KEYNOTE-006
Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006)
Phase 3N = 834NCT01866319
- Population
- Advanced (unresectable stage III or IV) melanoma, ipilimumab-naive, up to one previous systemic therapy (excluding anti-CTLA-4, PD-1 or PD-L1 agents), ocular melanoma excluded
- Design
- Randomised (1:1:1) phase 3 trial of pembrolizumab 10 mg per kilogram every 2 weeks or every 3 weeks versus four doses of ipilimumab 3 mg per kilogram every 3 weeks. Progression-free and overall survival were the primary end points in the 2015 paper. Eligibility (2017 and 2019 abstracts): ipilimumab-naive, up to one previous systemic therapy, no active brain metastases. The pooled pembrolizumab arm is an exploratory combination of the two schedules, not protocol-specified.
- Primary endpoint
- PFS, OS
- Arms
- Pembrolizumab every 2 weeks (experimental, n = 279): Pembrolizumab 10 mg per kilogram every 2 weeks
- Pembrolizumab every 3 weeks (experimental, n = 277): Pembrolizumab 10 mg per kilogram every 3 weeks
- Ipilimumab (control, n = 278): Ipilimumab 3 mg per kilogram every 3 weeks for four doses
- Pembrolizumab, both schedules combined (analysis grouping, not a randomised arm) (experimental, n = 556): Pembrolizumab 10 mg per kilogram every 2 weeks or every 3 weeks, combined in the 5- and 10-year reports; an exploratory grouping of the two randomised pembrolizumab arms, not protocol-specified
- People
- Robert C, senior author Ribas A
PFSHR 0.58 (95% CI 0.46–0.72)Δ 6-month PFS+20.8 pointsPFSHR 0.58 (95% CI 0.47–0.72)Δ 6-month PFS+19.9 pointsOSHR 0.63 (95% CI 0.47–0.83)Δ 12-month OS+15.9 points
Show the numbers
| Endpoint | Analysis | Pembrolizumab every 2 weeks / Pembrolizumab every 3 weeks / Pembrolizumab, both schedules combined (analysis grouping, not a randomised arm) | Ipilimumab | Effect |
|---|---|---|---|---|
| PFSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 47.3% at 6 mo | 26.5% at 6 mo | HR 0.58 (95% CI 0.46–0.72)P<0.001Estimated 6-month progression-free survival rates. Hazard ratio for disease progression. |
| PFSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 46.4% at 6 mo | 26.5% at 6 mo | HR 0.58 (95% CI 0.47–0.72)P<0.001Estimated 6-month progression-free survival rates. Hazard ratio for disease progression. |
| OSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 74.1% at 12 mo | 58.2% at 12 mo | HR 0.63 (95% CI 0.47–0.83)P=0.0005Estimated 12-month survival rates. |
| OSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 68.4% at 12 mo | 58.2% at 12 mo | HR 0.69 (95% CI 0.52–0.90)P=0.0036Estimated 12-month survival rates. |
| ORRRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 33.7% | 11.9% | P<0.001P<0.001 for both pembrolizumab schedules versus ipilimumab. Responses were ongoing in 89.4%, 96.7% and 87.9% of responders at a median follow-up of 7.9 months. |
| OSIntention-to-treat (all randomly assigned patients) | finalmedian follow-up 22.9 monthsSchachter 2017 | 55% at 2 y | median 16 months; 43% at 2 y | HR 0.68 (95% CI 0.53–0.87)P=0.0009Median overall survival was not reached in either pembrolizumab group. |
| OSIntention-to-treat (all randomly assigned patients) | finalmedian follow-up 22.9 monthsSchachter 2017 | 55% at 2 y | median 16 months; 43% at 2 y | HR 0.68 (95% CI 0.53–0.86)P=0.0008Median overall survival was not reached in either pembrolizumab group. |
| OSAll randomly assigned patients (efficacy analysis), pembrolizumab schedules combined | long term-updatemedian follow-up 57.7 monthsRobert 2019 | median 32.7 months (24.5–41.6) | median 15.9 months (13.3–22.0) | HR 0.73 (95% CI 0.61–0.88)P=0.00049Post-hoc five-year analysis (the report's own title); the combination of the two pembrolizumab groups was not protocol-specified. Median follow-up is among surviving patients. |
| PFSAll randomly assigned patients (efficacy analysis), pembrolizumab schedules combined | long term-updatemedian follow-up 57.7 monthsRobert 2019 | median 8.4 months (6.6–11.3) | median 3.4 months (2.9–4.2) | HR 0.57 (95% CI 0.48–0.67)P<0.0001Post-hoc five-year analysis; pembrolizumab schedules combined (exploratory). |
| OSRandomly assigned patients, pembrolizumab schedules pooled (556 versus 278) | long term-updateLong 2024 | median 32.7 months (24.5–41.6); 34% at 10 y | median 15.9 months (13.3–22.0); 23.6% at 10 y | HR 0.71 (95% CI 0.60–0.85)Ten-year follow-up report; the abstract gives the same median overall survival values as the five-year report. Ten-year overall survival rates are given without confidence intervals. The abstract states that patients could move to KEYNOTE-587 for long-term follow-up and that the primary end point was overall survival. |
| Endpoint | Analysis | Pembrolizumab every 2 weeks / Pembrolizumab every 3 weeks / Pembrolizumab, both schedules combined (analysis grouping, not a randomised arm) | Ipilimumab | Effect |
|---|---|---|---|---|
| PFSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 47.3% at 6 mo | 26.5% at 6 mo | HR 0.58 (95% CI 0.46–0.72)P<0.001Estimated 6-month progression-free survival rates. Hazard ratio for disease progression. |
| PFSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 46.4% at 6 mo | 26.5% at 6 mo | HR 0.58 (95% CI 0.47–0.72)P<0.001Estimated 6-month progression-free survival rates. Hazard ratio for disease progression. |
| OSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 74.1% at 12 mo | 58.2% at 12 mo | HR 0.63 (95% CI 0.47–0.83)P=0.0005Estimated 12-month survival rates. |
| OSRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 68.4% at 12 mo | 58.2% at 12 mo | HR 0.69 (95% CI 0.52–0.90)P=0.0036Estimated 12-month survival rates. |
| ORRRandomised population as described in the abstract (analysis population not stated there) | interimRobert 2015 | 33.7% | 11.9% | P<0.001P<0.001 for both pembrolizumab schedules versus ipilimumab. Responses were ongoing in 89.4%, 96.7% and 87.9% of responders at a median follow-up of 7.9 months. |
| OSIntention-to-treat (all randomly assigned patients) | finalmedian follow-up 22.9 monthsSchachter 2017 | 55% at 2 y | median 16 months; 43% at 2 y | HR 0.68 (95% CI 0.53–0.87)P=0.0009Median overall survival was not reached in either pembrolizumab group. |
| OSIntention-to-treat (all randomly assigned patients) | finalmedian follow-up 22.9 monthsSchachter 2017 | 55% at 2 y | median 16 months; 43% at 2 y | HR 0.68 (95% CI 0.53–0.86)P=0.0008Median overall survival was not reached in either pembrolizumab group. |
| OSAll randomly assigned patients (efficacy analysis), pembrolizumab schedules combined | long term-updatemedian follow-up 57.7 monthsRobert 2019 | median 32.7 months (24.5–41.6) | median 15.9 months (13.3–22.0) | HR 0.73 (95% CI 0.61–0.88)P=0.00049Post-hoc five-year analysis (the report's own title); the combination of the two pembrolizumab groups was not protocol-specified. Median follow-up is among surviving patients. |
| PFSAll randomly assigned patients (efficacy analysis), pembrolizumab schedules combined | long term-updatemedian follow-up 57.7 monthsRobert 2019 | median 8.4 months (6.6–11.3) | median 3.4 months (2.9–4.2) | HR 0.57 (95% CI 0.48–0.67)P<0.0001Post-hoc five-year analysis; pembrolizumab schedules combined (exploratory). |
| OSRandomly assigned patients, pembrolizumab schedules pooled (556 versus 278) | long term-updateLong 2024 | median 32.7 months (24.5–41.6); 34% at 10 y | median 15.9 months (13.3–22.0); 23.6% at 10 y | HR 0.71 (95% CI 0.60–0.85)Ten-year follow-up report; the abstract gives the same median overall survival values as the five-year report. Ten-year overall survival rates are given without confidence intervals. The abstract states that patients could move to KEYNOTE-587 for long-term follow-up and that the primary end point was overall survival. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.58 | 0.46–0.72 |
| PFS | 0.58 | 0.47–0.72 |
| OS | 0.63 | 0.47–0.83 |
| OS | 0.69 | 0.52–0.9 |
| OS | 0.68 | 0.53–0.87 |
| OS | 0.68 | 0.53–0.86 |
| OS | 0.73 | 0.61–0.88 |
| PFS | 0.57 | 0.48–0.67 |
| OS | 0.71 | 0.6–0.85 |
- Ipilimumab (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Ipilimumab |
|---|---|
| 0 | 100.0% |
| 10 | 64.8% |
| 20 | 42.0% |
| 30 | 27.3% |
| 40 | 17.7% |
- Ipilimumab (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Ipilimumab |
|---|---|
| 0 | 100.0% |
| 10 | 64.8% |
| 20 | 42.0% |
| 30 | 27.3% |
| 40 | 17.7% |
Appears in
Sources
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-32.
Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853-1862.
Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20(9):1239-1251.
Long GV, Carlino MS, McNeil C, Ribas A, Gaudy-Marqueste C, Schachter J, et al. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study. Ann Oncol. 2024;35(12):1191-1199.