Lilly’s pemetrexed (Alimta) offers potential improvements in the treatment of non-small cell lung cancer (NSCLC)

DailyUpdates 20th April: Nearly 423,000 new cases of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are expected to have been diagnosed in the seven major pharmaceutical markets in 2003. Despite the high level of pharmaceutical interest, there are significant unmet needs in the disease in terms of poor survival. Docetaxel is the only drug currently approved in both the and to treat patients with non-small cell lung cancer in the second-line setting. While the drug extends survival when compared to best supportive care, it is associated with several side effects, including neutropenia which frequently results in hospitalization.  In a recent head-to-head comparison Lilly’s pemetrexed (Alimta) was found to be as effective as docetaxel but with fewer side-effects and hospitalizations.

Nearly 423,000 new cases of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are expected to have been diagnosed in the seven major pharmaceutical markets in 2003. Despite the high level of pharmaceutical interest, there are significant unmet needs in the disease in terms of poor survival.

Of the five major ATC-defined cytotoxic classes, vinca alkaloids, which include the taxanes, represent the largest in terms of sales. BMS’s Taxol (paclitaxel) once dominated not only the class but also the cytotoxic market as a whole. However, because of its patent expiry, it has lost its leading position to its rival drug, Aventis’s Taxotere (docetaxel).

Docetaxel has the potential to become the gold-standard first-line therapy for NSCLC in the , and indeed docetaxel is the only drug currently approved in both the and to treat patients with non-small cell lung cancer in the second-line setting. While the drug extends survival when compared to best supportive care, it is associated with several side effects, including hair loss and blood-related toxicities, including neutropenia, a lowering of the white blood cell count that can cause infections and fever, thus requiring hospitalisation. Due in part to these side-effects, many analysts believe that docetaxel will not in fact become a first line NSCLC therapeutic, with other cytotoxics providing stiff competition (see Lung Cancer - Third-Generation Cytotoxics Set to Dominate the Market). In particular the anti-metabolites, a second class of cytotoxic agent may be of considerable utility in the treatment of NSCLC. Lilly anti-metabolite, Gemzar (gemcitabine) currently leads this class, achieving sales of $708m in 2002 increasing to over $2 billion by 2008. However, by 2010, when its patent expires, it is expected to see a significant decline in its sales.  Lilly’s new antimetabolite, pemetrexed (Alimta) is expected to gradually erode into the Gemzar market (for an evaluation of the taxenes and the anti-metabolites see Cytotoxics - Third-Generation Cytotoxics To Offset Taxol’s Generic Woes).

The U.S. Food and Drug Administration (FDA) recently approved pemetrexed, in combination with cisplatin, for use in the treatment of malignant pleural mesothelioma, a cancer often associated with asbestos exposure. In a recent study, the largest head-to-head Phase III trial ever reported to date in second-line NSCLC, published in May’s edition of the Journal of Clinical Oncology, researchers from compare docetaxel with pemetrexed.

This new study suggests that pemetrexed, administered in 10 to 15-minute infusions once every three weeks, showed a survival rate (the primary end-point) comparable to that of docetaxel (median survival was 8.3 months vs. 7.9 months respectively), but with fewer serious side effects. In particular Grade 3 or 4 neutropenia was seen in 5 vs 40% of patients respectively and as a result fewer hospitalizations were seen in the pemetrexed treated group (1.5% 13.5%).

"Pemetrexed clearly had fewer drug-related hematological side effects, which resulted in fewer hospitalisations," said Nasser Hanna M.D., lead author of the study and assistant professor Indiana University School of Medicine and member of the . "So in short, pemetrexed is better tolerated, it's convenient to administer and it's equally as effective as docetaxel." Patients on pemetrexed did show an increased transient elevation in the liver enzyme, Alanine Transaminase (ALT), said Hanna.

Lilly has submitted a New Drug Application to the FDA for the use of pemetrexed in the second-line treatment of non-small cell lung cancer. Lilly anticipates a regulatory decision by the fourth quarter in the U.S. Lilly has also submitted a dual European submission, with the first part for pemetrexed, combined with cisplatin, in the treatment of malignant pleural mesothelioma and the second for pemetrexed as a single-agent in the second-line treatment of non-small cell lung cancer. Lilly anticipates a European regulatory decision in 2005.

"We commend the scientists in this study for their commitment to conducting quality research in an effort to support patients and physicians who are affected by this devastating disease," said Paolo Paoletti, M.D., vice-president, clinical research, oncology products, Eli Lilly and Company. "Importantly, this was a study in which pemetrexed was compared to the standard of care in the treatment of second-line non-small cell lung cancer and the results suggest similar efficacy and less blood-related toxicity for pemetrexed."

Source DailyUpdates 20^th May; for a full abstract of the original papers see  J Clin Oncol. 2004 May 1;22(9):1589-97

Recommended further reading:

• Lung Cancer - Third-Generation Cytotoxics Set to Dominate the Market
• Cytotoxics - Third-Generation Cytotoxics To Offset Taxol’s Generic Woes

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