Combining Therapies to Improve Outcomes

Combination therapies have proven to be vitally important in the successful treatment of patients with many types of cancer. Combining treatments that have different mechanisms of action can kill more cancer cells and reduce the chance that drug resistance will emerge. The overall goal is to improve a patient’s response to therapy without substantially increasing toxicity.

In recent years, the identification of new combination therapies has accelerated, with hundreds of clinical trials testing combinations that include chemotherapy drugs, radiation therapy, hormonal therapies, molecularly targeted therapies, and immunotherapies. However, a more systematic approach is needed to identify the most promising combinations among the many thousands of possibilities, advance them to clinical trials, and make them available to patients who will benefit from them.

NCI plays an important role in supporting the research needed to develop combination therapy approaches. In addition, NCI brings different institutions and organizations together to advance this area of research. Examples of Food and Drug Administration (FDA)-approved drug combinations that have been studied in NCI-sponsored clinical trials are docetaxel (Taxotere®), doxorubicin, and cyclophosphamide for breast cancer and oxaliplatin (Eloxatin®), 5-fluorouracil, and leucovorin (Wellcovorin®) for colorectal cancer.

Research Priorities

NCI advances combination therapies for cancer by supporting preclinical research and testing promising combinations in clinical trials.

Support Basic and Preclinical Research to Identify Combination Therapies

Research should guide the selection of candidate combination treatments. This research can provide deeper insights into the mechanism(s) of action of individual treatments, how different treatments might work together, the potential side effects that may occur when treatments are combined, and how new combinations might be given to patients (doses and schedule).

NCI efforts include several resources for researchers:

  • To aid in the systematic development of combination therapies, NCI’s Developmental Therapeutics Program created the NCI ALMANAC, a public resource that contains data on more than 5,000 pairs of FDA-approved drugs that were screened at different doses against 60 human cancer cell lines (the NCI-60 Human Tumor Cell Lines Screen). In one study, NCI researchers tested two drug pairs in the NCI ALMANAC that exhibited potent cell-killing activity. Nilotinib (Tasigna®) plus paclitaxel (Taxol®) and bortezomib (Velcade®) plus clofarabine (Clolar®) had antitumor activity in several mouse models of human cancer. The results of these studies were convincing enough that both combinations are being tested in early-phase clinical trials.
  • Models of human cancer help researchers screen drug combinations for effectiveness and study ways to overcome the problem of drug resistance. NCI facilitates the development of new models of human cancer, including new tumor cell lines and mice bearing patient-derived tumor grafts (known as patient-derived xenografts, or PDXs). Some models are available upon request to researchers in the United States through the NCI Patient-Derived Models Repository.

Facilitate Clinical Trials of Promising Treatment Combinations

NCI leads several initiatives to investigate promising combination therapies in clinical trials, including funding for investigator-initiated trials and resources for researchers.

  • NCI has funded more combination therapy studies than any other organization. Stories about several of these trials are highlighted in this section, including the story of trial participant and ovarian cancer survivor Betsy Brauser of Florida; Valerie Winston of Maryland, who participated in a trial for high-risk smoldering myeloma; and a research team at the University of Pennsylvania, who combined radiation therapy with immune checkpoint blockade.
  • To facilitate testing of new drug combinations by academic investigators, NCI launched the NCI Formulary in 2017. The formulary is a public–private partnership between NCI and pharmaceutical and biotechnology companies that gives investigators at NCI-Designated Cancer Centers rapid access to agents or combinations of agents, from multiple pharmaceutical companies, for preclinical testing and clinical trials. The formulary is designed to drastically shorten the amount of time needed to obtain treatments from more than one company.
  • A major activity of NCI’s Cancer Therapy Evaluation Program is oversight of the National Clinical Trials Network (NCTN), which can facilitate combination therapy trials. NCTN is one of the largest publicly funded cancer trials organizations in the world and provides the infrastructure and streamlined mechanisms to plan and conduct cancer clinical trials efficiently throughout the United States. NCTN facilitates proposal submission, timely review by the collaborating pharmaceutical companies, agent distribution, serious adverse event reporting, and clinical data reporting, while providing a coordination mechanism between the clinical investigators and the pharmaceutical company collaborators.

Stories of Impact

NCI supports the discovery and development of combination therapies for cancer to bring even more effective treatments to patients.

Combining Drugs to Treat Ovarian Cancer

Betsy Brauser was diagnosed with stage IIC ovarian cancer in 2009. She underwent standard platinum-based chemotherapy, and her doctors gave her an all-clear. But a year later, scans revealed her cancer had returned. So, she found a phase I clinical trial for patients with ovarian cancer at the NCI-Designated Dana-Farber/Harvard Cancer Center in Massachusetts.

Stopping Multiple Myeloma in Its Tracks

Valerie Winston is thankful that she went to her doctor for a routine physical examination in 2009. The results of standard tests indicated that she was at risk for multiple myeloma. Thanks to a clinical trial testing a combination of therapies for individuals like Valerie, she never had to experience cancer’s full impact.

Joining Forces against Cancer

A cross-disciplinary team of scientists and physicians at the University of Pennsylvania is redefining the role of one of cancer medicine’s oldest tools and blazing a new trail in the treatment of patients. Their efforts, led by cancer immunologist and oncologist Bob Vonderheide and radiation oncologist Andy Minn, are demonstrating the promise of combining immune checkpoint inhibitors and radiation therapy.

Key Takeaways

  • NCI is committed to developing new combination therapies that will extend the lives of more cancer patients.
  • NCI supports the development of new models of human cancer, including in racial/ethnic populations, to advance the testing of combination therapies and find ways to overcome the problem of drug resistance.
  • NCI is uniquely positioned to bring together different institutions, organizations, and companies to advance this area of research.