COSMIC-311
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects With Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed After Prior Vascular Endothelial Growth Factor Receptor (VEGFR) -Targeted Therapy
Phase 3N = 187NCT03690388
- Population
- Patients aged 16 years or older with radioiodine-refractory differentiated thyroid cancer (papillary or follicular and variants), ECOG performance status 0 or 1, who had received lenvatinib or sorafenib and progressed during or after up to two VEGFR tyrosine kinase inhibitors
- Design
- Global, randomised (2:1), double-blind, placebo-controlled phase 3 trial of cabozantinib 60 mg daily versus matching placebo, stratified by previous lenvatinib and age. Co-primary end points: confirmed objective response rate per RECIST 1.1 in the first 100 randomised patients (OITT population) and progression-free survival in all patients (ITT), both by blinded independent radiology committee. Placebo patients could cross over to open-label cabozantinib at confirmed progression. The primary report presents the ORR analysis and a concurrent preplanned interim PFS analysis.
- Primary endpoint
- ORR, PFS
- Arms
- Cabozantinib (experimental, n = 125): Cabozantinib 60 mg orally once daily
- Placebo (control, n = 62): Matching placebo
- People
- Brose MS
PFSHR 0.22Δ ORR+15 pointsPFSHR 0.22Δ median PFS+9.1 monthsΔ ORR+11 points
Show the numbers
| Endpoint | Analysis | Cabozantinib | Placebo | Effect |
|---|---|---|---|---|
| PFSITT (187 patients: 125 cabozantinib, 62 placebo) | interimmedian follow-up 6.2 monthsBrose 2021 | — | median 1.9 months | HR 0.22P<0.0001Median PFS with cabozantinib was not reached (96% CI 5.7 to not estimable) versus 1.9 months with placebo (96% CI 1.8 to 3.6). The hazard ratio 0.22 has a 96% confidence interval of 0.13 to 0.36. Interim analysis at which the PFS end point was met. |
| ORROITT population (first 100 randomised: 67 cabozantinib, 33 placebo) | primarymedian follow-up 8.9 monthsBrose 2021 | 15% | 0% | P=0.028Ten of 67 versus 0 of 33 responded; the 99% CIs were 5.8 to 29.3 and 0 to 14.8. The result did not meet the prespecified significance level (alpha 0.01), as stated in the abstract. |
| PFSRandomised patients at the extended data cut (258: 170 cabozantinib, 88 placebo) | exploratorymedian follow-up 10.1 monthsBrose 2022 | median 11 months | median 1.9 months | HR 0.22P<.0001Exploratory analysis with an extended data cut. 96% CIs: cabozantinib 7.4 to 13.8 months, placebo 1.9 to 3.7 months, hazard ratio 0.15 to 0.32. Forty placebo patients crossed over to open-label cabozantinib. |
| ORRRandomised patients at the extended data cut; the abstract does not state the response analysis population | exploratorymedian follow-up 10.1 monthsBrose 2022 | 11% (6.9–16.9%) | 0% (0.0–4.1%) | P=.0003One complete response with cabozantinib. |
| Endpoint | Analysis | Cabozantinib | Placebo | Effect |
|---|---|---|---|---|
| PFSITT (187 patients: 125 cabozantinib, 62 placebo) | interimmedian follow-up 6.2 monthsBrose 2021 | — | median 1.9 months | HR 0.22P<0.0001Median PFS with cabozantinib was not reached (96% CI 5.7 to not estimable) versus 1.9 months with placebo (96% CI 1.8 to 3.6). The hazard ratio 0.22 has a 96% confidence interval of 0.13 to 0.36. Interim analysis at which the PFS end point was met. |
| ORROITT population (first 100 randomised: 67 cabozantinib, 33 placebo) | primarymedian follow-up 8.9 monthsBrose 2021 | 15% | 0% | P=0.028Ten of 67 versus 0 of 33 responded; the 99% CIs were 5.8 to 29.3 and 0 to 14.8. The result did not meet the prespecified significance level (alpha 0.01), as stated in the abstract. |
| PFSRandomised patients at the extended data cut (258: 170 cabozantinib, 88 placebo) | exploratorymedian follow-up 10.1 monthsBrose 2022 | median 11 months | median 1.9 months | HR 0.22P<.0001Exploratory analysis with an extended data cut. 96% CIs: cabozantinib 7.4 to 13.8 months, placebo 1.9 to 3.7 months, hazard ratio 0.15 to 0.32. Forty placebo patients crossed over to open-label cabozantinib. |
| ORRRandomised patients at the extended data cut; the abstract does not state the response analysis population | exploratorymedian follow-up 10.1 monthsBrose 2022 | 11% (6.9–16.9%) | 0% (0.0–4.1%) | P=.0003One complete response with cabozantinib. |
- Placebo (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Placebo |
|---|---|
| 0 | 100.0% |
| 1 | 69.4% |
| 2 | 48.2% |
| 4 | 23.2% |
| 5 | 16.1% |
- Cabozantinib (experimental)
- Placebo (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Cabozantinib | Placebo |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 7 | 64.3% | 7.8% |
| 14 | 41.4% | 0.6% |
| 21 | 26.6% | 0.0% |
| 28 | 17.1% | 0.0% |
Appears in
Sources
Brose MS, Robinson B, Sherman SI, Krajewska J, Lin CC, Vaisman F, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-1138.
Brose MS, Robinson BG, Sherman SI, Jarzab B, Lin CC, Vaisman F, et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial. Cancer. 2022;128(24):4203-4212.