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
Open accessAbstract
Purpose: Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods: Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results: At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion: Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Time on therapy is not the reason for the relationship between IRAE onset and ICI efficacy.
“Another study which suggests time on therapy is not the reason for the relationship between IRAE onset and ICI efficacy was a pooled retrospective analysis of melanoma patients from the randomized Checkmate 067 and Checkmate 069 trials [51].”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [51]
ORR was 58.3% and 50.2% in patients who did and did not discontinue ICIs during the induction phase, respectively (p = .18).
“ORR was 58.3 and 50.2% in patients who did and did not discontinue ICIs during the induction phase, respectively (p = .18).”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [51]
No difference in PFS (HR .99; 95% CI .72-1.34; p = .97) was observed between patients who did and did not discontinue ICIs during the induction phase.
“No difference in PFS (HR .99; 95% CI .72–1.34; p = .97) or OS (HR .79; 95% CI .54–1.17; p = .23) was observed between patients who did and did not discontinue ICIs during the induction phase.”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [51]
No difference in OS (HR .79; 95% CI .54-1.17; p = .23) was observed between patients who did and did not discontinue ICIs during the induction phase.
“No difference in PFS (HR .99; 95% CI .72–1.34; p = .97) or OS (HR .79; 95% CI .54–1.17; p = .23) was observed between patients who did and did not discontinue ICIs during the induction phase.”
From Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors (2019) · cites this paper as [51]
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · see citing works
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,314 · see citing works
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157 · see citing works
Self-citationPembrolizumab versus Ipilimumab in Advanced Melanoma
Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L., Daud, A., Carlino, M. S., McNeil, C., Lotem, M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1503093 · Cited by 5,887 · see citing works
Self-citationNivolumab and ipilimumab versus ipilimumab in untreated melanoma
Postow, M. A., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K., McDermott, D., Linette, G. P., Meyer, N., Giguere, J. K., Agarwala, S. S., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1414428 · Cited by 2,781 · see citing works
Self-citationSafety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma
Weber, J. S., Hodi, F. S., Wolchok, J. D., Topalian, S. L., Schadendorf, D., Larkin, J., Sznol, M., Long, G. V., Li, H., Waxman, I. M., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2015.66.1389 · Cited by 1,158 · see citing works
Self-citationHodi, F. S., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K. F., McDermott, D. F., Linette, G. P., Meyer, N., Giguere, J. K., Agarwala, S. S., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30366-7 · Cited by 968 · see citing works
Self-citationMenzies, A. M., Johnson, D. B., Ramanujam, S., Atkinson, V. G., Wong, A. N. M., Park, J. J., McQuade, J. L., Shoushtari, A. N., Tsai, K. K., Eroglu, Z., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdw443 · Cited by 817 · see citing works
Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis
Eisen, T. G., Ahmad, T., Flaherty, K. T., Gore, M. E., Kaye, S. B., Marais, R., Gibbens, I., Hackett, S., James, M., Schuchter, L. M., et al. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603291 · Cited by 644 · see citing works
Randomized discontinuation design: application to cytostatic antineoplastic agents.
Rosner, G., Stadler, W., & Ratain, M. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.11.126 · Cited by 195 · see citing works
Stadler, W. M., Rosner, G. L., Small, E. J., Hollis, D. R., Rini, B. I., Zaentz, S. D., Mahoney, J. F., & Ratain, M. J. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.44.150 · Cited by 81 · see citing works
Menzies, A. M., Gonzalez, M., Guminski, A. D., Nieweg, O. E., Shannon, K. F., Thompson, J. F., Kefford, R. F., Ch’ng, S., Stretch, J. R., Spillane, A. J., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx377.007 · Cited by 37 · see citing works
Weber, J. S., Larkin, J., Schadendorf, D., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2017.35.15_suppl.9523 · Cited by 21 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Immune-Related Adverse Events Associated with Immune Checkpoint Blockade
Postow, M. A., Sidlow, R., & Hellmann, M. D. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1703481 · Cited by 4,849 · see citing works
Self-citationBrahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Ernstoff, M. S., Gardner, J. M., Ginex, P., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.6385 · Cited by 3,713 · see citing works
Self-citationHodi, F. S., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Cowey, C. L., Lao, C. D., Schadendorf, D., Wagstaff, J., Dummer, R., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30700-9 · Cited by 1,399 · see citing works
Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors
Das, S., & Johnson, D. B. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0805-8 · Cited by 1,145 · see citing works
Arbour, K. C., Mezquita, L., Long, N., Rizvi, H., Auclin, E., Ni, A., Martínez-Bernal, G., Ferrara, R., Lai, W. V., Hendriks, L. E. L., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.79.0006 · Cited by 1,071 · see citing works
Thompson, J. A., Schneider, B. J., Brahmer, J., Andrews, S., Armand, P., Bhatia, S., Budde, L. E., Costa, L., Davies, M., Dunnington, D., et al. (2019) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2019.0013 · Cited by 570 · see citing works
Lebbé, C., Meyer, N., Mortier, L., Marquez-Rodas, I., Robert, C., Rutkowski, P., Menzies, A. M., Eigentler, T., Ascierto, P. A., Smylie, M., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01998 · Cited by 408 · see citing works
Self-citationClinical features and outcomes of immune checkpoint inhibitor-associated AKI: a multicenter study
Cortazar, F. B., Kibbelaar, Z. A., Glezerman, I. G., Abudayyeh, A., Mamlouk, O., Motwani, S. S., Murakami, N., Herrmann, S. M., Manohar, S., Shirali, A. C., et al. (2020) · Journal of the American Society of Nephrology · doi:10.1681/asn.2019070676 · Cited by 407 · see citing works
Santini, F. C., Rizvi, H., Plodkowski, A. J., Ni, A., Lacouture, M. E., Gambarin-Gelwan, M., Wilkins, O., Panora, E., Halpenny, D. F., Long, N. M., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0755 · Cited by 331 · see citing works
Considerations for treatment duration in responders to immune checkpoint inhibitors
Marron, T. U., Ryan, A. E., Reddy, S. M., Kaczanowska, S., Younis, R. H., Thakkar, D., Zhang, J., Bartkowiak, T., Howard, R., Anderson, K. G., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001901 · Cited by 137 · see citing works
George, S., Rini, B. I., & Hammers, H. J. (2019) · JAMA Oncology · doi:10.1001/jamaoncol.2018.4604 · Cited by 84 · see citing works
Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go?
De Bruyn, P., Van Gestel, D., Ost, P., Kruse, V., Brochez, L., Van Vlierberghe, H., Devresse, A., del Marmol, V., Le Moine, A., & Aspeslagh, S. (2019) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000505 · Cited by 79 · see citing works
- Authors
- Schadendorf, D., Wolchok, J. D., Hodi, F. S., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-J., Cowey, C. L., Lao, C. D., Chesney, J., Robert, C., Grossmann, K., McDermott, D., Walker, D., Bhore, R., Larkin, J., & Postow, M. A.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Dirk Schadendorf, University Hospital Essen and the German Cancer Consortium, Essen, Germany; Jedd D. Wolchok and Michael A. Postow, Memorial Sloan Kettering Cancer Center; Michael A. Postow, Weill Cornell Medical College, New York, NY; F. Stephen Hodi, Dana-Farber Cancer Institute; David McDermott, Beth Israel Deaconess Medical Center, Boston, MA; Vanna Chiarion-Sileni, Istituto Oncologico Veneto, Veneto, Italy; Rene Gonzalez, University of Colorado Denver, Aurora, CO; Piotr Rutkowski, Maria Skłodowska...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2017-12-01
- Volume
- 35
- Issue
- 34
- Pages
- 3807-3814
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5791828
- OpenAlex
- W2746991247
- Cited by
- 441
- References
- 14
- Citations by year
- 2026: 10 · 2025: 35 · 2024: 30 · 2023: 42 · 2022: 44 · 2021: 59 · 2020: 82 · 2019: 65 · 2018: 61 · 2017: 13
- FWCI
- 26.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK (20265)
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- advanced melanoma, nivolumab, ipilimumab, immune checkpoint inhibitors, combination immunotherapy, treatment discontinuation, adverse events, progression-free survival, objective response rate, overall survival, induction phase
- MeSH terms
- Ipilimumab, Nivolumab, Antibodies, Monoclonal, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Male, Melanoma, Neoplasm Invasiveness, Neoplasm Staging, Prognosis, Retrospective Studies, Skin Neoplasms, Proportional Hazards Models, Survival Analysis, Randomized Controlled Trials as Topic, Databases, Factual, Treatment Outcome, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Disease-Free Survival, Statistics, Nonparametric, Withholding Treatment, Kaplan-Meier Estimate, Patient Safety
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
