Molecular profiling has the potential to revolutionize cancer medicine by helping clinicians select treatments based on the genomic characteristics of each patient’s tumor. But for most types of cancer, this potential has yet to be verified by a randomized clinical study. Such a study—in which treatment selection based on tumor molecular profiling is compared with treatment selection not based on tumor molecular profiling—is now enrolling patients with metastatic solid tumors at The University of Texas MD Anderson Cancer Center.
The study, IMPACT2, is based on early results from the ongoing first IMPACT study, in which researchers are examining the molecular profiles of tumors from patients enrolled in phase I clinical trials at MD Anderson. In a preliminary analysis of 1,144 cases, genomic alterations have been identified in 40% of the tumors. The analysis also showed that patients treated with targeted therapies known to work against at least one of their tumors’ molecular alterations have had significantly higher overall response rates and longer median overall survival and time to treatment failure than patients whose treatments did not match their tumors’ alterations.
The preliminary results of the first IMPACT study were presented at the 2011 American Society of Clinical Oncology Annual Meeting by Apostolia Tsimberidou, M.D., Ph.D., an associate professor in the Department of Investigational Cancer Therapeutics and the principal investigator of that study and the IMPACT2 study. Dr. Tsimberidou said, “These results are very encouraging, but they need to be confirmed by a randomized study before precision medicine can be widely implemented.”
Precision medicine, also known as personalized medicine, is the integration of tumor molecular data into medical practice decisions. Previous studies of precision medicine, such as the BATTLE trials in lung cancer, have focused on single tumor types, but Dr. Tsimberidou envisions a day when all cancer treatment will be guided by molecular profiling. “We wanted to develop a randomized trial to test precision medicine across multiple tumor types,” she said.
The IMPACT2 study is enrolling patients with solid tumors who have metastatic disease and have received 0–3 prior therapies. Patients must have tumors that are accessible by biopsy or have tumor tissue available that was removed within the previous year, with no therapeutic intervention in the interim.
The tumor biopsy specimens are screened with a profiling assay that detects alterations in 315 cancer-related genes. Patients are eligible for trial randomization if their tumors have genomic alterations for which a treatment is available commercially or is being studied in a clinical trial at MD Anderson. However, patients whose tumors can be treated with a targeted drug that is approved by the U.S. Food and Drug Administration (FDA) for their cancer type are not eligible for randomization; such patients would instead receive the FDA-approved drug from their treating physician.
For example, BRAF gene mutations are seen in about half of patients with melanoma. Two drugs that target the BRAF protein, vemurafenib and dabrafenib, are approved by the FDA for the treatment of melanoma; therefore, a patient with BRAF-mutant melanoma would not be a candidate for randomization in IMPACT2. However, BRAF mutations also occur, although less frequently, in patients with other tumor types, such as lung cancer or head and neck carcinoma. Such patients would be eligible for IMPACT2 because BRAF inhibitors are available but not approved for their cancer types.
Eligible patients are randomly assigned to receive targeted therapy or treatment not selected on the basis of the tumor’s molecular alterations; the latter is determined by the treating physician. Treatments for patients assigned to receive targeted therapies are determined by a tumor board that uses a standardized treatment algorithm. This algorithm is updated weekly based on the available clinical trials that are actively recruiting patients.
The tumor board, which consists of investigators from each participating department, establishes the ordered lists of molecular alterations to be targeted and of available clinical trials and targeted drugs. Each individual department determines the trial priority for each tumor type and provides updated lists of clinical trials.
“This study would not be possible without the active participation of several departments in the Division of Cancer Medicine and other divisions in our institution,” Dr. Tsimberidou said.
The study’s primary objective is to determine whether patients whose treatment is selected based on molecular profiling have longer progression-free survival than do patients whose treatment is not based on molecular profiling.
Increasing access to targeted therapy
Dr. Tsimberidou said that the IMPACT2 study is designed to address some of the barriers to the implementation of precision medicine. These barriers include the absence of routine biopsies (required for molecular profiling) for many types of cancer, the subjective nature of targeted therapy selection, and the long waits (weeks or months) for the results of molecular profiling. The study’s standardized treatment algorithms address the subjective use of targeted agents, and the turnaround time for results of the profiling assays is 14 days.
Another barrier that the study aims to help overcome is the limited access to targeted agents. By providing molecular profiling to patients who typically would not receive it because of their cancer type, IMPACT2 enables these patients to receive targeted therapy in clinical trials that they otherwise would not have been considered for.
“Access to clinical trials of targeted therapies is extremely limited,” Dr. Tsimberidou said. “In a best-case scenario, at an academic institution such as ours, perhaps 10%–30% of patients have access to targeted therapies. These should be available to all cancer patients.”
Several initiatives are under way to improve access to targeted drugs, including one by the American Society of Clinical Oncology. Dr. Tsimberidou hopes that her results will increase support for these initiatives.
Dr. Tsimberidou said, “If our results from the first IMPACT study are confirmed by IMPACT2, hopefully molecular profiling will become the standard of care for all patients with cancer.”
For more information, contact Dr. Apostolia Tsimberidou at 713-792-4259.
OncoLog, January 2015, Volume 60, Issue 1