Roxanne Nelson

April 04, 2011

April 4, 2011 (Orlando, Florida) — The data are very early, but combining 2 compounds that inhibit different mutated cancer pathways is showing promise in an ongoing phase 1 trial.

The researchers presented their results here at the American Association for Cancer Research 102nd Annual Meeting. They observed early signs of antitumor activity in patients with solid tumors who received combination treatment with the MEK inhibitor GDC-0973 and the class I PI3K inhibitor GDC-0941. Both drugs are under development by Genentech.

The combination was well tolerated; toxicities were similar to those seen when the agents were used alone.

"It is a pioneering effort to put 2 agents together," said Daniel D. Von Hoff, MD, physician-in-chief and distinguished professor at the Translational Genomics Research Institute in Phoenix, Arizona. "The results were pretty impressive for a phase 1 study."

"I think that combination will very likely go into a phase 2 trial for melanoma fairly soon," he told Medscape Medical News. "As for bringing it into clinical practice, I would say that is probably 18 months to 2 years away — probably closer to 2 years, by the time the phase 2 trial is completed."

Dr. Von Hoff was not involved in the study.

Two Pathways Better Than One

Dr. Johanna Bendell

The 2 pathways involved — the RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling pathways — are both deregulated in multiple tumor types. Thus, targeting both pathways may be more effective than targeting either pathway alone, explained lead author Johanna Bendell, MD, director of gastrointestinal oncology research and associate director of the drug development unit at the Sarah Cannon Research Institute in Nashville, Tennessee.

"There has been a lot of interest in blocking these pathways, both individually and together, in order to decrease the expression in cancer cells and to stop tumor growth," she said during a press briefing that highlighted the results. "The study was designed to see if these drugs could potentially be given safely together and to look at the toxicity of these agents when given in combination."

Another objective was to look for signs of potential antitumor activity, she added.

GDC-0973 is a selective inhibitor of MEK, also known as mitogen-activated protein kinase kinase (MAPKK), and is a key component of the RAS/RAF/MEK/ERK pathway, which is frequently activated in human tumors. The PI3K/Akt/mTOR pathway regulates cell growth and survival, and GDC-0941 is a novel, potent, highly specific class I PI3K inhibitor.

Evidence of antitumor activity has been observed with both of these compounds when used as single agents, she pointed out.

Dr. Bendell and colleagues conducted this phase 1b study to evaluate the safety and pharmacokinetics of the GDC-0973 and GDC-0941 combination. A total of 27 patients with advanced solid tumors have been enrolled in 6 cohorts, receiving once-daily GDC-0973 and GDC-0941 on a 21-day on/7-day off (21/7) schedule. A unique dose-escalation schedule was devised so that the dose of each agent could be increased independently on a 21/7 schedule.

They found that, for the most part, the combination therapy was well tolerated; most adverse events were grade 1/2. The grade 3 and higher events were in line with the high-grade toxicities that would be observed if the study compounds were administered alone.

The common adverse events attributed to GDC-0973 and/or GDC-0941 were diarrhea (90%; all grade 1/2), fatigue (61%; 50% grade 1/2, 11% grade 3), nausea (61%; all grade 1/2), rash (50%; 45% grade 1/2, 5% grade 3), vomiting (33%; all grade 1/2), decreased appetite (17%; all grade 1/2), and dysgeusia (17%; all grade 1/2).

Their preliminary analysis showed that the pharmacokinetics of both agents were not altered when administered in combination.

Antitumor Activity Observed

To date, 5 patients achieved more than a 10% reduction in RECIST measurable target lesions: 2 melanoma patients, 1 prostate cancer patient, and 2 patients with KRAS-mutant nonsmall-cell lung cancer (NSCLC).

In addition, 3 patients (1 KRAS-mutated NSCLC and 2 BRAF-mutated melanoma) had prolonged stable disease for more than 6 months. "In 1 patient with melanoma whose mutation status was not known, the patient had a 27% reduction in target lesions," said Dr. Bendell.

"We found that this combination has been well tolerated, we continue to look into dose escalation, and we will continue looking at further antitumor activity that this combination may have," Dr. Bendell concluded.

Dr. Von Hoff pointed out that, previously, patients with advanced melanoma had few treatment options. "But now we have BRAF inhibitors, and now there is another combination," he said.

He noted that it will be important to do genetic sequencing on the melanoma patients who responded to this combination therapy. "There is something special about those patients," he said. "We have all seen occasional responses like that in almost every trial, but why? We have never had the tools to try to dissect it, but now we do."

The study was supported by Genentech.

American Association for Cancer Research (AACR) 102nd Annual Meeting. Abstract LB-89. Presented April 3, 2011.


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