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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

Pralatrexate: Novel Chemotherapy Being Tested in Lung Cancer
Author
Howard (Jack) West, MD

In my last post I described a new study that will be randomizing previously treated advanced NSCLC patients with a current or prior smoking history to receive either tarceva or a new chemotherapy called pralatrexate. Now it’s time to provide a little background on this new agent.

The name pralatrexate may not roll off the tongue, but its full name is just plain painful: 10-propargyl-10-deazaaminopterin. Mercifully, this is abbreviated PDX, which is what how we’ll refer to it from now on. It’s one of a class of drugs in the family called antifolates, descendants of the venerable chemo methotrexate, and they work by interfering with the cell’s ability to make purines, one of the building blocks of DNA. Alimta, with the full name pemetrexed, is a newer member of the antifolate class as well. A chemical modification on pralatrexate leads to increased cellular uptake and maximal concentrations in cells. This agent is very effective in lab models of breast or lung cancer cells (references here and here).

The earliest phase I studies in human cancer patients were done at Memorial Sloan Kettering Cancer Center in NYC, led and reported by Dr. Lee Krug there (abstract here). The first included 33 patients with advanced NSCLC who had received a median of two lines of prior treatment and then received PDX either weekly or every two weeks by vein. They were only able to get up to a dose of 30 mg/m2 IV every week (6 patients in total), before being limited by mouth sores and other side effects, but they were able to get much higher doses with an every two week schedule. Among the 27 who received PDX every two weeks, they got up to a dose of 170 mg/m2 before the point of prohibitive side effects, and they recommended moving ahead with a dose of 150 mg/m2 IV every two weeks as the best dose for future study. Importantly, two of the patients in the study had partial responses. While this may not sound like a high rate of response, I’ll remind you that our current FDA-approved best agents for previously treated patients – taxotere, alimta, and tarceva – have response rates below 10% in the larger trials of pre-treated patients.

Dr. Krug from MSKCC also led a phase II trial in advanced NSCLC (abstract here). This study enrolled 39 patients who had either received no prior treatment or who had demonstrated stable disease or a partial response to their prior treatment (maximum of one regimen). This trial was therefore in a group of patients who you would hope and expect would do a little better. Toxicity, primarily mouth sores, was a problem, and the investigators reduced the dose from 150 mg/m2 to 135 mg/m2 for the last 10 patients. The response rate was 10% (4 patients), with responses lasting up to 15 months, and another third of the patients had stable disease. The median survival exceeded a year, and more than a third of patients remained alive two years into the study. Overall, the results were felt to be encouraging enough to justify further clinical studies.

Several years ago, during the development of alimta, it was discovered that if patients took folate (also known as folic acid) supplementation as a daily pill they could “rescue” normal, non-cancer cells in patients on a similar anti-folate drug like alimta (cancer cells don’t take up folate as well and are therefore more likely to still be damaged by the chemo). Subsequent work also done at MSKCC and just published (abstract here) indicates that adding B12 and folate supplementation during treatment with PDX reduces side effects and allows for escalation of the dose. This is why B12 and folate supplementation are added in the treatment plan for the new trial (link here) that compares PDX to tarceva among previously treated smokers with advanced NSCLC. The supplemental vitamins will also be given to the recipients of tarceva, just in case it’s the vitamins that provide benefit greater than the presumed anti-cancer drug.

In addition to the trial described above, new research with PDX is moving forward that is studying combinations of PDX with other anti-cancer therapies, in solid tumors such as lung cancer as well as certain lymphomas. I'll try to keep people posted on any new information on this agent in the future.

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