Table 2.
Analysis of the trial results.
| Generic name | Comparator | Prognostic risk group, MSKCC favourable %, both values presented if >1% difference | Prior nephrectomy, both values presented if >1% difference | mPFS (mo) | ORR (%) | CR (%) | Durable responses reported | Survival benefit shown, mOS (mo) | Primary endpoints (not met) | Gr 3–4 AEs | Trial number, references |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Targeted therapies | |||||||||||
| Sorafenib | placebo | 52% vs 50% | 93% vs 95% | 5.5 vs 2.8 | 10% vs 2% | 0.2% vs 0 | No | No 17.8 vs 15.2 (p = 0.15) |
(OS) | 34% vs 24% |
NCT00073307 [2], [3], [4] |
| Sunitinib | Interferon-alpha | 38% vs 34% | 91% vs 89% | 11.0 vs 5 | 31% vs 6% | 0 vs 0 | No | No 28.6 vs 23.7 (p = 0.051)a |
PFS a | 46% vs 26% |
NCT00083889 [5], [6] |
| Temsirolimus | Interferon-alpha + temsirolimus | 0% (poor risk 76% interferon and combination, 69% temsirolimus) |
67% | 3.1 interferon, 5.5 temsirolimus, 4.7 combination | 4.8% interferon, 8.6% temsirolimus, 8.1% combination | NA | No | Yes b 7.3 interferon, 10.9 temsirolimus, (8.4 combination) |
(OS) | 67% temsirolimus, 78% interferon, 87% combination |
NCT00065468 [39] |
| Everolimus | Placebo (2nd line) | 52% | 96% | 4.9 vs 1.9 | 1.8% vs 0% | 0 vs 0 | No | No 14.8 vs 14.4 |
PFS | % not reported |
NCT00410124 [33], [34] |
| Pazopanib hydrochloride | Placebo | 39% | 89% | 9.2 vs 4.2 | 30% vs 3% | <1% vs 0 | No | No 22.9 vs 20.5 |
PFS | % not reported |
NCT00334282 [35], [36] |
| Sunitinib | Not addressed | 82% vs 84% | 8.4 vs 9.5 (noninferiority trial) | 31% vs 25% (p = 0.03) | 0.2% vs 0.5% | No | No 28.4 vs 29.3 |
PFS | % not reported |
NCT00720941 [26] |
|
| Axitinib | Sorafenib (2nd line) | 28% | 91% total but not specified for different arms | 6.8 vs 4.7 (investigator assessed 8.3 vs 5.7) | 19% vs 9% | 0 vs 0 | No | No 20.1 vs 19.2 |
PFS | More with axitinib, % not available |
NCT00678392 [62], [63], [64], [65] |
| Sorafenib (1 st line) | ?, ECOG 0–1 | 85% vs 90% | 10.1 vs 6.5 | 32% vs 15% | Missing | No | No 21.7 vs 23.3 |
(PFS) | 34% vs 25% (serious AE) |
NCT00920816 [37] |
|
| Cabozantinib-S-malate | Sunitinib (phase II) | 0% | 72% vs 77% | 8.2 vs 5.6 8.6 vs 5.3 (IRC) |
33% vs 12% 20% vs 9% (IRC) |
1% vs 0 0 vs 0 (IRC) |
No | No 26.6 vs 21.2 c (HR 0.8) |
PFS (OS) | 67% vs 68% |
NCT01835158 [66], [67] |
| Everolimus (2nd line) | 45%, (IMDC favourable 20%) | 86% | 7.4 vs 3.8 | 17% vs 3% | 0 vs 0 | No | Yes d 21.4 vs 16.5 |
PFS | 68% vs 60% |
NCT01865747 [31], [32] |
|
| Lenvatinib mesylate (Lenvima) + everolimus | Everolimus (2nd line) | 24% | 86% vs 96% | 14.6 vs 5.5 mo | 43% vs 6% | 2% (one patient) | No | No (post hoc analysis suggested) | PFS | 71% vs 50% |
NCT01136733 [68] |
| Immunotherapies | |||||||||||
| Interferon-alpha | Several RCTs | – | – | 25% “decrease in tumour progression risk” | 12.5% vs 1.5% (pooled results form 4 trials) | 1–9% | Yes 4.1% vs 0% alive at 5 yr |
Yes 3.8 mo weighed average (Cochrane review) |
Several RCTs addressed OS | 26–78% (vs comparator 46–87%) |
– [1], [15], [16] |
| High-dose interleukin-2, aldesleukin, proleukin | Phase II, 255 patients | – | – | – | 15% (14–48% in contemporary series) | 7% (up to 22% in contemporary series) | Yes (response duration 3–131 mo, median duration of CR > 80 mo) | Yes 10–20% (30–50% in contemporary series) alive 5–10 yr after treatment | – | Short-term intensive treatment, Gr 3 100%, mortality 4% (<1% in contemporary series) | – [17], [18], [19], [20] |
| Nivolumab | Everolimus (2nd line) |
36% | 89% vs 87% | 4.2 vs 4.5 | 25% vs 5% | 1% vs 0.5% | Yes (26/94 of responses on-going at 60 mo) |
Yes 25.8 vs 19 (26% vs 18% alive at 60 mo) |
OS | 19% vs 37% |
NCT01668784, JCO.2020.38.6_suppl.617 [43] |
| Ipilimumab + nivolumab | Sunitinib | IMDC 23% | 80% vs 76% (82% vs 80% ITT) |
11.6 vs 8.4 (9.7 vs 9.7 ITT) |
42% vs 26% (39% vs 33% ITT) |
10% vs 1% (11% vs 2% ITT) |
Yes (88% on-going CRs; 59% on-going ORs) | Yes NR vs 26.6 (NR vs 37.9 ITT) |
OS, ORR, PFS | 46% vs 63% |
NCT02231749 [45], [46], [48], [53] |
| Combination of targeted therapy and immunotherapy | |||||||||||
| Bevacizumab + interferon-alpha | Interferon-alpha | 29% | 100% | 10.2 vs 5.4 | 31% vs 13% | – | – | No | (OS) | – | centerwatch.com, BO17705E [69], [70] |
| 26% | 85% | 8.5 vs 5.2 | 25.5% vs 13.1% | – | – | No 18.3 vs 17.4 |
(OS) | 80% vs 63% |
NCT00072046 [71], [72] |
||
| Pembrolizumab + axitinib | Sunitinib | IMDC 31% | 83% | 15.1 vs 11.1 | 59% vs 36% | 5.8% vs 1.9% | – | Yes 90% vs 78% alive, HR 0.53 |
OS, PFS | 75.8% vs 70.6% |
NCT02853331 [73] |
| Avelumab + axitinib | Sunitinib | IMDC 20% PD-L1 positive (22% all) | 86% (80% all) | 13.8 vs 7.2 (13.8 vs 8.4 all) | 55.2% vs 25.5% (51% vs 26% all) | 4.4% vs 2.1% (3.4% vs 1.8% all) | – | No “OS data were immature”, HR 0.80 |
PFS (OS), among PD-L1–positive tumours | 71.2% vs 71.5% |
NCT02684006 [59], [60] |
AE = adverse event; CR = complete response; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; IMDC = International Metastatic RCC Database Consortium; IRC = independent review committee; ITT = intention to treat; mOS = median OS; mPFS = median PFS; MSKCC = Memorial Sloan Kettering Cancer Center; NA = not applicable; NR = not reported; OR = overall response; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; RCT = randomised controlled trial.
Imbalance in randomisation; sunitinib patients had better prognostic MSKCC (38% vs 32%). When considering favourable-risk patients only, more patients died in the sunitinib group than in the interferon-alpha group at 2 yr (72% vs 76%) [6].
Imbalance in randomisation; patients in the temsirolimus arm were younger, had a better performance score, and had better prognostic MSKCC risk classification.
Graphs overlapping for 6 mo before; censoring affects mOS.
Only 18-mo unplanned survival analyses, representing 78% of the 408 deaths planned for the prespecified final analysis (these data have not been published).