EXAM
An International, Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 Versus Placebo in Subjects With Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer
Phase 3N = 330NCT00704730
- Population
- Progressive, metastatic medullary thyroid cancer with documented radiographic progression
- Design
- Double-blind phase 3 trial; patients with documented radiographic progression of metastatic medullary thyroid cancer randomised 2:1 to cabozantinib 140 mg/day or placebo. Primary endpoint progression-free survival; additional outcome measures were tumour response rate, overall survival and safety.
- Primary endpoint
- PFS
- Arms
- Cabozantinib (experimental): Cabozantinib 140 mg per day (capsules)
- Placebo (control): Placebo
- People
- Elisei R, senior author Sherman SI
PFSHR 0.28 (95% CI 0.19–0.40)Δ median PFS+7.2 monthsΔ 12-month PFS+40.1 pointsΔ ORR+28 pointsOSHR 0.85 (95% CI 0.64–1.12)Δ median OS+5.5 months
Show the numbers
| Endpoint | Analysis | Cabozantinib | Placebo | Effect |
|---|---|---|---|---|
| PFSRandomised patients (330); the abstract does not name the analysis population | primaryElisei 2013 | median 11.2 months; 47.3% at 12 mo | median 4 months; 7.2% at 12 mo | HR 0.28 (95% CI 0.19–0.40)P<.001Estimated median PFS. Prolonged PFS was observed across subgroups including age, prior TKI treatment and RET mutation status (hereditary or sporadic). The 12-month figures are Kaplan-Meier estimates of patients alive and progression-free. |
| ORRRandomised patients (330); the abstract does not name the analysis population | primaryElisei 2013 | 28% | 0% | Responses were seen regardless of RET mutation status. Common cabozantinib-associated adverse events included diarrhoea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea and fatigue; they led to dose reductions in 79% and holds in 65% of cabozantinib-treated patients, and to treatment discontinuation in 16% of cabozantinib-treated and 8% of placebo-treated patients. |
| OSRandomised patients (330); minimum follow-up 42 months | finalSchlumberger 2017 | median 26.6 months | median 21.1 months | HR 0.85 (95% CI 0.64–1.12)P=0.24Stratified hazard ratio. The abstract states that the difference did not reach statistical significance and that the secondary endpoint was not met. |
| OSRET M918T mutation-positive subgroup | exploratorySchlumberger 2017 | median 44.3 months | median 18.9 months | HR 0.60 (95% CI 0.38–0.94)P=0.03Exploratory subgroup; the abstract states the P value is not adjusted for multiple subgroup analyses. |
| OSSubgroup without RET M918T mutation | exploratorySchlumberger 2017 | median 20.2 months | median 21.5 months | HR 1.12 (95% CI 0.70–1.82)P=0.63Exploratory subgroup. |
| Endpoint | Analysis | Cabozantinib | Placebo | Effect |
|---|---|---|---|---|
| PFSRandomised patients (330); the abstract does not name the analysis population | primaryElisei 2013 | median 11.2 months; 47.3% at 12 mo | median 4 months; 7.2% at 12 mo | HR 0.28 (95% CI 0.19–0.40)P<.001Estimated median PFS. Prolonged PFS was observed across subgroups including age, prior TKI treatment and RET mutation status (hereditary or sporadic). The 12-month figures are Kaplan-Meier estimates of patients alive and progression-free. |
| ORRRandomised patients (330); the abstract does not name the analysis population | primaryElisei 2013 | 28% | 0% | Responses were seen regardless of RET mutation status. Common cabozantinib-associated adverse events included diarrhoea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea and fatigue; they led to dose reductions in 79% and holds in 65% of cabozantinib-treated patients, and to treatment discontinuation in 16% of cabozantinib-treated and 8% of placebo-treated patients. |
| OSRandomised patients (330); minimum follow-up 42 months | finalSchlumberger 2017 | median 26.6 months | median 21.1 months | HR 0.85 (95% CI 0.64–1.12)P=0.24Stratified hazard ratio. The abstract states that the difference did not reach statistical significance and that the secondary endpoint was not met. |
| OSRET M918T mutation-positive subgroup | exploratorySchlumberger 2017 | median 44.3 months | median 18.9 months | HR 0.60 (95% CI 0.38–0.94)P=0.03Exploratory subgroup; the abstract states the P value is not adjusted for multiple subgroup analyses. |
| OSSubgroup without RET M918T mutation | exploratorySchlumberger 2017 | median 20.2 months | median 21.5 months | HR 1.12 (95% CI 0.70–1.82)P=0.63Exploratory subgroup. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.28 | 0.19–0.4 |
| OS | 0.85 | 0.64–1.12 |
| OS | 0.6 | 0.38–0.94 |
| OS | 1.12 | 0.7–1.82 |
- 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 | 64.8% | 29.7% |
| 14 | 42.0% | 8.8% |
| 21 | 27.3% | 2.6% |
| 28 | 17.7% | 0.8% |
- 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% |
| 17 | 64.2% | 57.2% |
| 33 | 42.3% | 33.8% |
| 50 | 27.2% | 19.3% |
| 67 | 17.4% | 11.1% |
Appears in
Sources
Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-46.
Schlumberger M, Elisei R, Müller S, Schöffski P, Brose M, Shah M, et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017;28(11):2813-2819.