Genomic Profiling Yields OS Benefit for Patients With Targeted Therapy Matches

Author(s):

Olivier Tredan, MD, PhD, chair of the Department of Medical Oncology at the Centre Léon Bérard in Lyon, France

Olivier Tredan, MD, PhD

Comprehensive genomic testing is not yet widespread, but a French study presented at the 2017 ASCO Annual Meeting suggested that DNA profiling can be of important value in advancing personalized medicine. Patients who received molecularly targeted agents based on genomic profiles had longer 3-year and 5-year overall survival (OS) than those who did not.

The ongoing ProfiLER test of tumors from patients with advanced cancer found at least 1 clinically actionable genetic alteration in 52% of the tumor samples tested. Clinically actionable was defined as a mutation that could be matched with a targeted therapy. After reviewing the genomic profiles, a tumor board was able to recommend treatments to 676 patients, 143 of whom received the recommended treatments and, on average, had better OS than patients who did not.

“This study confirms that comprehensive genomic profiling can be performed in routine practice to select patients for targeted cancer therapies,” said lead study author Olivier Tredan, MD, PhD, chair of the Department of Medical Oncology at the Centre Léon Bérard in Lyon, France, in a statement. “The technology is widely available and requires only a small amount of DNA. Theoretically, we could do this testing for every patient in France.”

The 5-year OS rate for those who received a molecularly targeted agent was 34.8% (CI 95%, 26.2-43.6) versus 28.1% (CI 95%, 23.7-32.8) for those who did not. The 3-year survival rate was 53.7% (CI 95%, 44.9-61.7) versus 46.1% (CI 95%, 41.4-50.6), respectively. The OS rates reflect the 143 patients who received targeted therapy based on genomic testing and 533 who did not.

The DNA from tumor samples was analyzed by next-generation sequencing of 69 cancer-related genes and whole-genome-comparative genomic hybridization, a means of rapidly comparing DNA samples. “We recommended molecularly targeted therapies to patients who had mutations in pathways that could be targeted with either commercially available drugs or those tested in early clinical trials,” Tredan said.

To date, 2676 patients have been enrolled in the study and 1944 tumors have been analyzed, representing approximately 16 cancer types including breast, colorectal, gynecologic, head and neck, and sarcoma. Actionable mutations were found in 1004 samples. The authors said 609 patients had just 1 actionable mutation, whereas 394 had from 2 to 6.

A main reason tumor analysis was not successful was the receipt of an inadequate quantity or quality of tumor DNA, Tredan said. The authors said PI3K/mTOR pathway was the most common actionable mutation, encompassing more than 60 patients. Approximately 30 patients were given multitarget TKR inhibitors and antiangiogenics. The next most commonly prescribed agents were cell-cycle inhibitors, received by nearly 20 patients.

Sumanta Kumar Pal, MD, a medical oncologist with City of Hope who provided expert commentary for ASCO during a presscast about the research, said that what he found significant about the study was that more than half of the samples were found to have mutations that could be matched with available targeted therapies. “In those cases where treatment could not be defined by the study algorithm, the dominant cause was the lack of availability of a molecularly targeted agent,” he said. In other cases, he said, patients died before treatment could be implemented.

These factors point to the need to expand the repertoire of molecularly targeted agents and to consider implementing such therapies sooner in clinical trials to enable patients to participate, Pal said.

Comparison With TAPUR Study

The ProfiLER 02 study will compare the gene test used in this research with a commercial, 315-gene test in an effort to determine whether screening for a larger number of mutations will identify more potential targeted therapies for patients.Richard L. Schilsky, MD, senior vice president and chief medical officer for ASCO, related the ProfiLER trial to the TAPUR study, through which study participants get access to targeted drugs matched to the genomic profiles of their tumors. The goal of TAPUR, which ASCO is sponsoring, is to learn about potential new uses of targeted agents.

“We’re finding increasingly that patients with advanced cancer no longer have standard treatment options,” said Schilsky, during the presscast Saturday. “We are having genomic profiling tests performed on their tumors, but there are many questions that remain. Who pays? That’s an obstacle. And more importantly, is it worth it? Does the test actually provide information that leads to a therapeutic initiative that wasn’t previously considered and that actually could benefit the patient?”

Schilsky said that the first TAPUR results could be released by the end of this year. He said the rapid expansion of the TAPUR trial, which is attracting huge interest from clinics around the world that want to participate, will be of value in gathering structured data on the amount of experimentation that is already taking place with targeted medicines.

“Because this type of off-label prescribing of drugs is going on every day in clinical practice in the United States and around the world, a big issue is how do we learn from these experiences? We really have to be able to capture these data in a way that we can all learn from the experience of these patients,” he said.

The TAPUR study is a nonrandomized, phase II basket trial whose objective is to describe the antitumor activity of commercially available targeted anticancer drugs that are prescribed for treatment of patients with advanced cancer.

The trial was launched 15 months ago and has about 300 patients enrolled so far; 65 cancer centers in the United States are currently participating, a number that is expected to grow to 103 centers in 21 states this year, Schilsky said. The eligibility age for patient enrollment in the trial has been lowered from 18 to 12 years. The trial provides access to 17 commercially available therapies, and Schilsky, who serves as primary investigator, said more are hoped for. So far, researchers are achieving a 60% to 65% match rate for actionable mutations, he said.

However, the widening spectrum of known driver mutations is a sign of the increasing difficulty and complexity of the task now before the oncology community, he said.

Tredan O, Corset V, Wang Q, et al. Routine molecular screening of advanced refractory cancer patients: an analysis of the first 2490 patients of the ProfiLER study. J Clin Oncol. 2017;35(suppl; abstr LBA100).

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