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Introduction

Immunotherapy with immune checkpoint inhibitors (ICPIs) delivers profound benefit to a subset of patients. Many patients, however, have disease that is unresponsive to current treatment from the outset (primary resistant disease) or have disease that relapses following a period of initial benefit (acquired resistance). Strategies to improve on single-agent ICPI activity include combining these drugs with other drugs of the same or a different class.

The principle of combining drugs in an attempt to overcome resistance underpins much of the development of modern chemotherapy. Combination regimens are frequently the standard of care for many tumours in both the curative and palliative settings. These regimens result from clinical trials in which the design compares a new combination against a historical single-agent treatment. Two drugs are frequently more active than a single agent using conventional efficacy criteria (response rate, progression-free survival [PFS] and overall survival [OS]); thus, the combination becomes the new standard of care.

Trials rarely examine whether combination therapy confers greater benefit than sequential treatment with all components of the combination. As combination therapy may be associated with increased toxicity, this is an important but usually unanswered question. Once a combination has become a standard of care it may be difficult to perform a study in which patients are randomized to receive combination components given sequentially, owing to an ethical concern that they risk receiving a less effective treatment. The ideal time to test whether a combination is superior to sequenced treatment is therefore before the combination has become a standard of care; however, it may not be in a sponsor's interest to perform such a study. Detection of a synergistic rather than an additive signal would give confidence that patients derive significant benefit from combination treatment.

Combinations of ICPIs

Combination programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibition has become a standard of care in both melanoma and renal cell carcinoma (RCC), delivering significant benefit over single-agent ICPI therapy in both diseases. In melanoma, ipilimumab in combination with nivolumab showed superior efficacy over single-agent nivolumab or ipilimumab.1 At 36 months' minimum follow-up, median OS was 37.6 months in the nivolumab group and 19.9 months in the ipilimumab group but had not been reached in the combination group. The HR for OS for combination ipilimumab plus nivolumab vs ipilimumab was 0.55 (p<0.001) and for single-agent nivolumab vs ipilimumab it was 0.65 (p<0.001). In RCC, combination ipilimumab plus nivolumab was compared with sunitinib, a standard of care tyrosine kinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor.2 Ipilimumab plus nivolumab delivered an improvement in OS (HR 0.63; p<0.001). Combination immunotherapy also induced a significantly higher response rate compared with sunitinib (42% vs 27%, respectively) Combination ipilimumab and nivolumab in non-small-cell lung carcinoma (NSCLC) showed a highly significant improvement in PFS and response rate compared with chemotherapy or single-agent nivolumab in patients whose tumours contained a high mutational burden.3 The benefit appeared to be independent of programmed death-ligand 1 (PD-L1) expression at a 1% immunohistochemistry cut-off: 1 year PFS was 42.6% with nivolumab plus ipilimumab vs 13.2% with chemotherapy; median PFS was 7.2 months vs 5.5 months, respectively (HR for disease progression or death, 0.58; 97.5% CI 0.41, 0.81; p<0.001).

The toxicity of combination CTLA-4 and PD-1 inhibition is significantly greater than that seen with a single-agent ICPI. The dose of ...

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