Metastatic Renal Cell Carcinoma: A Meta‑Analysis Review of Therapy
In 2021, there will be an estimated 76,080 new cases of kidney cancer in the US (48,780 in men and 27,300 in women) and about 13,780 patients (4,990 women, 8,790 men) will die from this disease. The most common form of kidney cancer arises from the proximal renal tubular epithelium and is named renal cell carcinoma (RCC). With a lack of RCC-specific screening tests, around 30% of RCC patients will have metastases at diagnosis; approximately 25 – 30% of the RCCs will recur despite the surgical removal of the primary tumor. Metastatic renal cell carcinoma (mRCC) is chemotherapy- and radiotherapy-resistant.
Until the middle of this past decade, immune-modulating therapy with multiple tyrosine kinase inhibitors (TKI), targeting either the vascular endothelial growth factor (VEGF) and VEGF-receptors, or the mammalian target of rapamycin (mTOR) pathways were considered as the treatment option for patients with RCC. This landscape has changed with the introduction of immune checkpoint inhibitors (ICI) or an ICI/TKI combination. More recently, ICI-based combination therapies using nivolumab plus ipilimumab, atezolizumab plus bevacizumab, pembrolizumab plus axitinib, and avelumab plus axitinib showed better overall survival (OS) and/or progression-free survival (PFS) compared with sunitinib. However, the head-to-head randomized controlled trials (RCTs) are insufficient to evaluate the effectiveness of all available therapies. Given the numerous treatment options for patients with advanced/metastatic RCC and the limited evidence regarding the optimum treatment regimen, it is a great challenge for clinicians to make the best treatment decision.
The objective of this systematic review was to assess first-line systemic therapy of mRCC and to compare the efficacy and safety of currently available treatments using the network meta-analysis data.
Materials and methods
Methodological reports which investigated metastatic clear cell renal cell carcinona (mccRCC) patients who had undergone systemic therapy as first-line treatment were included. Studies that assessed the differential effects of systemic therapy in PFS, OS, objective response, and AEs in phase III randomized study were also included. In cases of multiple publications on the same cohort, either the higher quality or the most recent one was included. Studies where patients received sunitinib 50 mg as the control arm were also included.
This study excluded observational studies, case reports, replies from authors; and other publication types such as reviews, letters, and editorials. Reports in languages other than English were excluded. Studies involving patients with systemic therapy history or studies in which this subset could not be excluded from the cohort were excluded. And finally, studies, where interferon or placebo was used as the control arms, were excluded. This is because tyrosine kinase inhibitors (TKI) are an approved first-line systemic treatment for mRCC.
Search Methods & Screening
The systematic review and network meta-analysis (NMA) of phase III randomized controlled trials (RCT) were conducted with sunitinib monotherapy as the control arm. A completed PRISMA 2009 checklist was used to describe the study design and methodology. The PubMed, Web of Science and Scopus databases were searched, noting the abstracts of the published studies on first-line systemic therapy for mRCC published until June 2020. Potentially eligible titles and/or abstracts were identified using a combination of titles (e.g., “metastatic or advanced”, “Randomized”) and keywords (e.g., “renal cell carcinoma”, “renal cell cancer”, “kidney carcinoma”, “kidney cancer”). Overall and/or progression-free survival (OS/PFS) was the primary outcome measure; Objective response and adverse events (AEs) were the secondary outcomes. Additional reports eligible for inclusion were identified independently by two authors. The full-text screening was completed independently, and the relevancy was confirmed post data extraction process. All screening disagreements were discussed among a separate committee of reviewers until consensus was reached.
Two reviewers extracted the items of interest from the included reports. For example, first author’s name, year of publication, period of patient recruitment, number of patients, treatment dosage, age, sex, study design, risk group, a component of RCC, oncologic outcomes, and AE outcomes. Additionally, the hazard ratios (HRs) and 95% confidence intervals (CIs) associated with PFS and OS, objective response rate, and AE rate were retrieved. Cox models were used to derive HRs.
Risk of bias assessment
The Cochrane Collaboration tool was used to assess the risk of bias (RoB) among randomized controlled trials (RCTs). It covers six domains of bias: selection, performance, detection, attrition, reporting, and other sources of bias. All disagreements were resolved by the coauthors.
PFS is defined as the time from randomization until tumor progression or death whereas OS is the percentage of patients who achieved either complete or partial response based on investigator assessment. PFS and OS were analyzed by network meta-analysis using Bayesian framework based on both fixed-effect and random-effect models; relative treatment effects were represented as HRs and 95% credibility intervals (CrI).
Contrast-based (CB) models were also used to assess PFS and OS. Subgroup analyses were performed for patients with intermediate/poor-risk disease and favorable-risk disease as defined by the Memorial Sloan Kettering Cancer Center (MSKCC) or International mRCC Database Consortium risk categorization.
Arm-based analyses were performed to estimate ORs of objective response and AEs. The relative ranking of the different treatments for each outcome was estimated using a p-value. The connectivity of the treatment networks in terms of each outcome was illustrated using network plots. For all statistical tests, significance was set at P <0.05.
Study selection and patient characteristics
Of the 4116 records retrieved from electronic searching, 3667 were unique and independent. A total of 3611 were excluded for not matching the title/abstract, and a full-text screening was done for 56 articles. 6 articles comprising 5297 mRCC patients for the systematic review and network meta-analysis were identified. All reports spanned 6 years (between 2013 and 219) and included 2568 patients (male: 1912; age: 61 – 62 years) treated with sunitinib and 2639 patients (male: 1895; age: 60-62 years) treated with other systemic drugs.
A network meta-analysis of seven different chemotherapy drugs was conducted for the primary outcome of PFS, OS, and AEs.
Progression‑free survival (PFS)
- Compared with sunitinib, avelumab plus axitinib and pembrolizumab plus axitinib showed significantly improved PFS (HR 0.85, 95% CrI 0.74–0.98 and HR 0.86, 95% CrI 0.76–0.97, respectively).
- Avelumab plus axitinib had the maximal PFS. P score = 0.8255 for both fixed and random effects.
- Pembrolizumab plus axitinib was deemed as the preferred treatment choice. P score = 0.8022 for both fixed and random effects.
Overall survival (OS)
- Compared with sunitinib, nivolumab plus ipilimumab, and pembrolizumab plus axitinib showed significantly improved OS (HR 0.86, 95% CrI 0.75–0.99 and HR 0.85, 95% CrI 0.73–0.98, respectively).
- Pembrolizumab plus axitinib had the maximal OS. P score = 0.8052 for both fixed and random effects.
- Nivolumab plus ipilimumab was deemed as the preferred treatment choice. P score = 0.7625 for both fixed and random effects.
Adverse events (AEs)
Rates of grade 3 ≧ AEs were evaluated as a measure of the toxicity of treatment. The network meta-analysis of six different chemotherapy drugs showed that,
- Compared with sunitinib, nivolumab plus ipilimumab (OR 0.50, 95% CrI 0.39–0.64) had lower levels of toxicity.
- Nivolumab plus ipilimumab was found to have the lowest rate of serious AEs. P score = 0.9999 for both fixed and random effects.
Objective response (OR)
As per the network meta-analysis of six chemotherapeutic agents,
- Compared with sunitinib, avelumab plus axitinib and nivolumab plus ipilimumab and pazopanib, and pembrolizumab plus axitinib showed significantly higher objective response rates (ORRs).
- Avelumab plus axitinib had the highest objective response rate (P score = 0.9855), followed by pembrolizumab plus axitinib (P score = 0.8132).
Complete response (CR)
The outcome of CR rates showed that,
- Compared with sunitinib, atezolizumab plus bevacizumab and nivolumab plus ipilimumab, and pembrolizumab plus axitinib had higher CR rates.
- Nivolumab plus ipilimumab had the highest CR rate (P score = 0.9742), followed by pembrolizumab plus axitinib (P score = 0.6998).
- In mRCC patients with intermediate/poor-risk, pembrolizumab plus axitinib had provided the maximal OS (P score = 0.8220), followed by nivolumab plus ipilimumab (P score = 0.7677).
- Bayesian analysis and analysis of the treatment ranking showed that avelumab plus axitinib had provided the maximal PFS (P score = 0.7582), followed by pembrolizumab plus axitinib (P score = 0.7293).
- In mRCC patients with favorable risk, IMA901 plus sunitinib had provided the maximal OS (P score = 0.6136).
- Based on Bayesian analysis and analysis of the treatment ranking, avelumab plus axitinib had given the maximal PFS (P score = 0.8480).
This updated analysis aimed to assess the first-line therapy for mRCC and to analyze and compare the efficacy and safety of all major systemic therapies. Findings of this network meta-analysis might help choose potential systemic drugs for advanced or metastatic RCC treatment.
In terms of survival, pembrolizumab plus axitinib was most likely to be the best treatment regimen. Avelumab plus axitinib and nivolumab plus ipilimumab were the second-best options in terms of survival, and nivolumab plus ipilimumab seemed to be the best tolerated one of all the seven systemic agents tested.
The immune-checkpoint inhibitors (ICI) based combination treatments (nivolumab plus ipilimumab, pembrolizumab plus axitinib, and avelumab plus axitinib) were seemed to be with fewer or similar high-grade AEs than sunitinib. As the previous network meta-analyses did not analyze heterogeneous populations, this study focused only on phase III studies with sunitinib as the control arm or included the most recently published data (e.g., KEYNOTE-426 trial).
In terms of OS and PFS, pembrolizumab plus axitinib, a combination of an anti-programmed death 1 (PD-1) monoclonal antibody and VEGF receptor (VEGFR) TKI, seemed to be the best therapeutic option. Studies on checkpoint inhibitors of renal cell carcinoma reported that blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-1 could eradicate tumors through reactivation and enhancement of T-cell response. Some studies reported the role of VEGF inhibition in suppressing angiogenesis and increasing the recruitment of tumor infiltration of T cells. Thus, the finding that ICI – VEGF axis inhibitors’ combo could play a vital role in mRCC treatment led to numerous clinical trials to test such combinations. This analysis showed that pembrolizumab plus axitinib resulted in high-grade AEs to those with sunitinib; this may be because axitinib is a selective inhibitor of VEGFR, while sunitinib and pazopanib have a wider range of targets.
Nivolumab plus ipilimumab, a dual checkpoint inhibitor, has a selective affinity for immune cells that express PD-1 and CTLA-4 molecules. This network meta-analysis showed that this combination was superior to sunitinib, both in terms of PFS/OS and its safety profile. Meaning, nivolumab plus ipilimumab provides the most favorable treatment efficacy (of course, next to pembrolizumab plus axitinib)
Limitations of this study
- The main limitation lies in the fact that it lacks a head-to-head treatment comparison, which demands more direct well-curated comparative trials.
- Second, the reporting quality of the trials reviewed. There were several types of bias, which might affect the validity of the findings.
- Third, different patient characteristics between the studies. Moreover, the OS benefits of metastatic renal cell carcinoma treatment were not tested in the trials that assessed PFS as the primary outcome. Prognostic risk categories and PD-L1 status may also have influenced the treatment benefit.
- Fourth, the doses and administration methods in the studies included may differ greatly from the real-world clinical data. Meaning, doses, and method of administration might have influenced efficacy and treatment. Most importantly, while individual dose adjustment of sunitinib has been shown to improve efficacy and treatment tolerability, the studies included in this network meta-analysis used the standard dose regimen only.
- Fifth, some of the treatments such as sunitinib plus IMA901 remain of only relative interest.
Finally, differences in the systemic therapies in the trials evaluated have influenced the OS results. Immature OS data was another concern.
This systematic review and network meta-analysis suggested that: pembrolizumab plus axitinib might be the optimum treatment option for metastatic renal cell carcinoma, providing maximum PFS and OS benefits. Nivolumab plus ipilimumab was most likely to be the best option considering the lower rates of AEs and better efficacy–tolerability equilibrium. These findings may guide selecting optimal therapy for patients with mRCC.
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