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Clinical trial of Combination of Targeted Anti-Kras Therapy for Pancreatic Cancer

Dutch and primarily other European researchers are about to begin a human clinical trial involving a regimen of two relatively new targeted therapies (afatinib plus selumetinib) for the treatment of pancreatic cancer (ductal adenocarcinoma of the pancreas).  Afatinib is known as Gilotrif in the U.S., and is produced by the family-owned global but German-headquartered Boehringer Ingelheim Pharmaceuticals firm.  Selumetinib is produced by the AstraZeneca firm (AZ); it is currently in the Phase III SELECT-1 clinical trial in combination with docetaxel for the second-line treatment of KRAS positive non-small cell lung cancer.  AZ is partnering with Roche Molecular Systems to develop a test marker to help identify those patients who are most likely to respond to selumetinib.

The lead institution for the upcoming clinical trial involving pancreatic cancer will be the Antoni van Leeuwenhoek Hospital in Amsterdam. The work is based on earlier study by Bernards, Sun and other researchers who laid the predicate for this research in a recently published medical article on March 17, 2014 in the journal Cell Reports about the effects of this combination regimen in overcoming Kras resistant lung and colon cancer.  The coming human clinical trial will also include lung and colon cancer, as well as pancreatic cancer.

The mutated ras oncogene is found in approximately 90% of cases of pancreatic cancer (pancreatic adenocarcinoma), and generally in about 20 – 30% of human cancer. These cancers tend to be ones that are particularly difficult to treat – with a tendency to poor outcome.  In fact, one of the four specific initiatives proposed by the recent Scientific Framework for Pancreatic Ductal Adenocarcinoma of the U.S. National Cancer Institute is: “Developing new treatment approaches [for pancreatic cancer] that interfere with RAS oncogene-dependent signaling pathways.”

The recent study by Bernards et al. on Kras mutant colon and lung cancer found that suppression of the tyrosine kinase receptor ERBB3 had the effect of sensitizing these tumor cells to MEK inhibitors. Afatinib is a tyrosine kinase receptor inhibitor that not only affects epidermal growth factor receptor (EGFR – as does erlotinib -Tarceva), but also acts in a wider manner in these regards.  Afatinib received U.S. FDA approval on July 12, 2013 for the treatment of metastatic non-small cell lung cancer which has EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.  Selumetinib blocks the enzyme MAPK kinase (MEK) that is just “downstream” from the BRAF gene and which is also involved in the Kras gene signaling pathways.

In the recent published study, the authors found that the combination of these targeted therapies acted synergistically in promoting cell death in Kras resistant lung and colon cancer cells, AND in significantly reducing tumor growth (to about zero growth over the 4-week study period) in referent mice models. It is easy to see why the authors have now added pancreatic cancer to the study.

Thus, the researchers have presented biological plausibility of the regimen in mutated Kras tumors and have established a basis for possible preliminary efficacy in pre-clinical studies in regard to pancreatic cancer. And so the process of human testing begins. It will be of some interest to see if the efficacy holds in human subjects, and what the tolerability profile will reveal.  And the effect specifically on pancreatic cancer.  This is interesting and promising work.

More Here (PDF download)

Dale O’Brien, MD