Table 4.
Pre-specified analysis of the VELOUR trial.
| Analysis | Objectives | Variables | Results | Reference |
|---|---|---|---|---|
| Pre-specified subgroup analysis | Assessment of treatment effect in specific subgroups | Demographic characteristics: | No significant treatment interaction between FOLFIRI-aflibercept vs FOLFIRI-placebo and factors for both OS and PFS | (107) |
| Age <65/≥65 years | Treatment effect favored aflibercept over control (HR: <1.0) for OS and PFS in all subgroups | |||
| Male/female | ||||
| Caucasian-white/other | ||||
| Western Europe/Eastern Europe/North America/South America/Other countries | ||||
| Baseline characteristics: | Consistent treatment effect in favor of the aflibercept for OS and PFS for all subgroups | |||
| Prior/no prior hypertension | Significantly greater aflibercept benefit in case of liver-only metastases vs no liver metastases or liver and other sites metastases: p=0.090 for OS; p=0.008 for PFS | |||
| Number of organs with metastasis ≤1/>1 | ||||
| No liver metastasis or liver and other | ||||
| metastasis/liver metastasis only | ||||
| Colon-rectosigmoid-other/rectum | ||||
| Stratification factors: | A difference in favor of aflibercept over placebo in OS and PFS in each stratification subgroup; no significant interaction at the two-sided 10% level between treatment and stratification levels → no evidence of heterogeneity in treatment effect | |||
| ECOG PS | ECOG PS 0 vs 1 vs 2: p=0.7231 for OS; p=0.6954 for PFS | |||
| Prior bevacizumab | Prior bevacizumab (30.4% of ITT) vs no prior bevacizumab: p=0.5668 for OS; p=0.1958 for PFS | |||
| FOLFIRI-aflibercept vs control: | ||||
| mOS | ||||
| Prior bevacizumab: 12.5 m vs 11.7 m | ||||
| No prior bevacizumab: 13.9 m vs 12.4 m | ||||
| mPFS | ||||
| Prior bevacizumab: 6.7 m vs 3.9 m | ||||
| No prior bevacizumab: 6.9 m vs 5.4 m | ||||
| No evidence of greater toxicity in pts previously treated with bevacizumab | ||||
| Pre-specified post hoc multivariate analysis of the ITT population | - Identification of prognostic factors associated with improved OS with FOLFIRI-aflibercept | Better efficacy subgroup: | Better efficacy subgroup FOLFIRI-aflibercept vs FOLFIRI-placebo: | (108) |
| -Primary endpoint: OS in the better and poorer efficacy patient subgroup identified in the multivariate analysis | ECOG PS 0 with any number of metastatic site or ECOG PS 1 with <2 metastatic sites | Interaction with treatment: p = 0.0147 → differential OS effect of aflibercept compared with placebo | ||
| Poorer efficacy subgroup: | mOS 16.2 m (95% CI: 14.5–18.1) vs 13.1 m (95% CI: 11.7–14.2) (absolute difference in mOS: 3.1 m; aHR: 0.73; 95%CI: 0.61–0.86) | |||
| ECOG PS 1 with ≥2 metastatic sites or ECOG PS 2 with any number of metastatic sites or ARR (excluded from the analysis) | Continuous increase over time of the entity of survival differences between the two treatment arms: absolute OS rate difference 5% at 6 m →15% at 30 m | |||
| mPFS 7.2 m (95%CI: 6.8–8.2) vs 4.8 m (95%CI: 4.2–5.4)(absolute difference: 2.4 m) | ||||
| Absolute difference in 6-month PFS rates: 25% | ||||
| ORR 23.7% (95% CI: 19.3–28.2) vs 11% (95% CI: 7.8–14.3) | ||||
| Poorer efficacy subgroup FOLFIRI-aflibercept vs FOLFIRI-placebo: | ||||
| No OS, PFS and ORR improvement with FOLFIRI-aflibercept vs FOLFIRI-placebo | ||||
| mOS | ||||
| 9.6 m (95% CI: 8.6–11.5) vs | ||||
| 10.4 m (95% CI: 9.5–12.1) | ||||
| (aHR: 0.97; 95% CI: 0.78–1.21) | ||||
| Aged-based analysis | Assessment of benefit and safety of aflibercept in association with FOLFIRI according to age | Age ≥65 y | No treatment interaction between treatment group and age was reported for OS (p=0.683) or PFS (p=0.930) | (109) |
| (36%; 84% aged 65–74 y, 97% ECOG PS 0–1) | ≥65 y FOLFIRI-aflibercept vs FOLFIRI-placebo: | |||
| Age <65 y (64%) | mOS 12.6 m vs 11.3 m | |||
| (HR: 0.85; 95.34%CI: 0.68–1.07), absolute difference: 1.3 m | ||||
| mPFS 6.6 m vs 4.4 m | ||||
| (HR: 0.75; 99.99% CI: 0.48–1.17), absolute difference: 2.2 m | ||||
| <65 y FOLFIRI-aflibercept vs FOLFIRI-placebo: | ||||
| mOS 14.5 m vs 12.5 m | ||||
| (HR: 0.80; 95.34%CI: 0.67–0.95) | ||||
| mPFS 6.9 m vs 4.9 m | ||||
| (HR: 0.77; 99.99%CI: 0.55–1.08), absolute difference 2 m |
AEs, adverse events; aHR, adjusted HR; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; FOLFIRI, fluorouracil, levofolinic acid, irinotecan; G, grade; HR, hazard ratio, ITT, intent to treat; m, months; mOS, median overall survival; mPFS, median progression free survival; ORR, objective response rate; OS, overall survival; PFS, progression free survival; y, years.
The underlined text and the bold values refer to some points that we would like to emphasize, e.g. endpoints, treatment arms.