FDA approves pemetrexed as maintenance therapy for non-squamous NSCLC

Today, the FDA announced that it has approved pemetrexed as maintenance therapy for metastatic non-small cell lung cancer, specifically in patients with non-squamous histology in which disease has not progressed after four cycles of platinum-based first-line chemotherapy.

The approval is based on findings from a multicenter, double blind, phase-3 trial that compared pemetrexed (Alimta, Eli Lilly) with placebo. Data were presented at the 2009 ASCO Annual Meeting in May 2009.

In that study, researchers enrolled 663 patients to compare OS in a pemetrexed treatment plus best supportive care group vs. a placebo plus supportive care group. Patients had stage IIIb/IV NSCLC and had not progressed after four cycles of platinum-based induction chemotherapy.

According to the FDA, people with predominantly squamous cell cancer did not benefit from the drug. However, in those with other subtypes, the OS rate for patients with NSCLC assigned to pemetrexed was 15.5 months compared with 10.3 months for patients assigned to placebo. Adverse events included damage to blood cells, fatigue, nausea, loss of appetite, tingling or numbness in the hands and feet and skin rash, according to a press release.

Pemetrexed (Alimta, Eli Lilly) was approved in October 2008 in combination with cisplatin as a first-line treatment for locally advanced metastatic NSCLC in patients with nonsquamous history.

Prior to that, pemetrexed plus cisplatin was approved for the treatment of mesothelioma and as a single agent for second-line treatment of patients with locally advanced NSCLC after prior chemotherapy treatment.

The approval of pemetrexed in this setting is the first of its kind in advanced NSCLC. The survival advantage of more than five months observed in patients with adenocarcinoma is unprecedented, and toxicity was minimal; hence, this improvement represents an important advance. But it is important to acknowledge the limitations of the trial:

Patients with squamous histology did not benefit. This cohort constitutes approximately 30% of advanced disease patients. Moreover, how to handle patients with mixed squamous-adenoma histology is unclear.

There was no mandatory crossover in the control arm at the time of progression, and <20% of those randomly assigned to placebo actually went on to receive pemetrexed. Whether the survival advantage would have held up had the study mandated crossover is open to speculation.

Pemetrexed has already moved into the first-line setting based on work done by Scagliotti et al, in which patients with adenocarcinoma of the lung undergoing platinum-based therapy had a preferential survival advantage on pemetrexed compared with gemcitabine. None of the patients enrolled in this trial received pemetrexed upfront; so, it is not safe to assume that the maintenance findings would automatically apply to patients who have already received pemetrexed.

Finally, none of the patients enrolled in this trial received bevacizumab as part of their first-line therapy. So, again, it is unclear if the findings observed in the maintenance trial would apply to those already receiving bevacizumab. The Eastern Cooperative Oncology Group intends to address this issue in part by comparing bevacizumab to pemetrexed to the combination in the maintenance setting; and Eli Lilly is sponsoring a trial comparing the first-line combination of pemetrexed, carboplatin and bevacizumab to paclitaxel, carboplatin and bevacizumab, with maintenance therapy consisting of pemetrexed and bevacizumab in the experimental arm and bevacizumab alone in the control arm.

– Corey J. Langer MD, FACP

Professor of Medicine, Hematology-Oncology Division,
University of Pennsylvania, Philadelphia