Treatment of Recurrent Disease After Prior Chemotherapy
The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B12 . The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure.
A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC.
The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 16 and 17, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)].
|Efficacy Parameter||Pemetrexed (N=283)||Docetaxel (N=288)|
|Median (months) (95% CI)||8.3(7.0-9.4)||7.9(6.3-9.2)|
|Hazard ratioa (95% CI)||0.99(0.82-1.2)|
|Median (months) (95% CI)||2.9(2.4-3.1)||2.9(2.7-3.4)|
|Hazard ratioa (95% CI)||0.97(0.82-1.16)|
|Overall response rate (95% CI)||8.5%(5.2-11.7)||8.3%(5.1-11.5)|
a Hazard ratios are not adjusted for multiplicity or for stratification variables.
|Histologic Subgroups||Pemetrexed (N=283)||Docetaxel (N=288)|
|Non-squamous NSCLC (N=399)|
|Median (months) (95% CI)||9.3(7.8-9.7)||8(6.3-9.3)|
|HRa (95% CI)||0.89(0.71-1.13)|
|Median (months) (95% CI)||9(7.6-9.6)||9.2(7.5-11.3)|
|HRa (95% CI)||1.09(0.83-1.44)|
|Large Cell (N=47)|
|Median (months) (95% CI)||12.8(5.8-14)||4.5(2.3-9.1)|
|HRa (95% CI)||0.38(0.18-0.78)|
|Median (months) (95% CI)||9.4(6.0-10.1)||7.9(4.0-8.9)|
|HRa (95% CI)||0.62(0.32-1.23)|
|Squamous NSCLC (N=172)|
|Median (months) (95% CI)||6.2(4.9-8.0)||7.4(5.6-9.5)|
|HRa (95% CI)||1.32(0.93-1.86)|
a Hazard ratio unadjusted for multiple comparisons.
b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m2 intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m2 intravenously over 2 hours on Day 1 of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1000 mcg daily beginning 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B12 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration.
A total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed, 74% received full supplementation with folic acid and vitamin B12 during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had a baseline KPS score of 90-100% and 46% had a KPS score of 70 to 80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population.
The efficacy results from Study JMCH are summarized in Table 18 and Figure 9.
|Efficacy Parameter||All Randomized and Treated Patients (N=448)||Fully Supplemented Patients (N=331)|
|Pemetrexed /Cisplatin (N=226)||Cisplatin (N=222)||Pemetrexed /Cisplatin (N=168)||Cisplatin (N=163)|
|Median overall survival (months)||12.1||9.3||13.3||10|
|Log rank p-value||0.02||NAb|
a Hazard ratios are not adjusted for stratification variables.
b Not a pre-specified analysis.
Figure 9: Kaplan-Meier Curves for Overall Survival in Study JMCH
Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm.
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