Molecular Profiling Boosts Targeted Therapies in Phase I Trial

The ability to match individual patients with targeted cancer therapies based on the molecular profile of their tumors resulted in dramatically superior clinical outcomes in a phase I trial that builds support for personalized medicine and may help speed drug development.

The study, an initiative of the MD Anderson Cancer Center at the University of Texas in Houston, was among the encouraging research developments highlighted Friday as the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) got underway.

“The message is becoming increasingly clear: If we can figure out what molecular abnormality is driving the tumor and if we have a therapy that targets that abnormality… we can get much better results than has customarily been the case,” Richard L. Schilsky, MD, a past president of ASCO who is chief of the Hematology-Oncology section at the University of Chicago Pritzker School of Medicine and deputy director of the university’s Comprehensive Cancer Center, said at a press briefing.

He said the results hold implications for clinical trials because better-matched therapies will display activity in phase I that typically is not seen until later phases, thus moving up the research timetable.

Investigators conducted molecular tests on the tumors of 1144 patients referred for phase I trials who had a variety of advanced cancers, particularly melanoma and colorectal cancers, and had undergone ≥4 previous therapies, said lead author Apostolia-Maria Tsimberidou, MD, PhD, associate professor in the Department of Investigational Cancer Therapeutics at MD Anderson. One to 4 aberrations were found in the tumors of 460 patients, or 40.2%.

Of those participants whose tumors exhibited 1 aberration, 291 patients were treated, with therapy matched to the molecular tumor abnormality for 175 patients, while 116 patients were treated with nonmatched therapies.

Tsimberidou said patients who received matched therapy had a partial and complete response rate totaling 27%, a median time to treatment failure (TTF) of 5.2 months, and a median survival time of 13.4 months.

By contrast, patients who received nonmatched therapy had a response rate of 5%, a TTF of 2.2 months, and a median survival of 9 months, Tsimberidou said.

Additionally, participants in the matched therapy group experienced a TTF of 5.2 months versus 3.1 months for their previous systemic therapy, while those in the nonmatched group saw no statistically significant difference.

For the matched group, regimens included 1 or more drugs that target molecular aberrations in genes such as PIK3CA,mTOR, BRAF, MET,KIT,EGFR, and RET.

“A therapy was considered to be matched to a patient’s tumor molecular abnormality if at least one of the drugs in the regimen was known to target the functionality of at least one of the patient’s molecular aberrations,” Tsimberidou said.

She said the results “further support the evidence of the effectiveness of the matched therapy and the superiority of the personalized medicine approach compared to the standard approach.”

Schilsky said the proportion of patients who benefit from a particular therapy in phase I is typically in the 5% range. “If you actually have a way of identifying which therapy is likely to work in a patient, you can substantially increase the likelihood of benefit for a patient even with advanced cancer, even in a phase I trial,” he said.

He said the study represents “a substantial improvement in drug development” even though 75% of the patients had no response.

Tsimberidou said in an interview there were a number of limitations to the study, which was conducted during a 4-year period. She said the study was exploratory, nonrandomized, and used archival tissue. The technology, she added, must be advanced to include more genes.

“We need to improve our technology and we need to discover targeted therapies,” she said.

For next steps, Tsimberidou said researchers should seek to “understand the emergence of resistance in patients treated with targeted therapy” as well as the impact of tumors with more than 1 aberration.

She said screening of patients for molecular aberrations should expand, noting that researchers at MD Anderson want to screen all patients who come to the center for treatment. The center sees about 30,000 patients a year, she noted.

The study, she said, “shows in a large scale that the personalized medicine approach is the future.’

Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center Initiative. J Clin Oncol. 2011. (suppl; abstract CRA2500).