Antifolate + Platinum in Advanced NSCLC

TOKYO—A platinum-based regimen including the investigational antifolate pemetrexed disodium (Alimta) is active and well tolerated in stage IIIb/IV non-small cell lung cancer (NSCLC), according to the final results of a phase II trial conducted by the National Cancer Institute of Canada Clinical Trials Group and presented at the 9th World Conference on Lung Cancer. The drug may also represent a new option for patients with mesothelioma.

The multicenter study included 31 patients given Alimta plus cisplatin (Platinol) in 3-week cycles. There were no complete responses, but 13 partial responses were externally validated. The overall response rate was 44.8% for all patients and 45.8% for stage IV patients.

“It is a very well-tolerated regimen, it is convenient in the outpatient setting, and it deserves comparison to other regimens,” said Frances Shepherd, MD, of Princess Margaret Hospital, Toronto. One-year survival was a “very favorable” 49%, she said. Median survival was 8.9 months.

A median of six courses was delivered, “which attests to the tolerability and efficacy of this regimen,” Dr. Shepherd said. Over 164 courses, only one patient experienced grade 4 thrombocytopenia, while 11 patients had grade 3-4 granulocytopenia. There was a single episode of febrile neutropenia.

Only one patient had grade 3 nausea and vomiting (no grade 4). Two patients had grade 3 diarrhea, and one had grade 4. One patient discontinued therapy due to rash. There were two episodes of grade 3 neuromotor toxicity and one grade 2 episode of neurosensory toxicity. Several cardiovascular events occurred but were not thought to be related to therapy. Nine patients had minor infectious complications during therapy.

Antifolates represent one potential new treatment option for NSCLC. But despite demonstrated activity in a number of studies, they have not yet gained a solid place in the therapeutic spectrum.

Alimta, a multitargeted antifolate, has produced response rates of up to 30% as a single agent in NSCLC therapy. It is also being studied in nonplatinum regimens and specifically with gemcitabine (Gemzar), a drug that has demonstrated significant activity as a single agent and in combination with cisplatin.

Mesothelioma may also be amenable to treatment with Alimta plus a platinum agent. Underway is a single-blind, randomized phase III clinical trial, known as EMPHACIS, that will compare cisplatin alone with cisplatin/Alimta in patients with malignant pleural mesothelioma.

“These patients do not have a lot of treatment options,” said Richard Gralla, MD, director of clinical research, Herbert Irving Comprehensive Cancer Center, Columbia University. “One could argue whether any chemotherapy today is truly worth the trouble in this very difficult disease.”

Phase II studies with Alimta in mesothelioma have had a “surprisingly high” response rate, Dr. Gralla said. The first goal of therapy, however, is to ameliorate the diverse symptoms of this disease, which have a significant negative effect on quality of life. Accordingly, the EMPHACIS trial is designed to show differences in both survival and quality of life.“I think people will be as interested in the symptomatic relief as they will be in the survival differences,” he said.