The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

Abstract

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03-2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78-0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72-1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03-2.19, p = 0.036) than that of monotherapy. This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further.

Microsatellite instability in endometrial cancer: New purpose for an old test

“…Combinations of immunotherapy agents have been found to be effective in other tumor types, as highlighted in a recent meta-analysis. 55 Although toxicities were higher, better survival outcomes were demonstrated. Although to the best of our knowledge these studies have not yet been completed in patients with endometrial cancer, conceptually, individuals with this tumor type are excellent candidates for this combination approach.…”

“…Now that there is a better appreciation for the therapeutically favorable immune microenvironment in endometrial tumors with MSI‐high/MMR deficiency, novel strategies for targeting this patient population should be investigated. Combinations of immunotherapy agents have been found to be effective in other tumor types, as highlighted in a recent meta‐analysis . Although toxicities were higher, better survival outcomes were demonstrated.…”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…Improved outcomes are being reported for combined checkpoint therapies, though at the cost of more adverse events [195,196] . Even those withdrawing from combination treatment due to severe adverse events may still be receiving benefit [197] .…”

Rash and Pruritus With PD‐1 Inhibitors in Cancer Patients: A Meta‐Analysis of Randomized Controlled Trials

“…Antibodies that target key immune checkpoints, such as programmed death‐1 (PD‐1), have emerged as clinically effective treatment options for melanoma and other tumor types. The United States Food and Drug Administration's approval of nivolumab and pembrolizumab had brought hope to the patients and the scientific community . Nivolumab is an engineered humanized IgG4 anti‐PD‐1 antibody that has been approved for the management of unresectable or metastatic melanoma, metastatic squamous non‐small‐cell lung cancer (NSCLC), and advanced renal cell carcinoma .…”

“…The United States Food and Drug Administration's approval of nivolumab and pembrolizumab had brought hope to the patients and the scientific community. 1,2 Nivolumab is an engineered humanized IgG4 anti-PD-1 antibody that has been approved for the management of unresectable or metastatic melanoma, metastatic squamous non-small-cell lung cancer (NSCLC), and advanced renal cell carcinoma. 3,4 Pembrolizumab is another human PD-1-blocking antibody that has been approved for the management of NSCLC, melanoma, and squamous-cell carcinoma of the head and neck.…”