Immune Checkpoint Inhibitor Combination Therapy versus Sunitinib as First-Line Treatment for Favorable-IMDC-Risk Advanced Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials

Abstract

Background: Novel combination therapies have been shown to improve the outcomes of treatment-naive patients with locally advanced or metastatic renal cell carcinoma (aRCC). However, the optimal systemic therapy for aRCC of favorable risk has yet to be clarified. We aimed to evaluate the efficacy and safety of different immunotherapy (IO) combinations, either with another IO (IO–IO) or with an antiangiogenic (IO–TKI), versus sunitinib in the first-line setting in aRCC patients with favorable IMDC risk. Methods: We conducted a systematic search for evidence in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials published up to February 2021. The GRADE approach was used to assess the quality of evidence. Survival hazard ratios were extracted for analysis in the favorable-risk aRCC subgroup (IMDC). A sensitivity analysis was performed excluding trials of combination therapy without TKI. Results: Five randomized controlled phase III trials with a total of 1088 patients were included in the analysis. The studies compared different combinations versus sunitinib monotherapy. All clinical trials reported overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) data. Four out of five trials reported complete response (CR). There was no difference in OS nor PFS between treatment arms in the IMDC favorable-risk subgroup analysis (OS: HR = 1.07, 95% CI = 0.81–1.41; PFS: HR = 0.74, 95% CI = 0.46–1.19). A benefit in ORR and CR was found for combination therapy vs. sunitinib (ORR: HR = 1.89, 95% CI = 1.29–2.76; CR: HR = 3.58, 95% CI = 2.04–6.28). In the sensitivity analysis, including only IO–TKI vs. sunitinib, no difference in OS was found; however, an advantage in PFS was observed (OS: HR = 0.99, 95%CI 0.69–1.43; PFS: HR = 0.60 (0.45–0.81). The safety profile reported is consistent with previous reports. We did not find differences in the incidence of any adverse event (AE) or of grade ≥3 AEs. Conclusion: This meta-analysis shows that combinations of IO–KI as first-line treatment in favorable-IMDC-risk aRCC improve PFS, ORR, and CR, but not OS, versus sunitinib.

Real‐world effectiveness of nivolumab and subsequent therapy in Japanese patients with metastatic renal cell carcinoma (POST‐NIVO study): 36‐month follow‐up results of a clinical chart review

“…4 Recent studies have shown that IO + IO combination therapy improves the prognosis for patients with mRCC 19,27 ; however, a meta-analysis of randomized clinical trials showed no significant difference in OS in patients with favorable IMDC risk for IO + TKI combination therapy compared with TKI monotherapy with sunitinib. 28 When this study began, TKI monotherapy was the standard therapy. Thus, patients treated with nivolumab as second-line in this study received IO therapy after TKI monotherapy.…”

“…According to National Comprehensive Cancer Network guidelines, IO + TKI or TKI monotherapy is the first‐line treatment recommended for patients with favorable IMDC risk 4 . Recent studies have shown that IO + IO combination therapy improves the prognosis for patients with mRCC 19,27 ; however, a meta‐analysis of randomized clinical trials showed no significant difference in OS in patients with favorable IMDC risk for IO + TKI combination therapy compared with TKI monotherapy with sunitinib 28 . When this study began, TKI monotherapy was the standard therapy.…”

A novel seven-immune-genes-based model to improve prognosis prediction of clear cell renal cell carcinoma

“…Patients with localized RCC receiving treatments like radiofrequency ablation, enucleoresection or simple nephrectomy have improved disease-free survival rates up to 90% [4,5], while the treatment methods for advanced and metastatic ccRCC are still limited. Immunotherapy is currently used as a first-line treatment [6], but only a small proportion of patients can benefit from immunotherapy due to the complexity and highly modulated nature of the immune system [7].…”

PNI as a Potential Add-On Biomarker to Improve the IMDC Intermediate Prognostic Score

“…The current STAR trial also demonstrated that planned breaks in tyrosine kinase inhibitor treatment in patients with renal cell carcinoma might be a reasonable option when there is a patient or healthcare need (e.g., a pandemic or drug shortage); with caution, this should be exercised since these patients would typically have shorter progression-free survival than those receiving first-line tyrosine kinase inhibitors [9]. In addition, a meta-analysis showed that favorable-risk group patients who have been treated with TKI (sunitinib) have similar overall survival rates compared to immunotherapy plus TKI treatment regimens [10]. On the other hand, the IMDC and Memorial Sloan Kettering Cancer Center models stratify patients with 1 or 2 risk factors as intermediate prognoses.…”