- •In advanced cancer treated with anti–PD-1 antibodies nivolumab or pembrolizumab, incidence of irAEs was associated with a marked efficacy.
- •Response rate increased significantly from 16.6% to 82.5% when an irAE was present.
- •The follow-up showed an increase of PFS from 3 to 10 months when an irAE was present.
- •The follow-up showed an increase of OS from 22 to 32 months when an irAE was present.
Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti–PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti–PD-1 treatment efficacy.
Patients and methods
We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS.
We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5–31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences.
In advanced cancer treated with single-agent anti–PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti–PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.
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- Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639
- Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N Engl J Med. 2015; 373: 123-135
- Overall survival and long-term safety of nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer.J Clin Oncol. 2015 Jun 20; 33: 2004-2012
- Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomized, controlled, open-label, phase 3 trial.Lancet Oncol. 2015 Apr; 16: 375-384
- Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015 Jan 22; 372: 320-330
- Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.N Engl J Med. 2015 May 21; 372: 2006-2017
- Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017 Oct 5; 377: 1345-1356
- Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015 Nov 5; 373: 1803-1813
- Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab.J Clin Oncol. 2015 Jun 20; 33: 2013-2020
- Nivolumab for recurrent squamous-cell carcinoma of the head and neck.N Engl J Med. 2016 Nov 10; 375: 1856-1867
- Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicenter, open-label, two-stage, multi-arm, phase 1/2 trial.Lancet Oncol. 2016 Nov; 17: 1590-1598
- Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicenter, single-arm, phase 2 trial.Lancet Oncol. 2017 Mar; 18: 312-322
- PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.N Engl J Med. 2015 Jan 22; 372: 311-319
- PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.Blood. 2017 Jul 13; 130: 221-228
- Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet. 2017; 389: 2492-2502
- Pembrolizumab versus chemotherapy for PD-L1–positive non–smallcell lung cancer.N Engl J Med. 2016; 375: 1823-1833
- Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015 Jun 25; 372: 2521-2532
- Preliminary results from KEYNOTE-055: pembrolizumab after platinum and cetuximab failure in head and neck squamous cell carcinoma (HNSCC).J Clin Oncol. 2016; 35: 1542-1549
- PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma.N Engl J Med. 2016; 374: 2542-2552
- Pembrolizumab as second-line therapy for advanced urothelial carcinoma.N Engl J Med. 2017; 376: 1015-1026
- Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports.PLoS One. 2016 Jul; 11e0160221
- Comprehensive meta-analysis of key immune-related adverse events front CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients.Cancer Immunol Res. 2017 Apr; 5: 312-318
- Toxicities of immunotherapy for the practitioner.J Clin Oncol. 2015 Jun 20; 33: 2092-2099
- Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168
- A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors.Ann Oncol. 2015 Sep; 26: 1824-1829
- Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis.Front Pharmacol. 2017 Oct 18; 8: 730
- Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes.Clin Cancer Res. 2016; 22: 886-894
- Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer.JAMA Oncol. 2018; 4: 374-378
- Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.Lung Canc. 2018; 115: 71-74
- Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab.JAMA Dermatol. 2016; 152: 45-51
- Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study.J Thorac Oncol. 2017 Dec; 12: 1798-1805
- 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. 2015; 33: 773-781
- iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017 Mar; 18: e143-e152
- Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.Invest N Drugs. 2018 Aug; 36: 638-646
- Nivolumab for NSCLC in Japanese patients: similar benefits, but beware of pneumonitis.ESMO Open. 2016; 1e000119
Published online: January 22, 2019
Accepted: October 22, 2018
Received in revised form: October 19, 2018
Received: June 21, 2018
© 2018 Elsevier Ltd. All rights reserved.
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- Immune-related adverse events predict the therapeutic efficacy of pembrolizumab in urothelial cancer patientsEuropean Journal of CancerVol. 116
- PreviewWe read with great interest the article published in the European Journal of Cancer by Rogado et al. , ‘Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients’. They clearly showed the relationship between the occurrence of immune-related adverse events (irAEs) and the efficacy of anti–programmed death receptor 1 (PD-1) antibodies in various types of tumours. Recently, we have had similar results in a single tumour type, urothelial cancer.