Addition of Ipilimumab to Nivolumab May be ‘Unnecessary’ in Select Cancers

"These findings suggest that combination therapy with nivolumab and ipilimumab may be unnecessary in many patient populations and that nivolumab alone may deliver equivalent clinical outcomes with lower toxicity [clinical and financial] in many advanced cancers other than melanoma," according to the authors of a study published in JAMA Oncology.

There were no clinically meaningful differences in overall survival (OS) and progression-free survival (PFS) between patients who received nivolumab (Opdivo) plus ipilimumab (Yervoy) and those who received nivolumab alone across 8 types of advanced cancer other than melanoma, according to findings from a meta-analysis published in JAMA Oncology.

Combining nivolumab with ipilimumab did not correlate with improvements in OS (pooled HR, 0.95; 95% CI, 0.85-1.06; P = .36; I² = 0%). Additionally, the combination therapy correlated with a marginal PFS improvement vs nivolumab monotherapy, although this improvement was not statistically significant (pooled HR, 0.88; 95% CI, 0.79-0.98; P = .02; I²= 0%).

Only 1 study—which was the largest with 792 patients—reported a statistically significant PFS benefit with nivolumab plus ipilimumab, which comprised the weight for more than 40% of the meta-analysis (HR, 0.84; 95% CI, 0.72-0.99). In a sensitivity analysis that did not include this study, the pooled HR was 0.97 (95% CI, 0.84-1.13) for OS and 0.91 (95% CI, 0.79-1.04) for PFS; this did not impact study heterogeneity (I² = 0%).

“These findings suggest that combination therapy with nivolumab and ipilimumab may be unnecessary in many patient populations and that nivolumab alone may deliver equivalent clinical outcomes with lower toxicity [clinical and financial] in many advanced cancers other than melanoma,” the study authors wrote.

Investigators of this meta-analysis assessed whether the addition of ipilimumab to standard-dose nivolumab could safely improve clinical outcomes in patients with advanced cancers besides melanoma. The literature review included a systemic search for studies of nivolumab plus ipilimumab vs nivolumab monotherapy in patients with advanced cancers up to October 31, 2022 via electronic databases including PubMed, EBSCO Information Services, and Embase.

To compare time-to-event OS and PFS outcomes, investigators performed estimations of log(HRs) and SEs for OS and PFS of each included study with summary statistics collected from individual Kaplan-Meier curves. Dichotomous data such as grade 3/4 treatment-related adverse effects (TRAEs) and treatment discontinuation rates were evaluated using odds ratios (ORs).

Investigators included 8 studies that met the selection criteria. There were 1727 patients overall, including 854 who received nivolumab plus ipilimumab and 873 treated with nivolumab alone. Disease types included metastatic squamous cell lung cancer, metastatic or recurrent PD-L1–positive non–small cell lung cancer, relapsed pleural mesothelioma, metastatic urothelial carcinoma, and advanced sarcoma. Disease types included in the analysis were metastatic esophagogastric carcinoma, glioblastoma, and recurrent small cell lung cancer.

With respect to grade 3/4 AEs, the pooled OR was 1.84 (95% CI, 1.47-2.31; P <.001; I²= 0%). Additionally, 272 toxicities of this kind occurred in 854 patients treated with nivolumab plus ipilimumab, and a further 173 AEs affected 873 patients who received nivolumab alone. The pooled OR for discontinuations related to study treatment was 1.96 (95% CI, 1.45-2.66; P <.001; I²= 2%); 150 discontinued the combination therapy, and 83 discontinued nivolumab monotherapy.

Common grade 3/4 AEs among patients receiving nivolumab plus ipilimumab included hepatoxicity (9.7%), gastrointestinal toxicity (4.0%), pneumonitis (3.6%), endocrine dysfunction (3.4%), dermatitis (3.2%), and fatigue (3.2%). Toxicity occurred less frequently in patients treated with nivolumab alone, with common high-grade AEs including hepatoxicity (3.0%), fatigue (1.7%), pneumonitis (1.5%), gastrointestinal toxicity (1.0%), dermatitis (0.9%), and endocrine dysfunction (0.2%).

The pooled ORs for specific types of grade 3/4 AEs favored nivolumab monotherapy, including hepatoxicity (OR, 2.94; 95% CI, 1.67-5.15; P <.001), gastrointestinal toxicity (OR, 3.28; 95% CI, 1.65-6.49; P <.001), and pneumonitis (OR, 2.37; 95% CI, 1.24-4.54; P = .009).

Reference

Serritella AV, Shenoy NK. Nivolumab plus ipilimumab vs nivolumab alone in advanced cancers other than melanoma: a meta-analysis. JAMA Oncol. Published online August 31, 2023. doi:10.1001/jamaoncol.2023.3295