Journal Article
. 2018 May; 179(2):296-300.
doi: 10.1111/bjd.16785.

Nivolumab versus ipilimumab in the treatment of advanced melanoma: a critical appraisal: ORIGINAL ARTICLE: Wolchok JD, Chiarion-Sileni V, Gonzalez R et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377:1345-56

M T Wan 1 M E Ming 1 
  • PMID: 29766492
  •     27 citations


Aim: To show whether either nivolumab in combination with ipilimumab or nivolumab monotherapy vs. ipilimumab monotherapy extends overall survival (OS) or progression-free survival (PFS) in adults with previously untreated, advanced melanoma.

Setting And Design: The trial was conducted at 137 sites in 21 countries. Randomization (n = 945; 1 : 1 : 1 ratio) was stratified according to metastasis stage, BRAF mutation status and programmed death ligand 1 status.

Study Exposure: Adults were randomized to one of the following: nivolumab plus ipilimumab every 3 weeks for four doses, followed by nivolumab every 2 weeks; nivolumab every 2 weeks plus placebo; or ipilimumab every 3 weeks for four doses plus placebo. Treatment was continued until progression, unacceptable toxicity or withdrawal.

Outcomes: OS, PFS and objective response rate were determined. Patients were also assessed for adverse events. The primary end points of interest were OS and PFS, comparing either the nivolumab plus ipilimumab group or the nivolumab-only group with the patients treated with ipilimumab only.

Results: At 3 years, the OS rates were 58%, 52% and 34% for the nivolumab plus ipilimumab, the nivolumab monotherapy and the ipilimumab monotherapy groups, respectively. For the nivolumab plus ipilimumab group, the median OS was not reached at the time of analysis. For the nivolumab-only group, the median OS was 37·6 months, and the ipilimumab-only group had a median OS of 19·9 months. The hazard ratio for death was 0·55 [95% confidence interval (CI) 0·45-0·69; P < 0·001] comparing nivolumab plus ipilimumab with ipilimumab, and 0·65 (95% CI 0·53-0·80; P < 0·001) comparing nivolumab with ipilimumab. The PFS rates at 3 years were 39% for the nivolumab plus ipilimumab group, 32% for the nivolumab monotherapy group and 10% for the ipilimumab monotherapy group, with 95% CIs for the two nivolumab groups that did not overlap with that for ipilimumab alone.

Conclusions: Among patients with advanced melanoma, significantly longer OS and PFS occurred with the combination of nivolumab plus ipilimumab or with nivolumab alone compared with ipilimumab alone. Furthermore, survival outcomes favoured the nivolumab-containing groups over the ipilimumab group in subgroup analyses.

Synthetic DNA-Encoded Monoclonal Antibody Delivery of Anti-CTLA-4 Antibodies Induces Tumor Shrinkage In Vivo.
Elizabeth K Duperret, Aspen Trautz, +10 authors, David B Weiner.
Cancer Res, 2018 Oct 06; 78(22). PMID: 30287678    Free PMC article.
Characteristics and outcomes of patients with recurrent ovarian cancer undergoing early phase immune checkpoint inhibitor clinical trials.
Emily Hinchcliff, David Hong, +5 authors, Amir Jazaeri.
Gynecol Oncol, 2018 Oct 28; 151(3). PMID: 30366646    Free PMC article.
Immunotherapy-related hepatitis: real-world experience from a tertiary centre.
Vincent Cheung, Tarun Gupta, +6 authors, Jeremy F Cobbold.
Frontline Gastroenterol, 2019 Oct 28; 10(4). PMID: 31656561    Free PMC article.
Survival analysis of immune-related lncRNA in low-grade glioma.
Xiaozhi Li, Yutong Meng.
BMC Cancer, 2019 Aug 20; 19(1). PMID: 31419958    Free PMC article.
NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma.
Ahmad A Tarhini, Paul Frankel, +12 authors, John M Kirkwood.
Cancer, 2018 Oct 12; 124(22). PMID: 30303516    Free PMC article.
A Computational Approach Identifies Immunogenic Features of Prognosis in Human Cancers.
Malini Manoharan, Nitin Mandloi, +5 authors, Amitabha Chaudhuri.
Front Immunol, 2019 Jan 10; 9. PMID: 30622534    Free PMC article.
Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma.
Bradley D Shields, Brian Koss, +8 authors, Alan J Tackett.
Cancer Res, 2019 Jan 25; 79(6). PMID: 30674537    Free PMC article.
The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation.
Anne Månsson Kvarnhammar, Niina Veitonmäki, +16 authors, Peter Ellmark.
J Immunother Cancer, 2019 Apr 13; 7(1). PMID: 30975201    Free PMC article.
A Case of Acute Heart Failure Following Immunotherapy for Metastatic Lung Cancer.
Ammar Al-Obaidi, Nathaniel A Parker, +2 authors, Jeremy M Deutsch.
Cureus, 2020 Jun 17; 12(5). PMID: 32542148    Free PMC article.
The Most Recent Oncologic Emergency: What Emergency Physicians Need to Know About the Potential Complications of Immune Checkpoint Inhibitors.
Duncan Simmons, Eddy Lang.
Cureus, 2017 Dec 19; 9(10). PMID: 29250474    Free PMC article.
Cytokines, Chemokines, and Other Biomarkers of Response for Checkpoint Inhibitor Therapy in Skin Cancer.
Jennifer A Bridge, James C Lee, +2 authors, Jeffrey A Bluestone.
Front Med (Lausanne), 2019 Jan 12; 5. PMID: 30631766    Free PMC article.
Combining Radiation and Immune Checkpoint Blockade in the Treatment of Head and Neck Squamous Cell Carcinoma.
Gregor Manukian, Voichita Bar-Ad, +2 authors, Jennifer M Johnson.
Front Oncol, 2019 Mar 22; 9. PMID: 30895168    Free PMC article.
Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy.
Esteban Cruz, Veysel Kayser.
Biologics, 2019 May 24; 13. PMID: 31118560    Free PMC article.
Highly Cited. Review.
Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies.
Huijuan Cheng, Guodong Sun, +6 authors, Yumin Li.
Am J Cancer Res, 2019 Sep 10; 9(8). PMID: 31497341    Free PMC article.
Osteonecrosis of the jaw induced by treatment with anti-PD-1 immunotherapy: a case report.
Xerxes Pundole, Amy Little Jones, +5 authors, Michael A Davies.
Immunotherapy, 2020 Sep 10; 12(17). PMID: 32900256    Free PMC article.
Peripheral and local predictive immune signatures identified in a phase II trial of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV melanoma.
Rahima Jamal, Réjean Lapointe, +13 authors, Wilson H Miller.
J Immunother Cancer, 2017 Nov 22; 5(1). PMID: 29157311    Free PMC article.
Mechanisms of Resistance to PD-1 and PD-L1 Blockade.
Theodore S Nowicki, Siwen Hu-Lieskovan, Antoni Ribas.
Cancer J, 2018 Jan 24; 24(1). PMID: 29360728    Free PMC article.
Highly Cited. Review.
PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma.
Maria Rita Gaiser, Michelle Bongiorno, Isaac Brownell.
Expert Rev Clin Pharmacol, 2018 Feb 27; 11(4). PMID: 29478343    Free PMC article.
Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials.
Wenwei Yang, Shuquan Li, Qingrui Yang.
Medicine (Baltimore), 2019 May 18; 98(20). PMID: 31096532    Free PMC article.
Elevated CRP levels indicate poor progression-free and overall survival on cancer patients treated with PD-1 inhibitors.
Sanna Iivanainen, Jarkko Ahvonen, +2 authors, Jussi Pekka Koivunen.
ESMO Open, 2019 Sep 27; 4(4). PMID: 31555483    Free PMC article.
An Immune-Related lncRNA Signature to Predict Survival In Glioma Patients.
Pengfei Xia, Qing Li, Guanlin Wu, Yimin Huang.
Cell Mol Neurobiol, 2020 May 16; 41(2). PMID: 32410107
Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain.
Hussein A Tawbi, Peter A Forsyth, +19 authors, Kim Margolin.
N Engl J Med, 2018 Aug 23; 379(8). PMID: 30134131    Free PMC article.
Highly Cited.
Hyponatremia and Fever in a Patient on Ipilimumab and Nivolumab (Immune Checkpoint Inhibitors): A Case Report.
Sumit S Patel, Sasmit Roy, +3 authors, Eesha S Patel.
J Investig Med High Impact Case Rep, 2021 Sep 21; 9. PMID: 34538118    Free PMC article.
Iron oxide nanoparticles for immune cell labeling and cancer immunotherapy.
Seokhwan Chung, Richard A Revia, Miqin Zhang.
Nanoscale Horiz, 2021 Jul 22; 6(9). PMID: 34286791    Free PMC article.
Applying artificial intelligence for cancer immunotherapy.
Zhijie Xu, Xiang Wang, +3 authors, Zhicheng Gong.
Acta Pharm Sin B, 2021 Dec 14; 11(11). PMID: 34900525    Free PMC article.
Vitiligo-specific soluble biomarkers as early indicators of response to immune checkpoint inhibitors in metastatic melanoma patients.
Maria Luigia Carbone, Gabriele Madonna, +10 authors, Cristina Maria Failla.
Sci Rep, 2022 Apr 02; 12(1). PMID: 35361879    Free PMC article.
Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons.
Adel Naimi, Rebar N Mohammed, +11 authors, Ehsan Razeghian.
Cell Commun Signal, 2022 Apr 09; 20(1). PMID: 35392976    Free PMC article.