Combined Nivolumab and Ipilimumab or Monotherapy in Previously Untreated Melanoma

By J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J. Grob, C. Cowey, C. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski and 21 more. New England Journal of Medicine, 2015

4,132 citations recorded by the source corpus.

Background The results of phase 1 and phase 2 studies suggest that nivolumab (a PD-1 checkpoint inhibitor) and ipilimumab (a CTLA-4 checkpoint inhibitor) have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab combined with ipilimumab versus ipilimumab alone were evaluated in patients with metastatic melanoma. Methods We randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma, in 1:1:1 ratio, to nivolumab alone (3 mg per kilogram of body weight every 2 weeks), or to nivolumab (at a dose of 1 mg per kilogram) plus ipilimumab (at a dose of 3 mg per kilogram) every 3 weeks for 4 doses followed by nivolumab (3 mg per kilogram every 2 weeks), or to ipilimumab alone (3 mg per kilogram every 3 weeks for 4 doses). Progression-free and overall survival were co-primary end points. Patients continue to be followed for overall survival. Results Median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) for nivolumab plus ipilimumab as compared with 2.9 months (95% CI, 2.8 to 3.4) for ipilimumab alone (hazard ratio, 0.42; 95% CI, 0.31 to 0.57; P<0.00001), and was 6.9 months (95% CI, 4.3 to 9.5) for nivolumab alone (hazard ratio in the comparison with ipilimumab alone, 0.57; 95% CI, 0.43 to 0.76; P<0.00001). In PD-L1-positive patients, median progression-free survival was 14.0 months in both the nivolumab plus ipilimumab and nivolumab alone groups, but in PD-L1-negative patients, progression-free survival was longer with the combination as compared with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] versus 5.3 months [95% CI, 2.8 to 7.1]). Grade 3–4 drug-related adverse events occurred in 16.3%, 55.0%, and 27.3% of patients in the nivolumab, nivolumab plus ipilimumab, and ipilimumab alone groups, with 1, 0, and 1 drug-related deaths, respectively. Conclusions Nivolumab alone or combined with ipilimumab significantly improved progression-free survival, as compared with ipilimumab, among previously untreated patients with metastatic melanoma. Results with the combination versus either agent alone suggest complementary activity between PD-1 and CTLA-4 blockade, particularly for patients with PD-L1-negative tumors. (Funded by Bristol-Myers Squibb; CheckMate 067, ClinicalTrials.gov number, NCT01844505.)

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/f1d33462f43c22bfc0b6d687ce5866eacb6b188e

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Citations in the corpus

Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, neutral): “Therapeutic interventions targeting immune cells have led to marked improvements in clinical outcomes (Hodi et al., 2010; Larkin et al., 2015; Le et al., 2017; Topalian et al., 2012).”
Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids (2018, positive): “The use of antibodies against immune checkpoints, such as CTLA-4 and PD-1/PD-L1, has shown clear clinical benefit for patients with advanced cancer, including melanoma, nonsmall-cell lung cancer (NSCLC), and mismatch repair-deficient (dMMR) colorectal cancer (CRC) (Larkin et al., 2015; Garon et al.,”
Pathophysiology of diabetes: An overview (2020, background): “[118,119] Furthermore, immune checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, used in cancer immunotherapy for treatment of advanced-stage cancers, including head and neck cancer, renal cancer, urothelial cancers, non-small-cell lung carcinoma, and melanoma besides other can”
Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence (2020, background): “Thereafter, it received expanded approval in combination with nivolumab for unresectable or metastatic melanoma regardless of BRAF mutation status in 2016, per Phase 3 CheckMate-067 trial data [30] (Category 1).”
Combination of CTLA-4 and PD-1 blockers for treatment of cancer (2019, background): “For instance, 1 mg/ kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks was effective dose for treatment of metastatic melanoma and esophagogastric cancer, whereas 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks was effective dose for metastatic renal cell carcinoma, metastatic colorectal can”
PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer (2019, background): “Notably, combination of nivolumab and ipilimumab (anti–CTLA-4 mAb), which reportedly target Treg cells for depletion (44, 45), can decrease HPD in malignant melanoma patients (46).”
Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, background): “, high rates of radiographic and pathologic response were achieved by combining nivolumab (anti–PD-1) with ipilimumab (anti–CTLA-4) for 8 to 9weeks preoperatively (49, 50); this drug combination was already FDA-approved as a standard of care in advanced unresectable melanoma (53).”
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq (2016, positive): “Exhaustion is promoted through the stimulation of co-inhibitory “checkpoint” molecules on the T cell surface (PD-1, TIM-3, CTLA-4, TIGIT, LAG3 and others) (41); blockade of checkpoint mechanisms has shown clinical benefit in subsets of melanoma and other malignancies (3, 10, 42, 43).”