Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma

By M. Postow, J. Chesney, A. Pavlick, C. Robert, K. Grossmann, D. McDermott, G. Linette, N. Meyer, J. Giguere, S. Agarwala and 11 more. New England Journal of Medicine, 2015

2,625 citations recorded by the source corpus.

Background In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab demonstrated a high objective response rate, including complete responses in patients with advanced melanoma. Methods In this double-blind study, 142 treatment-naïve patients with metastatic melanoma were randomized 2:1 to receive ipilimumab 3 mg/kg combined with either nivolumab 1 mg/kg or placebo every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg or placebo every 2 weeks until disease progression. The primary endpoint was investigator-assessed objective response in BRAF wild-type patients. Results Among BRAF wild-type patients, the confirmed objective response rate was 61.1% (44/72) in the nivolumab and ipilimumab combination group versus 10.8% (4/37) in the ipilimumab monotherapy group (P<0.001), with complete responses reported in 16 (22.2%) patients in the combination group; none in the ipilimumab group. Median duration of response was not reached with either treatment. Median progression-free survival was not reached for the combination versus 4.4 months for ipilimumab monotherapy (hazard ratio 0.40, 95% CI 0.23 to 0.68; P<0.001). Similar results for response and progression-free survival were also observed in 33 BRAF mutation-positive patients. Grade 3–4 drug-related adverse events were reported in 54.3% of patients receiving the combination compared with 23.9% with ipilimumab monotherapy. Select adverse events of immunological etiology were consistent with phase 1 reports, and most resolved with immune-modulating medication. Conclusion Nivolumab combined with ipilimumab significantly improved objective response rate and progression-free survival compared with ipilimumab monotherapy in treatment-naïve patients with advanced melanoma, and had a manageable safety profile. (ClinicalTrials.gov number, NCT01927419)

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b1e3c72cd1e4c7d3fc7e6fe5f680f1c4db862d92

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Anand Rotte
2. J. Wolchok
3. M. Postow
4. C. Robert
5. W. Zou
6. M. Lacouture
7. Benjamin Haaland
8. Mauro Delorenzi

In Oncology

1. J. Wolchok
2. Anand Rotte
3. Lieping Chen
4. M. Postow
5. W. Zou
6. E. Buchbinder
7. C. Robert
8. Anupam M. Desai

Citations in the corpus

• Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. (2015, background): “These data paved the way for phase II [35] and III studies [36] of this combination in advanced melanoma, and the exploration of similar combinations in other tumor types.”
• A systematic review and network meta‐analysis of immunotherapy and targeted therapy for advanced melanoma (2017, background): “Despite the lack of OS data for CTLA- 4iPD1i combination at the time of systematic review, PFS and RR data were suggestive that CTLA4iPD1i could also achieve meaningful benefit and consequently be a top- ranking option irrespective to BRAF status (see below) [14, 27].”
• Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations (2018, background): “The combination of nivolumab and ipilimumab was later approved as first-line treatment for BRAF-wildtype unresectable or metastatic melanoma on October 1, 2015 based on results from CheckMate 069 [19].”
• Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy (2016, neutral): “These mice were treated with both anti-PD-1 and anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAbs because combined checkpoint blockade can increase response rates in cancer patients (Sharma and Allison, 2015; Postow et al., 2015; Wolchok et al., 2013).”
• Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update (2021, positive): “001)(103) and patients treated with combinations may be less likely to experience resolution of the irAE compared with patients treated with monotherapy.(105,110) Newer data suggest that approximately 2% of patients with NSCLC or melanoma with immune-related toxicity experienced chronic pneumonitis,”
• Cancer immunotherapy: the beginning of the end of cancer? (2016, background): “4 months for ipilimumab -Not reached for ipilimumab plus nivolumab [147]”
• Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence (2020, background): “On 1 October 2015, ipilimumab in combination with nivolumab received FDA approval for BRAF V600 wild-type unresectable or metastatic melanoma based on CheckMate-069, a randomized, phase 2 study [29] (Category 1).”
• Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “Moreover, TILs activation by immune modulation can lead to eradication of human tumors in the context of adoptive T-cell therapy (Dudley et al., 2002; Garon et al., 2015; Postow et al., 2015; Wolchok et al., 2013).”
• Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. (2016, background): “These data paved the way for phase II [35] and III studies [36] of this combination in advanced melanoma, and the exploration of similar combinations in other tumor types.”
• Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma (2021, background): “Evidence from the randomized controlled, double-blind phase II CheckMate 069 and phase III CheckMate 067 trials established the combination of nivolumab and ipilimumab as a standard care option for patients with metastatic melanoma.(2-7) A 5-year follow-up analysis of the CheckMate 067 trial demonst”
• CTLA-4 and PD-1 Pathways (2016, background): “In patients with previously untreated melanoma or recurrent SCLC, the incidence of drug-related grade 3-4 AEs was 54% to 55% with concurrent blockade compared with 24% to 27% with ipilimumab alone and 15% to 16% with nivolumab alone.(58,83,89) Prior CTLA-4 inhibition does not appear to predispose pa”