Targeted drug treatment for kidney cancer which has spread

Review question

How effective is targeted drug treatment for patients with kidney cancer which has spread compared with other targeted drug treatments?

Background

Kidney cancer which has spread was treated over the last decade with a group of drugs called targeted therapy which act specifically on molecular pathways. However, the last few years have seen the emergence of a promising, newer group of drugs called immune checkpoint inhibitors which exploit the immune system (hence called immunotherapy). Some of these drugs are currently used in combinations. This review assesses how effective targeted therapies are in comparison with different targeted therapies, immune checkpoint inhibitors or different combinations of these drugs.

Study characteristics

We included only studies in which chance determined whether people got a targeted drug or other targeted drug, and which were reported in medical literature up to 18 June 2020. Most of the studies examined the effects on kidney cancer growth (called progression), survival (life expectancy) and serious unwanted effects.

Key results

We found 18 studies that answered our review question. Participants included in these trials had metastatic (cancer that has spread to other parts of the body) or advanced cancer that could not be removed by surgery. We reported up-to-date comparisons that are most important to doctors and participants.

1. Pazopanib versus sunitinib (targeted therapy versus targeted therapy)

Pazopanib may make little to no difference in progression, survival, and serious unwanted effects compared to sunitinib.

2. Sunitinib versus avelumab and axitinib (targeted agent versus immunotherapy + targeted agent)

Sunitinib probably results in more progression but may make little to no difference on death and serious unwanted effects compared to avelumab and axitinib.

3. Sunitinib versus pembrolizumab and axitinib (targeted agent versus immunotherapy + targeted agent)

Sunitinib probably results in more progression and death but may slightly reduce serious unwanted effects compared to pembrolizumab and axitinib.

4. Sunitinib versus nivolumab and ipilimumab (targeted therapy versus combinations of immunotherapy)

Sunitinib may result in more progression and serious unwanted effects compared to nivolumab and ipilimumab. Sunitinib results in more deaths compared to combinations.

Certainty of the evidence

The certainty of the evidence for most outcomes was low to high, meaning that there is some uncertainty regarding the findings. Nevertheless, there is sufficient data for us to make definitive conclusions regarding how these drugs should be used in the management of patients with kidney cancer which has spread.

Authors' conclusions: 

Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Read the full abstract...
Background: 

Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.

Objectives: 

To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.

Search strategy: 

We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.

Selection criteria: 

We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.

Data collection and analysis: 

Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.

Main results: 

We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons.

1. Pazopanib versus sunitinib

Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants.

2. Sunitinib versus avelumab and axitinib

Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants. 

3. Sunitinib versus pembrolizumab and axitinib

Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants. 

4. Sunitinib versus nivolumab and ipilimumab

Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants.

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