Jansen SN et al (2015) Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 33:773–781CrossRefPubMed
Zurück zum Zitat Toi Y, Sugawara S, Kawashima Y et al (2018) Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. Oncologist 23:1358–1365CrossRefPubMedPubMedCentral Toi Y, Sugawara S, Kawashima Y et al (2018) Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. Oncologist 23:1358–1365CrossRefPubMedPubMedCentral
Zurück zum Zitat Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454CrossRefPubMedPubMedCentral Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454CrossRefPubMedPubMedCentral
Zurück zum Zitat Weber JS, D’Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384CrossRefPubMed Weber JS, D’Angelo SP, Minor D et al (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384CrossRefPubMed
Zurück zum Zitat Weber J, Mandala M, Del Vecchio M et al (2017a) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835CrossRefPubMed Weber J, Mandala M, Del Vecchio M et al (2017a) Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824–1835CrossRefPubMed
Zurück zum Zitat Weber JS, Hodi FS, Wolchok JD et al (2017b) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792CrossRefPubMed Weber JS, Hodi FS, Wolchok JD et al (2017b) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792CrossRefPubMed
Zurück zum Zitat Weide B, Martens A, Hassel JC et al (2016) baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22:5487–5496CrossRefPubMedPubMedCentral Weide B, Martens A, Hassel JC et al (2016) baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22:5487–5496CrossRefPubMedPubMedCentral
Metadaten
Titel
Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma
verfasst von
Alice Indini
Lorenza Di Guardo
Carolina Cimminiello
Michele Prisciandaro
Giovanni Randon
Filippo De Braud
Michele Del Vecchio
Publikationsdatum
11.12.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
Journal of Cancer Research and Clinical Oncology / Ausgabe 2/2019
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-018-2819-x

Weitere Artikel der Ausgabe 2/2019

Journal of Cancer Research and Clinical Oncology 2/2019 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.