The National Cancer Institute (NCI) has launched a new set of large, precision medicine–based clinical trials—known as the ComboMATCH initiative—that will examine the efficacy of novel drug combinations targeting specific tumor mutations in adult and pediatric patients with cancer. The new initiative will seek to identify promising new treatment strategies that can advance to larger, more definitive clinical trials.
Background
ComboMATCH (ClinicalTrials.gov identifier NCT05564377) is a cross-group collaboration among NCI and all five U.S. clinical trial groups within NCI’s National Clinical Trials Network (NCTN)—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.
The new initiative is a successor to NCI-MATCH—NCI’s previous precision medicine clinical trial. In NCI-MATCH, patients were assigned agents based on the genetic mutations in their tumors rather than their cancer types. Researchers evaluated single drugs targeting mutations thought to be driving tumoral growth; 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,” highlighted Jeffrey Moscow, MD, Chief of the Investigational Drug Branch in the Division of Cancer Treatment and Diagnosis as well as Co-Leader of ComboMATCH at NCI.
ComboMATCH Overview and Goals
The new ComboMATCH initiative comprises numerous phase II trials that will each evaluate a different drug combination—either two targeted drugs or a targeted drug plus a chemotherapy agent. Some of the trials will include patients who have specific mutations in their cancer cells, disregarding their cancer types, whereas others will enroll patients on the basis of their cancer types.
“The majority of treatments that patients get nowadays are not genomically determined,” explained James H. Doroshow, MD, Director of the Division of Cancer Treatment and Diagnosis, Deputy Director of Clinical and Translational Research, and Head of the Oxidative Signaling and Molecular Therapeutic Group at NCI. “With ComboMATCH, we’re trying to show that genomic abnormalities can be used to determine the most effective treatment combinations for patients,” he added.
The treatment combinations will include both U.S. Food and Drug Administration–approved drugs and investigational agents contributed by pharmaceutical companies. The researchers stressed that with hundreds of thousands of potential drug combinations, a challenge has been to narrow down and prioritize the most promising ones.
“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 I studies,” revealed James Ford, MD, Professor of Medicine (Oncology) and Genetics at the Stanford University School of Medicine, Director of the Stanford Cancer Genetics Clinic and the Cancer Genomics Program at the Stanford University Medical Center, and Co-Leader of ComboMATCH at NCI. "There will be agreement among all the NCTN trial group representatives to evaluate each combination,” he noted.
ComboMATCH Trial Enrollment
The researchers detailed several ways in which they plan to identify patients with locally advanced or metastatic solid tumors for possible participation in the ComboMATCH clinical trials. In recent years, genomic tumor testing has become a standard part of care for patients with many cancer types. A physician at any of the community hospitals and cancer centers participating in ComboMATCH can refer their patients for additional eligibility screenings if their test results indicate that they have a particular mutation being investigated in one of the new 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 one of the ComboMATCH trials.
Patients who are matched to a trial will be asked to provide a pretreatment tumor biopsy specimen for genomic profiling—enabling researchers to later probe other questions, such as why some treatments worked and others didn’t.
Three of the ComboMATCH trials are currently open for enrollment:
- A trial evaluating the use of fulvestrant and binimetinib in patients with NF1-mutated, hormone receptor–positive metastatic breast cancer (NCT05554354)
- A trial testing the use of selumetinib in combination with olaparib or selumetinib alone in female patients with RAS-mutated, relapsed or refractory endometrial cancer or ovarian cancer (NCT05554328)
- A study of chemotherapy plus ipatasertib in patients with AKT-mutated metastatic solid tumors (NCT05554380).
The researchers detailed that six additional trials will be available in the coming months, and more will be added over time. Overall, NCI plans for ComboMATCH to include about 2,000 patients, but that number could grow.
Unlike NCI-MATCH—which did not include pediatric patients but rather had a separate parallel trial called PediatricMATCH—some ComboMATCH trials will include pediatric patients with cancer.
Conclusions
NCI will be launching two additional precision medicine–based clinical trials for patients with cancer. ImmunoMATCH has started with a pilot study to determine how prospective characterization of the immune status of a tumor can be used to improve the responses to targeted treatments using immunotherapy, with plans to expand into larger studies in the future. MyeloMATCH will test treatments based on genetic changes in the cancer cells of patients with acute myeloid leukemia or myelodysplastic syndromes.
Disclosure: To learn more about the ComboMATCH clinical trials, visit cancer.gov.
