Cell culture of human breast cancer conditionally reprogrammed cells. CREDIT: Ewa Krawczyk, National Cancer Institute\Georgetown Lombardi Comprehensive Cancer Center, National Institutes of Health
The National Cancer Institute (NCI), part of the National Institutes of Health, has launched a large precision medicine cancer initiative to test the effectiveness of treating adults and children with new drug combinations that target specific tumor alterations. Known as the Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH), the initiative is the largest of its kind to test combinations of cancer drugs guided by tumor biology. The endeavor aims to identify promising treatments that can advance to larger, more definitive clinical trials outside of ComboMATCH.
ComboMATCH comprises numerous phase 2 treatment trials that will each evaluate a drug combination—usually either two targeted drugs or a targeted drug plus a chemotherapy drug. Some trials will include patients with specific changes in their cancer cells, no matter where the cancer arose in the body, whereas others will enroll patients with specific cancer types.
Targeting genetic changes
“The majority of treatments that patients get nowadays are not genomically determined,” said James H. Doroshow, M.D., director of NCI’s Division of Cancer Treatment and Diagnosis. “With ComboMATCH, we’re trying to show that genomic abnormalities can be used to determine the most effective treatment combinations for patients.”
ComboMATCH (NCT05564377) is a cross-group collaboration among NCI and all five U.S. clinical trial groups within NCI’s National Clinical Trials Network (NCTN). ComboMATCH is a successor to NCI-MATCH, NCI’s groundbreaking precision medicine clinical trial. In NCI-MATCH, people were assigned to treatment based on genetic changes in their tumor rather than their type of cancer.
For the most part, NCI-MATCH evaluated single drugs targeting the mutation thought to be driving the growth of a patient’s tumor. However, many patients quickly developed resistance to these single drugs.
“With ComboMATCH, we’re hoping that by attacking both the genetic driver and the mechanisms of resistance, we will obtain more durable clinical responses and more benefit to patients,” said Jeffrey Moscow, M.D., of the Investigational Drug Branch in NCI’s Division of Cancer Treatment and Diagnosis and a co-leader of ComboMATCH.
Testing both FDA-approved and investigational drugs
The combinations will include both U.S. Food and Drug Administration-approved drugs and investigational agents contributed by pharmaceutical companies. Hundreds of thousands of potential drug combinations exist, so one challenge has been to narrow down and prioritize the most promising ones.
The overarching ComboMATCH coordination effort is led by the ECOG-ACRIN Cancer Research Group. All five U.S. NCTN groups, which include the Alliance for Clinical Trials in Oncology, Children’s Oncology Group, ECOG-ACRIN Cancer Research Group, NRG Oncology, and SWOG Cancer Research Network, will lead ComboMATCH treatment trials.
“An important strength of the study is that the combinations being evaluated in ComboMATCH will be based on preclinical data showing that indeed the combination is better than either agent alone, as well as safety data from phase 1 studies,” said James Ford, M.D., of Stanford University School of Medicine, a co-leader of ComboMATCH and lead investigator on the coordination effort by ECOG-ACRIN. “There will be agreement among all the NCTN trial group representatives to evaluate each combination.”
Several avenues for participating
There are several ways in which patients with locally advanced or metastatic solid tumors will be identified for possible participation in ComboMATCH. In recent years, genomic testing of tumors has become a standard part of care for people with many cancer types. A doctor at any of the community hospitals and cancer centers participating in ComboMATCH can refer their patient for additional eligibility screening if the patient’s test results show that they have a particular alteration being investigated in one of the treatment trials.
Any one of the nearly 35 designated commercial and academic labs that are conducting genomic testing as part of standard of care can also identify patients who might be eligible for a ComboMATCH trial.
Patients who are matched to a trial will be asked to provide a pretreatment tumor biopsy specimen for genomic profiling. This will enable ComboMATCH investigators to later probe other questions, such as why some treatments worked and others didn’t.
To learn more, visit the National Institutes of Health.