Efficacy and Safety of First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis

Abstract

Context: Considerable advances have been made in the first-line treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy-based combinations including immunotherapy-tyrosine kinase inhibitors (IO-TKIs) and dual immunotherapy (IO-IO) favored. A lack of head-to-head clinical trials comparing these treatments means that there is uncertainty regarding their use in clinical practice.

Objective: To compare and rank the efficacy and safety of first-line systemic treatments for mRCC with a focus on IO-based combinations.

Evidence acquisition: MEDLINE (Ovid), EMBASE, Cochrane Library, Web of Science, and abstracts of recent major scientific meetings were searched to identify the most up-to-date phase 3 randomized controlled trials (RCTs) of first-line IO-based combinations for mRCC up to June 2021. A systematic review and network meta-analysis were completed using the Bayesian framework. Primary endpoints included overall survival (OS) and progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), complete response (CR), grade 3-4 treatment-related adverse events (TRAEs), treatment-related drug discontinuation (TRDD), and health-related quality of life (HRQoL). The analysis was performed for the intention-to-treat (ITT) population as well as by clinical risk group.

Evidence synthesis: A total of six phase 3 RCTs were included involving a total of 5121 patients. Nivolumab plus cabozantinib (NIVO-CABO) had the highest likelihood of an OS benefit in the ITT population (surface under the cumulative ranking curve 82%). Avelumab plus axitinib (AVEL-AXI) had the highest likelihood of an OS benefit for patients with favorable risk (65%). Pembrolizumab plus AXI (PEMBRO-AXI) had the highest likelihood of an OS benefit for patients with intermediate risk (78%). PEMBRO plus lenvatinib (PEMBRO-LENV) had the highest likelihood of an OS benefit for patients with poor risk (89%). PEMBRO-LENV was associated with a superior PFS benefit across all risk groups (89-98%). Maximal ORR was achieved with PEMBRO-LENV (97%). The highest likelihood for CR was attained with NIVO plus ipilimumab (NIVO-IPI; 85%) and PEMBRO-LENV (83%). The highest grade 3-4 TRAE rate occurred with PEMBRO-LENV (95%) and NIVO-CABO (83%), but the latter was associated with the lowest TRDD rate (2%). By contrast, NIVO-IPI had the lowest grade 3-4 TRAE rate (6%) and the highest likelihood of TRDD (100%). HRQoL consistently favored NIVO-CABO (66-75%), PEMBRO-LENV (44-85%), and NIVO-IPI (65-93%) in comparison to the other treatments.

Conclusions: IO-TKI drug combinations are associated with consistent improvements in clinically relevant outcomes for all mRCC risk groups. This benefit may be at the cost of higher TRAE rates; however, lower TRDD rates suggest a manageable side-effect profile. Longer follow-up is required to determine if the benefits of IO-TKIs will be sustained and if they should be favored in the first-line treatment of mRCC.

Patient summary: Combination treatments based on immunotherapy agents continue to show meaningful benefits in the first-line treatment of metastatic kidney cancer. Our review and network meta-analysis shows that immunotherapy combined with another class of agents called tyrosine kinase inhibitors is promising. However, longer follow-up is needed for this treatment strategy to clarify if the benefits are long-lasting.

Keywords: Immunotherapy; Network meta-analysis; Renal cell carcinoma; Tyrosine kinase inhibitors.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for the literature search and study selection. RCC = renal cell carcinoma.

Fig. 2

OS results for the ITT population and by clinical risk group. (A) HRs for OS for the ITT population. Treatment strategies separate the table diagonally to present pairwise comparisons of all systemic therapies. HRs in the upper triangle portion of the table are for comparison of the treatment below against the treatment to the left. In the lower triangle, comparisons are made between the treatment above and the treatment to the right. Values in bold font are statistically significant. (B) Rankogram for OS in the ITT population. The x-axis indicates the probability of the preferential treatment being ranked in nth position. (C) SUCRA plot for OS for the ITT population, representing the overall ranking probability for each treatment. (D) SUCRA plots for OS by clinical risk group. ITT = intention to treat; OS = overall survival; HR = hazard ratio; SUCRA = surface under the cumulative ranking curve; Bev = bevacizumab; Nivo = nivolumab; Ipi = ipilimumab; Axi = axitinib; Pemb/Pembro = pembrolizumab; Lenv = lenvatinib.

Fig. 3

PFS results for the ITT population and by clinical risk group. (A) HRs for PFS for the ITT population. Treatment strategies separate the table diagonally to present pairwise comparisons of all systemic therapies. HRs in the upper triangle of the table are for comparison of the treatment below against the treatment to the left. In the lower triangle, comparisons are made between the treatment above and the treatment to the right. Values in bold font are statistically significant. (B) Rankogram for PFS in the ITT population. The x-axis indicates the probability of the preferential treatment being ranked in nth position. (C) SUCRA plot for PFS for the ITT population, representing the overall ranking probability for each treatment. (D) SUCRA plots for PFS by clinical risk group. ITT = intention to treat; PFS = progression free survival; HR = hazard ratio; SUCRA = surface under the cumulative ranking curve; Bev = bevacizumab; Nivo = nivolumab; Ipi = ipilimumab; Axi = axitinib; Pemb/Pembro = pembrolizumab; Lenv = lenvatinib.

Fig. 4

SUCRA plots of response rates for the ITT population and by clinical risk group, representing the overall preferential ranking probability for each treatment. (A) ORR for the ITT population. (B) ORR by clinical risk group. (C) CR by ITT. ITT = intention to treat; ORR = objective response rate; CR = complete response; HR = hazard ratio; SUCRA = surface under the cumulative ranking curve; Bev = bevacizumab; Nivo = nivolumab; Ipi = ipilimumab; Axi = axitinib; Pemb/Pembro = pembrolizumab; Lenv = lenvatinib.

Fig. 5

SUCRA plots of safety and health-related quality of life for the intention-to-treat population. (A) Treatment-related grade 3–4 adverse events and (B) treatment-related drug discontinuation, representing the overall ranking probability of an occurrence with the treatment strategy. Health-related quality of life, as measured with patient-reported outcome (PRO) questionnaires (C) EuroQol 5-Dimension (EQ-5D) (C) and (D) Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI), representing the preferential ranking probability for each treatment. SUCRA = surface under the cumulative ranking curve; Bev = bevacizumab; Nivo = nivolumab; Ipi = ipilimumab; Axi = axitinib; Pemb/Pembro = pembrolizumab; Lenv = lenvatinib.