In the context of advanced malignancies other than melanoma, the tango that exists between Nivo-Ipi combination or Nivo monotherapy treatment is an ongoing debate that remains prominent in the healthcare field. With this in mind, each study helps to create a clearer picture by advancing our understanding of the best mode of treatment, weaving it together with the findings of previous studies. Our comprehensive meta-analysis aims to address the gap in literature regarding the efficacy and safety of combination therapy in providing significant clinical benefits in terms of overall survival, which has shown conflicting results in the past studies. This gap is filled in by adding a recent phase 2 CheckMate 714 trial [21], in addition to the previous eight studies [13,14,15,16,17,18,19,20]. With the inclusion of 425 more patients in the analysis pool, this study intends to evaluate the dual immunotherapy of Nivo-Ipi compared to Nivo monotherapy, thereby assessing the contribution of each component of dual immunotherapy as first-line treatment for patients with advanced cancer.

The combination of Nivo and Ipi, compared to Nivo alone, when evaluating overall survival rate, exhibits a nonsignificant relation between the two treatment groups, defying the previous study results that supported in favor of the Nivo-Ipi combination therapy in terms of enhanced survival [4,5,6,7]. Since overall survival is the desired outcome, the risk of death in the group receiving combination therapy was nearly indistinguishable from that of the monotherapy group, with combination therapy resulting in only a marginal 3% increase in the risk of death; however, this difference is quite negligible and clinically insignificant between the two treatment groups. This finding may be explained by the fact that nivolumab and ipilimumab are both immune checkpoint inhibitors. Ipilimumab targets CTLA-4, while nivolumab inhibits PD-1 [22, 23]. It is possible that the combined blocking effect might not provide an additional benefit in terms of overall survival rate. Additionally, as indicated in the Shi Zhou (2019) study, this dual therapy administration synergistically enhances the immune-related toxic effects (immune-related adverse events) by amplifying the blockade affect and reducing the survival chances [24]. Moreover, the low heterogeneity exhibited indicates a low variability between the studies, signifying consistent and less chances of skewing of the outcome results.

The study revealed a slight 9% reduction in the risk of progression-free survival (PFS), favoring the combination of Nivo and Ipi over Nivo alone in patients with advanced carcinoma. While this statistically significant result suggests a potential benefit in slowing disease progression, the small effect size and marginally significant p-value (p = 0.04) underscore the need for cautious interpretation. The low heterogeneity across the nine included studies (I2 = 0%) adds to the reliability of the findings. However, to gain a more comprehensive understanding of the therapeutic impact, further research is needed to thoroughly explore the implications and potential benefits of the observed reduction in PFS risk [4,5,6,7]. Drug resistance in malignancies, for instance, can be one of the factors that can be brought on by monotherapies, enhancing PFS and making it less reliable comparatively. A recent medical publication, titled Combination Therapy Against Multidrug Resistance, discussed the potential of combination therapy in overcoming multidrug resistance, providing a broad spectrum of efficacy, better potency than the medications used in monotherapy [25]. Henceforth, combining treatments could stop or delay the development of resistance due to its amplified effect, reducing PFS. Based on this, further investigative trials are required to provide a much clearer picture for the contrasted results between OS and PFS outcomes.

Although the Nivo-Ipi dual therapy has shown lesser progression in disease, it shows an increase in incidence of treatment-related cumulative grades 3–4 AEs and discontinuations associated with treatment, when compared to Nivo alone. Hepatotoxicity, diarrhea, elevated lipase, weariness, and rash were the most frequent AEs linked to combination immunotherapy [26]. This could hypothesize a directly proportional relationship between severity of adverse effects and discontinuation of the combination therapy, suggesting its lack of safety. However, the severity and extent of adverse responses may vary according to the dosage, frequency, and mode of administration technique. Nevertheless, specified symptomatic treatments should be provided to combat particular AEs.

The secondary outcomes of this study showcase a significant association between the Nivo-Ipi and Nivo monotherapy group in terms of grades 3–4 adverse hepatotoxicity events, gastrointestinal toxicity, pneumonitis, endocrine dysfunction, and dermatitis; this questions its efficacy at the cost of its safety. To combat the higher toxicity associated with the combination treatment strategy, a striking balance should be obtained by lowering the Ipi dosage when combined with the standard dose of Nivo, to reduce the elevated immune-blocking effect. One study (D'Angelo et al., 2018) also supported the hypothesis that this combination therapy could be safer if Ipi were administered at a lower dose [14, 26]. This emphasizes the need of attaining optimal dosages that achieve the appropriate balance to establish a robust treatment approach for advanced carcinoma patients. It further urges the need to conduct more randomized investigations to subcategorize and divide Ipi into specified, lower dose regimen and then combine it with the standard Nivo dose, to find the ideal quantity required for each type of advanced-stage carcinoma.

This study has certain limitations. Firstly, to explore the underlying mechanisms and establish a cause-and-effect relationship between the two treatment groups and the outcomes, larger interventional studies are required. It is worth noting that although our meta-analysis had a sufficient number of studies included in the analysis, further large-powered studies are required to reach more prominent findings. Secondly, this meta-analysis caters to different types of malignancies, creating variability and unknowingly favoring the combination strategy group. Additionally, studies with lower Nivo dose (1 mg/kg) and higher Ipi dose (3 mg/kg) were not included in the pool, suggesting a proposed discrepancy that may change the outcomes and enhance the grades 3–4 adverse events if included [27]. Our study also faced a significant limitation due to the restricted number of trials available for analysis (nine studies). This constraint hindered our ability to assess publication bias through methods such as a funnel plot analysis. Lastly, Ipi dosage for CheckMate 714 was 1 mg per kilogram IV every 6 weeks. Despite the fact that Ipi was well tolerated in CheckMate 714, patients with R/M SCCHN may not have received the best dosage or timing [21]. Therefore, future studies should consider these loopholes to enhance the quality of the outcome results.