Roche Co-Developed Drugs Deliver Early Synergistic Results Without Added Toxicities

One + one turned into a possible three when Genentech drugs targeting PI3K and MEK were combined in an early solid tumor study reported at the American Association for Cancer Research meeting April 2.

ORLANDO, Fla. -Early data from a pioneering study that combines two Roche experimental cancer drugs show their effect may be greater than what might be expected from their individual profiles - with no added toxicities.

"We were concerned that when you block two major pathways within the cancer cells [the results would be] too toxic for the patients to handle, and what we were very pleased to find out from this study is that we can do it safely," Johanna Bendell, associate director of the drug development unit at the Sarah Cannon Research Institute, Nashville, said April 2 during a media briefing at the American Association for Cancer Research meeting in Orlando.

The potential for synergistic toxicities is one reason FDA, in the regulations it is drafting for co-development of drugs designed for use in combination, has said that the drugs must be aimed at only the most serious of diseases and conditions (Also see "FDA Issues Co-Development Guidance, But Only For Products Treating "Serious" Diseases" - Pink Sheet, 14 Dec, 2010.).

The ongoing Phase Ib study tests GDC-0973, which inhibits MEK1/2, and GDC-0941, which inhibits PI3K, in highly treatment-experienced patients with advanced solid tumors. Both are being developed by Roche's Genentech division. Bendell said this is the first project she is aware of involving this particular combination.

The drugs have already shown independent activity against targets in two of the most commonly abnormal pathways in cancer cells: PI3 kinase and RAS-RAF-MEK. The hope is that blocking both simultaneously will short circuit the crosstalk that enables tumors to develop resistance to single-agent, single-pathway therapies.

The study has so far enrolled 30 colorectal, melanoma or non-small cell lung cancer patients in six cohorts with a median of six prior therapies. While its primary purpose is to establish the safety and tolerability of the combination in patients with solid tumors, some indications of efficacy are emerging. One melanoma patient who has been on the study 245 days has experienced a 27% decrease in tumor burden shown by radiology, and five others have had a greater than 10% decrease in RECIST (response evaluation criteria in solid tumors) measurable lesions: two with melanoma, one with prostate cancer and two with KRAS mutant non-small cell lung cancer.

According to the study abstract, in single-agent Phase I trials, both compounds demonstrated suitable tolerability and pharmacokinetic properties. In preclinical models, concurrent administration showed improved efficacy in combination when compared to efficacy of either agent alone.

During a symposium on late-breaking research April 3, Bendell elaborated, noting the pharmacokinetic properties of the PI3K inhibitor didn't change when MEK was added, and that the MEK inhibitor's PK was not significantly altered either.

-Shirley Haley ([email protected] )