Zosia Chustecka

June 03, 2011

June 3, 2011 (Chicago, Illinois) — An innovative model for phase 1 clinical trials was highlighted at the opening press conference here at the American Society of Clinical Oncology 2011 Annual Meeting as an example of the progress being made in personalizing cancer therapy.

These trials test new anticancer agents in patients who have already failed numerous therapies and who are considered to have incurable cancer. Historically, the response rate is only about 5%. But in the new model, which personalizes therapy by targeting drugs at identified genetic and molecular aberrations, the response rate was 27%. In addition, patients treated with matched therapies had a significantly improved time to treatment failure and overall survival, compared with nonmatched therapy.

Dr. Apostolia-Maria Tsimberidou (right)

"We have demonstrated on a large scale that this personalized-medicine approach is associated with improved clinical outcomes," said lead investigator Apostolia-Maria Tsimberidou, MD, PhD, from the University of Texas M.D. Anderson Cancer Center, Houston.

"This is an innovative program that could be used as a model, not only for phase 1 clinical trials, but also for phase 2 and 3 trials," she explained, adding that "this therapeutic strategy should eventually be used for the treatment of every patient with cancer."

That is the eventual goal of the researchers, who are part of the Institute of Personalized Cancer Therapy at M.D. Anderson. The aim is to develop the capability to test all patients with cancer over the next 5 years (around 30,000 genetic/molecular aberrations) so that they can assign appropriate therapy.

This same plan is being put into place at several other leading cancer centers across the United States. The group at the Massachusetts General Hospital in Boston recently expanded its operations and now claims to be the only center that profiles each newly diagnosed cancer patient.

This is the future of cancer therapy, said Paula Fracasso, MD, PhD, Penniston Professor of Women's Oncology at the University of Virginia, in Charlottesville, who acted as discussant for the paper.

"At the moment, treatment is organ-specific, and this is how our clinical guidelines are written," she said. "We absolutely need to change this paradigm, and probably how we are trained as oncologists," she said.

In this vision of the future, a tumor will not be treated as a breast cancer or a colorectal cancer; the tumor will be treated according to the driver mutations that are found, and these will be targeted with mutation-specific drugs. "We must do molecular profiling," Dr. Fracasso stated.

The study by Dr. Tsimberidou and colleagues is "a commendable first step toward personalized therapy," she said.

Improved Outcomes

Dr. Tsimberidou and colleagues obtained tumor tissue for analysis from 1144 patients with a variety of advanced cancers who had failed on multiple therapies.

Polymerase chain reaction (PCR)-based sequencing, immunohistochemistry, and fluorescence in situ hybridization (FISH) were used to analyze the tumor tissue for specific genetic/molecular aberrations. Initially, the researchers looked for PIK3CA, KRAS, NRAS, BRAF, EGFR, CKIT, and PTEN, but then added to the profile a few more, including GNAQ, cMET, p53, and ALK.

Molecular aberrations are found in 40% of the tumors; the majority of these (33%) had 1 aberration. When considered by cancer type, the most aberrations were found in melanoma (73%), followed by thyroid (53%), colorectal (51%), endometrial (43%) and lung (41%) cancers.

Some of the patients with tumors who had molecular aberrations were placed into clinical trials of experimental targeted drugs when the drug was matched with the aberration (n = 175). Others were placed into clinical trials with unmatched experimental therapies (n = 116).

Although this was not a randomized trial, the 2 groups were fairly well matched, Dr. Tsimberidou explained.

There was a significant difference between the matched and unmatched groups in overall response rate (27% vs 5%), time to treatment failure (5.2 vs 2.2 months), and overall survival (13.4 vs 9.0 months).

The researchers looked back at the response that each patient showed to the systemic therapy they had been treated with. Time to treatment failure was significantly better with the matched therapy than with the previous systemic therapy (5.2 vs 3.1 months); in the unmatched group, there was no significant difference.

Dr. Fracasso suggested that there are some issues with these analyses, and emphasized that the study was not randomized, so the patients in the 2 groups might have had different molecular aberrations. Also, the analysis was carried out on a tumor sample taken on initial diagnosis, and there might have been changes in the molecular aberrations as the cancer progressed and relapsed.

Despite these issues, Dr. Fracasso praised the study, and said the researchers had done "amazing work. . . . I take my hat off to them."

"This initiative tried to treat each patient as an individual," she added.

American Society of Clinical Oncology (ASCO®) 2011 Annual Meeting: Abstract CRA2500. Presented June 3, 2011.

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