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Review
. 2022 Jun 28:14:17588359221108685.
doi: 10.1177/17588359221108685. eCollection 2022.

Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review

Aly-Khan A Lalani  1 , Daniel Y C Heng  2 , Naveen S Basappa  3 , Lori Wood  4 , Nayyer Iqbal  5 , Deanna McLeod  6 , Denis Soulières  7 , Christian Kollmannsberger  8
Affiliations
Review

Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review

Aly-Khan A Lalani et al. Ther Adv Med Oncol. .

Abstract

Background: Renal cell carcinoma (RCC) is a common malignancy with approximately 30% of cases diagnosed at the advanced or metastatic stage. While single-agent vascular endothelial growth factor-targeted therapy has been a mainstay of treatment, data from multiple phase III trials assessing first-line immune checkpoint inhibitor (ICI) combinations have demonstrated a significant survival benefit.

Methods: A systematic search of the published and presented literature was performed to identify phase III trials assessing ICI combination regimens in RCC using search terms 'immune checkpoint inhibitors' AND 'renal cell carcinoma,' AND 'advanced'.

Results: Six phase III trials showed significant benefits for ICI combinations compared with sunitinib. Nivolumab plus ipilimumab significantly improved overall survival [OS; median, 47.0 versus 26.6 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) = 0.58-0.81, p < 0.0001) and progression-free survival (PFS; median 11.6 versus 8.3 months, HR = 0.73, 95% CI = 0.61-0.87, p = 0.0004) in International Metastatic renal cell carcinoma Database Consortium intermediate and poor-risk patients. OS was also significantly improved for ICI plus tyrosine kinase inhibitor combinations regardless of risk, including pembrolizumab plus either axitinib (HR = 0.73, 95% CI = 0.60-0.88, p < 0.001) or lenvatinib (HR = 0.66, 95% CI = 0.49-0.88, p = 0.005) and nivolumab plus cabozantinib (HR = 0.66, 95% CI = 0.50-0.87, p = 0.003). No new safety signals were identified.

Conclusions: Phase III first-line trials of ICI combinations showed survival benefits compared with a control arm of sunitinib. Global access to these combinations should be made available to patients with advanced RCC.

Keywords: advanced disease; combination therapy; immune checkpoint inhibitors; metastatic or locally targeted therapy; renal carcinoma; tyrosine kinase inhibitors.

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Figures

Figure 1.
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram. aPrimary or associated reports of eligible studies that were not identified through database search. ASCO, American Society of Clinical Oncology; ASCO-GU, American Society of Clinical Oncology Genitourinary Cancers Symposium; ESMO, European Society for Medical Oncology.
Figure 2.
Figure 2.
Select TRAE rates in phase III trials of ICI combinations. (a) TKI combination trials (ICI + TKI). (b) Average ICI + TKI and ICI + ICI TRAE rates. ICI, immune checkpoint inhibitor; Nivo + Cabo, nivolumab plus cabozantinib; Nivo + Ipi, nivolumab plus ipilimumab; Pembro + Axi, pembrolizumab plus axitinib; Pembro + Lenva, pembrolizumab plus lenvatinib; PPE, palmar-plantar erythrodysesthesia; TKI, tyrosine kinase inhibitor; TRAE, treatment-related adverse event.
Figure 3.
Figure 3.
OS in select subgroups. (a) OS in IMDC risk subgroups. (b) OS in sarcomatoid subgroups. Avel + Axi, avelumab plus axitinib; HR, hazard ratio; IMDC, International Metastatic RCC Database Consortium; Nivo + Cabo, nivolumab plus cabozantinib; Nivo + Ipi, nivolumab plus ipilimumab; OS, overall survival; Pembro + Axi, pembrolizumab plus axitinib; Pembro + Lenva, pembrolizumab plus lenvatinib; RCC, renal cell carcinoma
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