COIN
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
Phase 3N = 2,445NCT00182715
- Population
- Previously untreated advanced colorectal cancer
- Design
- Open-label randomised phase 3 trial in previously untreated advanced colorectal cancer (patients fit for chemotherapy), registered as ISRCTN27286448. 2,445 patients were randomly assigned (1:1:1, 815 per arm) between March 2005 and May 2008 at 111 centres in the UK and Ireland. Arm A: oxaliplatin plus a fluoropyrimidine (capecitabine or infused fluorouracil with leucovorin, chosen before randomisation); arm B: the same plus cetuximab; arm C: intermittent chemotherapy (patients not progressing at the 12-week scan took a chemotherapy-free interval until progression, then restarted). Two papers report the pairwise comparisons, each of 1,630 patients (815 per group): arm A versus B (primary outcome overall survival in KRAS wild-type tumours) and arm A versus C (primary objective: non-inferiority of overall survival, predefined boundary 1.162).
- Primary endpoint
- OS
- Arms
- Arm A: continuous chemotherapy (control, n = 815): Continuous oxaliplatin plus fluoropyrimidine (capecitabine, or infused fluorouracil with leucovorin)
- Arm B: chemotherapy plus cetuximab (experimental, n = 815): Continuous oxaliplatin plus fluoropyrimidine plus cetuximab
- Arm C: intermittent chemotherapy (experimental, n = 815): Intermittent oxaliplatin plus fluoropyrimidine with a planned chemotherapy-free interval
- People
- Maughan TS
OSHR 1.04 (95% CI 0.87–1.23)Δ median OS−0.9 monthsPFSHR 0.96 (95% CI 0.82–1.12)Δ median PFS0 monthsΔ ORR+7 pointsOSHR 1.084
Show the numbers
| Endpoint | Analysis | Arm B: chemotherapy plus cetuximab / Arm C: intermittent chemotherapy | Arm A: continuous chemotherapy | Effect |
|---|---|---|---|---|
| OSKRAS wild-type tumours, intention-to-treat analysis (arm A n=367; arm B n=362) | primaryMaughan 2011 | median 17 months | median 17.9 months | HR 1.04 (95% CI 0.87–1.23)P=0.67Primary outcome of the A-versus-B comparison. Interquartile ranges: 10.3-29.2 months (arm A) and 9.4-30.1 months (arm B). |
| PFSKRAS wild-type tumours, intention-to-treat analysis (arm A n=367; arm B n=362) | primaryMaughan 2011 | median 8.6 months | median 8.6 months | HR 0.96 (95% CI 0.82–1.12)P=0.60Interquartile ranges: 5.0-12.5 months (arm A) and 5.1-13.8 months (arm B). |
| ORRKRAS wild-type tumours, intention-to-treat analysis (arm A n=367; arm B n=362) | primaryMaughan 2011 | 64% | 57% | P=0.049The abstract gives 209 responders in arm A and 232 in arm B. |
| OSITT (n=815 in both groups) | primaryAdams 2011 | median 14.4 months | median 15.8 months | HR 1.084Hazard ratio for intermittent versus continuous therapy with an 80% confidence interval of 1.008-1.165 (not a 95% interval). Interquartile ranges: 9.4-26.1 months (arm A) and 8.0-24.7 months (arm C). The abstract states that the upper limits of the confidence intervals in both the intention-to-treat and per-protocol analyses were greater than the predefined non-inferiority boundary of 1.162. |
| OSPer-protocol population (arm A n=467; arm C n=511) | primaryAdams 2011 | median 18 months | median 19.6 months | HR 1.087Hazard ratio for intermittent versus continuous therapy; the abstract prints the interval 0.986-1.198 without stating its level, so it is not recorded as a 95% interval. Interquartile ranges: 13.0-28.1 months (arm A) and 12.1-29.3 months (arm C). |
| OSPer-protocol population, normal baseline platelet count (preplanned subgroup) | exploratoryAdams 2011 | — | — | HR 0.96 (95% CI 0.80–1.15)P=0.66Hazard ratio for arm C (intermittent) versus arm A (continuous). Interaction between treatment and platelet count: P=0.0027. |
| OSPer-protocol population, raised baseline platelet count of 400,000 per microlitre or higher (271 of 978 patients, 28%; preplanned subgroup) | exploratoryAdams 2011 | — | — | HR 1.54 (95% CI 1.17–2.03)P=0.0018Hazard ratio for arm C (intermittent) versus arm A (continuous). Interaction between treatment and platelet count: P=0.0027. |
| Endpoint | Analysis | Arm B: chemotherapy plus cetuximab / Arm C: intermittent chemotherapy | Arm A: continuous chemotherapy | Effect |
|---|---|---|---|---|
| OSKRAS wild-type tumours, intention-to-treat analysis (arm A n=367; arm B n=362) | primaryMaughan 2011 | median 17 months | median 17.9 months | HR 1.04 (95% CI 0.87–1.23)P=0.67Primary outcome of the A-versus-B comparison. Interquartile ranges: 10.3-29.2 months (arm A) and 9.4-30.1 months (arm B). |
| PFSKRAS wild-type tumours, intention-to-treat analysis (arm A n=367; arm B n=362) | primaryMaughan 2011 | median 8.6 months | median 8.6 months | HR 0.96 (95% CI 0.82–1.12)P=0.60Interquartile ranges: 5.0-12.5 months (arm A) and 5.1-13.8 months (arm B). |
| ORRKRAS wild-type tumours, intention-to-treat analysis (arm A n=367; arm B n=362) | primaryMaughan 2011 | 64% | 57% | P=0.049The abstract gives 209 responders in arm A and 232 in arm B. |
| OSITT (n=815 in both groups) | primaryAdams 2011 | median 14.4 months | median 15.8 months | HR 1.084Hazard ratio for intermittent versus continuous therapy with an 80% confidence interval of 1.008-1.165 (not a 95% interval). Interquartile ranges: 9.4-26.1 months (arm A) and 8.0-24.7 months (arm C). The abstract states that the upper limits of the confidence intervals in both the intention-to-treat and per-protocol analyses were greater than the predefined non-inferiority boundary of 1.162. |
| OSPer-protocol population (arm A n=467; arm C n=511) | primaryAdams 2011 | median 18 months | median 19.6 months | HR 1.087Hazard ratio for intermittent versus continuous therapy; the abstract prints the interval 0.986-1.198 without stating its level, so it is not recorded as a 95% interval. Interquartile ranges: 13.0-28.1 months (arm A) and 12.1-29.3 months (arm C). |
| OSPer-protocol population, normal baseline platelet count (preplanned subgroup) | exploratoryAdams 2011 | — | — | HR 0.96 (95% CI 0.80–1.15)P=0.66Hazard ratio for arm C (intermittent) versus arm A (continuous). Interaction between treatment and platelet count: P=0.0027. |
| OSPer-protocol population, raised baseline platelet count of 400,000 per microlitre or higher (271 of 978 patients, 28%; preplanned subgroup) | exploratoryAdams 2011 | — | — | HR 1.54 (95% CI 1.17–2.03)P=0.0018Hazard ratio for arm C (intermittent) versus arm A (continuous). Interaction between treatment and platelet count: P=0.0027. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 1.04 | 0.87–1.23 |
| PFS | 0.96 | 0.82–1.12 |
| OS | 0.96 | 0.8–1.15 |
| OS | 1.54 | 1.17–2.03 |
- Arm B: chemotherapy plus cetuximab (experimental)
- Arm A: continuous chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Arm B: chemotherapy plus cetuximab | Arm A: continuous chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 11 | 63.9% | 65.3% |
| 22 | 40.8% | 42.7% |
| 34 | 25.0% | 26.8% |
| 45 | 16.0% | 17.5% |
- Arm B: chemotherapy plus cetuximab (experimental)
- Arm A: continuous chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Arm B: chemotherapy plus cetuximab | Arm A: continuous chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 5 | 66.8% | 66.8% |
| 11 | 41.2% | 41.2% |
| 16 | 27.5% | 27.5% |
| 22 | 17.0% | 17.0% |
Appears in
Sources
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103-14.
Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12(7):642-53.