The National Cancer Institute (NCI) has launched ComboMATCH, a large-scale precision medicine initiative designed to evaluate the effectiveness of novel drug combinations in treating various cancers. This program represents the largest effort to date in testing drug combinations guided by tumor biology, with the goal of identifying promising treatments for further clinical development.
ComboMATCH: A New Approach to Cancer Treatment
ComboMATCH (NCT05564377) is a phase 2 trial that will assess various drug combinations, typically involving two targeted therapies or a targeted agent combined with chemotherapy. The trials will enroll patients based on specific genetic changes in their cancer cells, irrespective of the cancer's origin, or based on specific cancer types. This approach contrasts with traditional methods, where treatments are primarily determined by the cancer's location in the body.
James H. Doroshow, M.D., director of NCI’s Division of Cancer Treatment and Diagnosis, emphasized the shift towards genomically-driven treatments: “With ComboMATCH, we’re trying to show that genomic abnormalities can be used to determine the most effective treatment combinations for patients.”
Addressing Drug Resistance
ComboMATCH builds upon the foundation of NCI-MATCH, which evaluated single drugs targeting specific mutations. However, many patients developed resistance to these single-agent therapies. ComboMATCH seeks to overcome this challenge by simultaneously targeting both the genetic drivers of cancer and the mechanisms of resistance.
Jeffrey Moscow, M.D., of NCI’s Investigational Drug Branch, explained the rationale behind this approach: “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.”
Trial Design and Enrollment
The drug combinations being tested in ComboMATCH include both FDA-approved drugs and investigational agents provided by pharmaceutical companies. The selection of these combinations is based on preclinical data demonstrating superior efficacy compared to single agents, as well as safety data from phase 1 studies. The ECOG-ACRIN Cancer Research Group leads the overall coordination of ComboMATCH, with all five U.S. clinical trial groups within NCI’s National Clinical Trials Network (NCTN) participating.
James Ford, M.D., of Stanford University School of Medicine, highlighted the rigorous selection process: "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."
Patients with locally advanced or metastatic solid tumors are identified for potential participation through genomic testing, now a standard part of care for many cancer types. Doctors at participating hospitals and cancer centers can refer patients with specific alterations identified in their genomic test results. Furthermore, designated commercial and academic labs conducting genomic testing can also identify eligible patients.
Current and Future Trials
Currently, three ComboMATCH trials are open for enrollment:
- A study of fulvestrant (Faslodex) and binimetinib (Mektovi) in patients with NF1-mutated, hormone receptor-positive breast cancer (NCT05554354).
- A study of selumetinib (Koselugo) and olaparib (Lynparza) or selumetinib alone in women with RAS-mutated endometrial or ovarian cancer that has recurred or persisted (NCT05554328).
- A study of chemotherapy plus ipatasertib in patients with AKT-mutated solid tumors that have spread (NCT05554380).
Six additional trials are planned for the coming months, with more to be added over time. NCI anticipates enrolling approximately 2,000 patients in ComboMATCH, with the possibility of expansion. Unlike NCI-MATCH, ComboMATCH will include pediatric patients in some trials.
NCI is also launching ImmunoMATCH and MyeloMATCH, focusing on immunotherapy and acute myeloid leukemia/myelodysplastic syndromes, respectively.
