Summary of findings 1. Summary of findings table for all risk groups combined.
| First‐line therapy for adults with advanced renal cell carcinoma | |||||||
|
Population: people with a confirmed diagnosis of advanced renal cell carcinoma (combined risk groups) without previous systemic anticancer therapy Setting: outpatient Interventions: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), pazopanib (PAZ), cabozantinib (CAB) Comparator: sunitinib (SUN) | |||||||
| Effect estimates (hazard ratio (HR) or risk ratio (RR) < 1 favours intervention) and 95% confidence intervals (CI). Main comparator is SUN1 | |||||||
| Outcomes |
№ of participants (trials) in the network |
Intervention |
Relative effect (95% CI) of the network meta‐analyses |
Anticipated absolute effects (95% CI) |
Certainty of the evidence (GRADE) |
Interpretation of findings | |
| Risk with SUN1,2,3 |
Risk with intervention4 |
||||||
|
Overall survival (OS) ‐ Network (subnet 1) included 19 pairwise comparisons ‐ Median follow‐up across trials5: 32.2 months ‐ Median OS with SUN across trials2 in this network: 28.7 months |
9705 (17 RCTs) |
PEM + AXI | HR 0.73 (0.50 to 1.07)6 |
28.7 months | 39.3 months (26.8 to 57.4) |
⊕⊕⊕⊝ moderatea |
PEM+AXI probably improve OS, when compared to SUN. |
| AVE + AXI | n.a.7 | ‐ | ‐ | ‐ | |||
| NIV + CAB | n.a.7 | ‐ | ‐ | ‐ | |||
| LEN + PEM | HR 0.66 (0.42 to 1.03)6 |
43.5 months (27.9 to 68.3) |
⊕⊕⊝⊝ lowa, b |
LEN+PEM may improve OS, when compared to SUN. | |||
| NIV+IPI | HR 0.69 (0.69 to 1.00)6 | 41.6 months (28.7 to 41.6) | ⊕⊕⊕⊝ moderatec |
NIV + IPI probably improve OS, when compared to SUN. | |||
| CAB | HR 0.84 (0.43 to 1.64)6 |
34.2 months (17.5 to 66.7) |
⊕⊝⊝⊝ very lowd, e |
We are uncertain whether CAB improves OS, when compared to SUN. | |||
| PAZ | HR 0.91 (0.64 to 1.32)6 |
31.5 months (21.7 to 44.8) |
⊕⊕⊕⊝ moderatef |
There is probably little or no difference in OS between PAZ and SUN. | |||
|
Quality of life (QoL) We reported this outcome narratively in this review. Here, long‐term results (i.e., at the end of treatment) are presented. In the comparison PAZ versus SUN, QoL was measured using FACIT‐F (score range 0‐52; higher scores represent better QoL). |
‐ | PEM + AXI | n.a.7 | ‐ | ‐ | ‐ | ‐ |
| AVE + AXI | n.a.7 | ‐ | ‐ | ‐ | ‐ | ||
| NIV + CAB | n.a.7 | ‐ | ‐ | ‐ | ‐ | ||
| LEN + PEM | n.a.7 | ‐ | ‐ | ‐ | ‐ | ||
| NIV+IPI | n.a.7 | ‐ | ‐ | ‐ | ‐ | ||
| CAB | n.a.7 | ‐ | ‐ | ‐ | ‐ | ||
| PAZ | ‐ | The mean post‐score of the control group was 29.5. | One RCT (N = 2) reported that the mean post‐score of the intervention group was 9.00 points higher (9.86 lower to 27.86 higher) than that of the control group. | ⊕⊝⊝⊝ very low g, h |
We are uncertain whether PAZ compared to SUN improves quality of life. | ||
|
Serious adverse events (SAEs) ‐ Network included 31 pairwise comparisons ‐ Mean risk with SUN across trials3 included in this network: 40.7% |
10,709 (22 RCTs) |
PEM + AXI | RR 1.29 (0.90 to 1.85)6 |
40.7% | 52.5% (36.6 to 75.3) |
⊕⊕⊕⊝ moderatef |
PEM+AXI probably increase slightly the risk for SAEs, when compared to SUN. |
| AVE + AXI | n.a.7 | ‐ | ‐ | ‐ | |||
| NIV + CAB | n.a.7 | ‐ | ‐ | ‐ | |||
| LEN + PEM | RR 1.52 (1.06 to 2.19) |
61.9% (43.1 to 89.1) |
⊕⊕⊕⊝ moderateb |
LEN+PEM probably increase the risk for SAEs, when compared to SUN. | |||
| NIV+IPI | RR 1.40 (1.00 to 1.97)6 |
57% (40.7 to 80.2) |
⊕⊕⊕⊝ moderateb |
NIV+IPI probably increase the risk for SAEs, when compared to SUN. | |||
| CAB | RR 0.92 (0.60 to 1.43)6 |
37.4% (24.4 to 58.2) |
⊕⊝⊝⊝ very lowb, i |
We are uncertain whether CAB reduces or increases the risk for SAE, when compared to SUN. | |||
| PAZ | RR 0.99 (0.75 to 1.31 6 |
40.3% (30.5 to 53.3) |
⊕⊕⊕⊝ moderatef |
There is probably little or no difference in the risk for SAEs between PAZ and SUN. | |||
|
Progression‐free survival (PFS) ‐ Network (subnet 1) included 27 pairwise comparisons ‐ Median follow‐up across trials5: 9.1 months ‐ Median PFS with SUN across trials2 in this network: 7.9 months |
11,737 (25 RCTs) |
PEM + AXI | HR 0.68 (0.52 to 0.89)6 |
9.2 months | 13.5 months (10.3 to 17.7) |
⊕⊕⊕⊝ moderateb |
PEM+AXI probably improve slightly PFS, when compared to SUN. |
| AVE + AXI | n.a.7 | ‐ | ‐ | ‐ | |||
| NIV + CAB | n.a.7 | ‐ | ‐ | ‐ | |||
| LEN + PEM | HR 0.39 (0.29 to 0.53)6 |
23.6 months (17.3 to 31.7) |
⊕⊕⊕⊝ moderateb |
LEN+PEM probably improve PFS, when compared to SUN. | |||
| NIV+IPI | HR 0.89 (0.68 to 1.16)6 |
10.3 months (7.9 to 13.5) |
⊕⊕⊝⊝ lowb, f |
There may be little or no difference between NIV+IPI and SUN in improving PFS. | |||
| CAB | HR 0.54 (0.37 to 0.76)8 |
17.0 months (12.1 to 24.9) |
⊕⊕⊝⊝ lowb, d |
CAB may improve PFS, when compared to SUN. | |||
| PAZ | HR 1.05 (0.81 to 1.36)6 |
8.8 months (6.8 to 11.3) |
⊕⊕⊕⊝ moderatef |
There probably is little or no difference in PFS between PAZ and SUN. | |||
|
Adverse events (AEs) (grade 3 or 4) ‐ Network included 19 pairwise comparisons ‐ Mean risk with SUN across trials3 in this network: 70.6% |
6909 participants (13 RCTs) |
PEM + AXI | n.a.7 | 70.6% | ‐ | ‐ | ‐ |
| AVE + AXI | RR 1.00 (0.92 to 1.08)6 | 70.6% (64.9 to 76.2) |
⊕⊕⊕⊝ moderateb |
There probably is little or no difference in the risk for AEs between AVE+AXI and SUN. | |||
| NIV + CAB | RR 1.07 (0.97 to 1.17)6 |
75.5% (68.5 to 82.6) |
⊕⊕⊕⊝ moderateb |
There probably is little or no difference in the risk for AEs between NIV+CAB and SUN. | |||
| LEN + PEM | RR 1.15 (1.06 to 1.25)6 |
81.2% (74.8 to 88.2) |
⊕⊕⊕⊝ moderateb |
LEN+PEM probably increase slightly the risk for AEs (grade 3 or 4), when compared to SUN. | |||
| NIV+IPI | n.a.7 | ‐ | ‐ | ‐ | |||
| CAB | RR 1.04 (0.83 to 1.31)6 |
73.4% (58.6 to 92.5) |
⊕⊝⊝⊝ very lowb, j |
We are uncertain whether CAB reduces or increases the risk for AEs, when compared to SUN. | |||
| PAZ | RR 1.02 (0.96 to 1.09)6 |
72% (67.7 to 76.9) |
⊕⊕⊕⊝ moderateb |
There probably is little or no difference in the risk for AEs between PAZ and SUN. | |||
|
Time to initiation of first subsequent therapy This outcome was not reported as a time‐to‐event outcome. Instead, authors of the trials reported the number of participants who received subsequent anticancer therapy after discontinuation of trial treatment. |
861 (1 RCT) |
PEM + AXI | RR 0.72 (0.64 to 0.81)6 |
65%3 | 46.8% (41.6 to 52.6) |
⊕⊕⊝⊝ lowk |
PEM+AXI may reduce the risk for subsequent therapy, when compared to SUN. |
| 886 (1 RCT) |
AVE + AXI | RR 0.61 (0.52 to 0.72)6 |
51%3 | 31.1% (26.5 to 36.7) |
⊕⊕⊝⊝ lowk |
AVE+AXI may reduce the risk for subsequent therapy, when compared to SUN. | |
| 651 (1 RCT) |
NIV + CAB | RR 0.57 (0.44 to 0.75)6 |
33%3 | 18.8% (14.5 to 24.7) |
⊕⊝⊝⊝ very lowb,k |
We are uncertain whether NIV+CAB reduce the risk for subsequent therapy, when compared to SUN. | |
| 712 (1 RCT) |
LEN + PEM | RR 0.57 (0.48 to 0.68)6 |
60%3 | 34.2% (28.8 to 40.8) |
⊕⊝⊝⊝ very lowb, k |
We are uncertain whether LEN+PEM reduce the risk for subsequent therapy, when compared to SUN. | |
| 1096 (1 RCT) |
NIV+IPI | RR 0.86 (0.79 to 0.94)6 |
70% | 60.2% (55.3 to 65.8) |
⊕⊕⊝⊝ lowk |
NIV+IPI may reduce the risk for subsequent therapy, when compared to SUN. | |
| 151 (1 RCT) |
CAB | RR 0.93 (0.74 to 1.16)6 |
64% | 59.5% (47.4 to 74.2) |
⊕⊝⊝⊝ very lowb, k, j |
We are uncertain whether CAB reduces or increases the risk for subsequent therapy, when compared to SUN. | |
| ‐ | PAZ | n.a.7 | ‐ | ‐ | ‐ | ||
| CI: confidence interval; HR: hazard ratio. | |||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. | |||||||
1 Basis for the assumed risks
2 The risk of SUN for OS and PFS was obtained from the included trials in the networks, respectively, and estimated by calculating the mean of all available medians for SUN
3 Mean risk for AEs and SAEs, respectively, was estimated by dividing the total events under SUN‐therapy by the total of participants treated with SUN across all trials in the network. For TFST, the risk for SUN was calculated using the number of events / number of participants for SUN in the respective trial.
4 Methods of calculating the assumed risks in the intervention group:
‐ For OS and PFS: The median survival in the intervention group was calculated using the methods by Tierney 2007: Corresponding median survival in the intervention group (in months) = comparator group median survival time (in months) divided by the HR. Upper and lower confidence limits for the corresponding intervention risk were obtained by replacing HRs by their upper and lower confidence limits, respectively.
‐ For AEs and SAEs: The assumed risk in the intervention group was calculated with the formula available in the Cochrane Handbook. For the meta‐analytic RR and assumed comparator risk (ACR) the corresponding intervention risk is obtained per 1000: 1000 x ACR x RR. Upper and lower confidence limits for the corresponding intervention risk were obtained by replacing RRs by their upper and lower confidence limits, respectively.
5 Median follow‐up across trials in the networks for OS and PFS, respectively, was estimated by calculating the mean of all available medians
6 Only direct evidence from one trial.
7 Not applicable, comparison not available.
8 Only direct evidence from two trials.
a Downgraded by 1 level for imprecision because of a wide CI and upper CI limit suggests no difference between interventions.
b Downgraded by 1 level for study limitations because the one trial contributing all direct evidence is at high risk of bias.
c Downgraded by 1 level for imprecision because upper CI limit suggests no difference between interventions.
d downgraded by 1 level for indirectness because in one trial, 7% of the total study population received previous systemic therapy.
e Downgraded by 2 levels for imprecision because of a very wide CI that includes values that favour either of the compared treatments, and evidence stems from only one trial with 90 participants.
f Downgraded by 1 level for imprecision because of a wide CI that favours either of the compared treatments.
g Downgraded by 2 levels for study limitations due to a high risk of bias.
h Downgraded by 2 levels for imprecision because of a very wide CI that includes values that favour either of the compared treatments, and evidence stems from only one trial with four participants analysed.
i Downgraded by 2 levels for imprecision because of a very wide CI that includes values that favour either of the compared treatments, and evidence stems from only one trial with 157 participants.
j Downgraded by 2 levels for imprecision because of a wide CI that includes values that favour either of the interventions, and the evidence stems from only one trial with 157 participants.
k Downgraded by 2 levels for indirectness due to indirect measurement of outcome of interest.