Pemetrexed in Extensive Stage Small Cell Lung Cancer
Small cell lung cancer (SCLC) represents about 20% of all lung cancers diagnosed in the US, with about 25,000 to 30,000 new cases each year. Of these cases, about two-thirds are considered "extensive stage" (ES), and combination chemotherapy is considered the standard of care. Specifically, the standard chemotherapy regimen is cisplatin and etoposide (EP). Unfortunately, the 2-year survival remains dismally low at less than 10%.
Attempts at improving this rate include the addition of new drugs, such as paclitaxel to EP or topotecan after EP. The replacement of etoposide with irinotecan has been shown to improve survival in a Japanese study (NEJM 346:85, 2002). Also, phase III trials looking at cisplatin plus irinotecan vs. cisplatin plus topotecan showed similar outcomes to standard EP. Thus the path is paved towards investigating various platinum-doublet combinations to treat ES SCLC.
Pemetrexed is a new drug that has already shown activity in non-small cell lung cancer, with response rates of 16-21% as a single agent and 27-45% in combination with platinum agents. It is well tolerated and easy to administer. Pemetrexed works through an anti-folate pathway, blocking multiple enzymes, including thymidine synthetase and dihydrofolate reductase.
At present, there are several phase II trials underway testing pemetrexed in ES SCLC. One is a randomized phase II study of pemetrexed in combination with either cisplatin or carboplatin. Pemetrexed will be delivered at a dose of 500 mg/m2, and the regimen will be repeated every 3 weeks for 6 cycles. The primary endpoint is response rate, with secondary endpoints of duration of response, time to progression (TTP), overall survival (OS), and toxicity. To be eligible for this trial, patients are not permitted to have a history of prior chemotherapy or radiation therapy. At present, 73 patients are enrolled, with 38 in the pemetrexed-cisplatin arm and 35 in the pemetrexed-carboplatin arm. Patients have received a median of 4 cycles of chemotherapy. Grade 3/4 hematologic toxicity appears to be acceptable, with nausea, vomiting, and fatigue being the most common side effects. In terms of response rates, 71% of patients in the cisplatin arm and 69% of patients in the carboplatin arm had complete response, partial response, or stable disease. The remaining patients either had progressive disease or unknown status. Median TTP was 4.9 months and 4.3 months for cisplatin and carboplatin, respectively. Median OS was 7.9 months and 10.8 months and one-year survival rates were 29% and 43% for cisplatin and carboplatin, respectively. These results are comparable to those seen with other cisplatin-based regimens.
In summary, platinum-pemetrexed combination chemotherapy appears to be safe and effective in ES SCLC. Maturation of the phase II data and confirmation in a phase III setting will be very instructive and will hopefully contribute to therapeutic strides in this disease.