EMPHACIS
Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma
Phase 3N = 456NCT00005636
- Population
- Chemotherapy-naive patients with malignant pleural mesothelioma who were not eligible for curative surgery (Karnofsky performance status of 70 or more, per the EMA assessment)
- Design
- Randomised phase 3 trial of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 versus cisplatin 75 mg/m2 alone, both given intravenously on day 1 of a 21-day cycle (the abstract states every 21 days). The EMA assessment, which names this Study JMCH ('EMPHACIS'), describes an international, multicentre, single-blind trial at 88 sites, with a regimen defined as six cycles and a primary endpoint of overall survival set before the first patient was enrolled. 456 patients were assigned; 448 received treatment (226 and 222) and eight never received therapy. After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity. The registry record lists no enrolment figure.
- Primary endpoint
- OS
- Arms
- Pemetrexed plus cisplatin (experimental, n = 226): Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously on day 1 of each 21-day cycle
- Cisplatin alone (control, n = 222): Cisplatin 75 mg/m2 intravenously on day 1 of each 21-day cycle
- People
- Vogelzang NJ
OSHR 0.77Δ median OS+2.8 monthsOSHR 0.77Δ median OS+2.8 monthsOSHR 0.75Δ median OS+3.3 months
Show the numbers
| Endpoint | Analysis | Pemetrexed plus cisplatin | Cisplatin alone | Effect |
|---|---|---|---|---|
| OSRandomised and treated patients, 448 of the 456 assigned (226 and 222): the abstract does not name the analysis population, and the identical values in the EMA assessment (Table 6) are for this populationMedian survival time, compared with a two-sided log-rank test (abstract wording) | primaryVogelzang 2003 | median 12.1 months | median 9.3 months | HR 0.77P=0.020The abstract gives no confidence interval for the hazard ratio or the medians; the EMA assessment values are in the next result. |
| OSRandomised and treated (RT) population, 448 of 456 assigned; the EMA assessment states this was the primary analysis population and that it cannot be considered an intention-to-treat analysisSurvival time from randomisation to death from any cause (EMA assessment definition) | primarymedian follow-up 9.3 monthsSource 2004 | median 12.1 months (10.0–14.4) | median 9.3 months (7.8–10.7) | HR 0.77P=0.020EMA scientific discussion, Table 6. Log-rank P value as printed; no confidence interval is printed for the hazard ratio. Median follow-up 9.3 months (range 0.1 to 29.2) at the cut-off for the primary survival analysis. |
| OSFully supplemented subgroup (patients randomised on or after 2 December 1999): 168 pemetrexed plus cisplatin, 163 cisplatin aloneSurvival time from randomisation to death from any cause, fully supplemented subgroup (EMA assessment) | exploratorySource 2004 | median 13.3 months (11.4–14.9) | median 10 months (8.4–11.9) | HR 0.75P=0.051Subgroup defined by randomisation date, after folic acid and vitamin B12 supplementation became part of the protocol. A secondary subgroup analysis, not the primary comparison: the EMA assessment says enrolment was extended to give it adequate power. Log-rank P value as printed in EMA Table 6. |
| TTPRandomised and treated patients, 448 of the 456 assigned (226 and 222): the abstract does not name the analysis population, and the identical values in the EMA assessment (Table 6, time to progressive disease) are for this populationMedian time to progression (abstract wording) | primaryVogelzang 2003 | median 5.7 months | median 3.9 months | P=0.001The abstract gives no hazard ratio or confidence interval for time to progression. |
| ORRRandomised and treated patients, 448 of the 456 assigned (226 and 222): the abstract does not name the analysis population, and the identical values in the EMA assessment (Table 6, investigator-assessed response rate) are for this populationResponse rate (abstract wording) | primaryVogelzang 2003 | 41.3% | 16.7% | P<0.0001The abstract does not give confidence intervals or the response criteria. |
| Endpoint | Analysis | Pemetrexed plus cisplatin | Cisplatin alone | Effect |
|---|---|---|---|---|
| OSRandomised and treated patients, 448 of the 456 assigned (226 and 222): the abstract does not name the analysis population, and the identical values in the EMA assessment (Table 6) are for this populationMedian survival time, compared with a two-sided log-rank test (abstract wording) | primaryVogelzang 2003 | median 12.1 months | median 9.3 months | HR 0.77P=0.020The abstract gives no confidence interval for the hazard ratio or the medians; the EMA assessment values are in the next result. |
| OSRandomised and treated (RT) population, 448 of 456 assigned; the EMA assessment states this was the primary analysis population and that it cannot be considered an intention-to-treat analysisSurvival time from randomisation to death from any cause (EMA assessment definition) | primarymedian follow-up 9.3 monthsSource 2004 | median 12.1 months (10.0–14.4) | median 9.3 months (7.8–10.7) | HR 0.77P=0.020EMA scientific discussion, Table 6. Log-rank P value as printed; no confidence interval is printed for the hazard ratio. Median follow-up 9.3 months (range 0.1 to 29.2) at the cut-off for the primary survival analysis. |
| OSFully supplemented subgroup (patients randomised on or after 2 December 1999): 168 pemetrexed plus cisplatin, 163 cisplatin aloneSurvival time from randomisation to death from any cause, fully supplemented subgroup (EMA assessment) | exploratorySource 2004 | median 13.3 months (11.4–14.9) | median 10 months (8.4–11.9) | HR 0.75P=0.051Subgroup defined by randomisation date, after folic acid and vitamin B12 supplementation became part of the protocol. A secondary subgroup analysis, not the primary comparison: the EMA assessment says enrolment was extended to give it adequate power. Log-rank P value as printed in EMA Table 6. |
| TTPRandomised and treated patients, 448 of the 456 assigned (226 and 222): the abstract does not name the analysis population, and the identical values in the EMA assessment (Table 6, time to progressive disease) are for this populationMedian time to progression (abstract wording) | primaryVogelzang 2003 | median 5.7 months | median 3.9 months | P=0.001The abstract gives no hazard ratio or confidence interval for time to progression. |
| ORRRandomised and treated patients, 448 of the 456 assigned (226 and 222): the abstract does not name the analysis population, and the identical values in the EMA assessment (Table 6, investigator-assessed response rate) are for this populationResponse rate (abstract wording) | primaryVogelzang 2003 | 41.3% | 16.7% | P<0.0001The abstract does not give confidence intervals or the response criteria. |
- Pemetrexed plus cisplatin (experimental)
- Cisplatin alone (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Pemetrexed plus cisplatin | Cisplatin alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 8 | 63.2% | 55.1% |
| 15 | 42.3% | 32.7% |
| 23 | 26.8% | 18.0% |
| 30 | 17.9% | 10.7% |
- Pemetrexed plus cisplatin (experimental)
- Cisplatin alone (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Pemetrexed plus cisplatin | Cisplatin alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 8 | 63.2% | 55.1% |
| 15 | 42.3% | 32.7% |
| 23 | 26.8% | 18.0% |
| 30 | 17.9% | 10.7% |
Appears in
Sources
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-44.
European Medicines Agency (EMEA), CHMP. Alimta: EPAR scientific discussion, initial approval (2004). Study JMCH ('EMPHACIS'), malignant pleural mesothelioma.