Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

Abstract

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.)

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…Mirroring findings in the clinic, 4,10 some subjects (mice) did not respond to immunotherapy at all, while others experienced slower tumor growth or eradication of the tumor altogether. RON inhibition alone (RON i single agent) did not result in appreciable clinical benefit, and it did not significantly reduce tumor growth rate compared to the vehicle group (Figure 3a-c).…”

“…Unfortunately, grade 3 and 4 treatment-related adverse events were observed in 55% of patients, twice as frequently compared to single-treatment arms. 4 These data emphasize that discovering cooperating immune pathways that can be safely modulated to provide synergistic clinical benefit will be a key step in improving immunotherapy outcomes.…”

“…Blocking immune checkpoints with “checkpoint inhibitor” therapy was shown to be a powerful approach to release T cell inhibition in preclinical models and is now approved by the FDA for the treatment of certain cancers. 3,4 In some cases, long-term durable responses and complete remissions are achieved with checkpoint inhibition, but only a fraction of patients mount a productive anti-tumor immune response and benefit from the treatment. To this end, numerous approaches have been proposed to potentiate responses to immunotherapy including combination treatment with various immune-modulating drugs, or co-treatment with chemotherapy or radiotherapy.…”

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

“…However, studies with animal models and cancer patients have also shown that combining antibody blockade of the PD‐1/PD‐L1 axis with other forms of immunotherapy can lead to more meaningful clinical responses 32, 33, 34, 35. Approaches to block checkpoint signals have not been previously tested for their capacity to prevent premalignant lesion progression to cancer, despite indications of subjects with premalignant lesions having increased expression of PD‐L1 and PD‐1 + cells36, 37.…”

“…A murine model of cervical cancer that showed antibody treatment to block PD‐1 was not sufficient to stimulate T‐cell reactivity or to increase survival of tumor‐bearing mice, instead showed effectiveness when used in combination with agonistic antibody to the co‐stimulatory receptor OX40 33. Combining nivolumab (anti‐PD‐1) and ipilimumab (anti‐CTLA‐4) antibody treatments targeting two distinct immune checkpoints resulted in greater clinical response than when used alone 34, 35…”