Pemetrexed-Erlotinib, Pemetrexed Alone, or Erlotinib Alone as Second-Line Treatment for East Asian and Non-East Asian Never-Smokers with Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer: Exploratory Subgroup Analysis of a Phase II Trial.

PURPOSE: This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model. RESULTS: Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months). CONCLUSION: The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients.

A phase II trial of pemetrexed and gemcitabine in patients with metastatic breast cancer who have received prior taxane therapy.

PURPOSE: This phase II trial assessed efficacy and safety of pemetrexed plus gemcitabine to treat metastatic or locally advanced breast cancer in patients previously treated with taxanes. PATIENTS AND METHODS: Eligible women with advanced breast cancer treated with taxanes in the adjuvant or metastatic setting received pemetrexed 500 mg/m2 on day 1 followed by gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle. Hematologic toxicities limiting day 8 gemcitabine dosing were observed in the first 20 patients, prompting a protocol amendment to evaluate pemetrexed 500 mg/m2 followed by gemcitabine 1500 mg/m2 on day 1 of a 14-day cycle. Patients received folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate (ORR). RESULTS: Between July 2003 and September 2006, 73 evaluable women (median age, 52.1 years; range, 28-73 years) were enrolled (21-day schedule: 21 patients, 52% estrogen receptor-positive, 24% HER2-positive; 14-day schedule: 52 patients, 58% ER-positive, 15% HER2-positive). For patients on the 21-day and 14-day schedules, median number of cycles was 4 (range, 1-8 cycles) and 5 (range, 1-38 cycles), respectively. The ORRs were 23.8% and 19.2%, respectively; median survival times were 16.2 months and 13.4 months. The most common grade 3/4 hematologic toxicities were neutropenia (71% vs. 33%) and leukopenia (24% vs. 14%); febrile neutropenia occurred in 10% and 6%. The most common grade 3/4 nonhematologic toxicity was fatigue (29% vs. 10%). CONCLUSION: Pemetrexed/gemcitabine given on a 21-day or 14-day schedule is active in patients with advanced breast cancer previously treated with taxanes. A 14-day schedule appears to result in fewer serious toxicities.

A phase I trial of pemetrexed plus gemcitabine given biweekly with B-vitamin support in solid tumor malignancies or advanced epithelial ovarian cancer.

PURPOSE: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B(12) and folate supplementation in patients with advanced solid tumors and ovarian cancer. EXPERIMENTAL DESIGN: Patients with no prior pemetrexed or gemcitabine therapy enrolled in cohorts of three, expanding to six if dose-limiting toxicity (DLT) was observed. Pemetrexed, escalated from to 700 mg/m(2), was given before gemcitabine 1,500 mg/m(2) every 14 days. DLTs were grade 4 neutropenia lasting >7 days or febrile neutropenia, grade 4 or 3 thrombocytopenia (with bleeding), grade > or =3 nonhematologic toxicity, or treatment delay of > or =1 week due to unresolved toxicity. RESULTS: The ovarian cancer cohort enrolled 24 patients with unlimited prior cytotoxic chemotherapies. MTD was observed at pemetrexed 600 mg/m(2), with 2 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (83%), leukopenia (67%), lymphopenia (73%), and febrile neutropenia (12%). Median cycle per patient was 8 (range, 1-16). Six of 21 (28%) patients had confirmed partial responses. Study protocol was modified for the solid tumor cohort (n = 30) to enroll patients with two or more prior cytotoxic regimens. MTD was observed at pemetrexed 500 mg/m(2), with 1 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (63%), lymphopenia (43%), leukopenia (70%) and febrile neutropenia (6.6%). Median cycle per patient was 4 (range, 1-20). Three of 29 (10.3%) response-evaluable patients had confirmed partial responses: 2 squamous cell carcinomas of head and neck and 1 nasopharyngeal cancer. CONCLUSION: MTDs for the solid tumor and ovarian cancer cohorts were reached at pemetrexed 500 and 600 mg/m(2), respectively, given biweekly with gemcitabine 1,500 mg/m(2).