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Making a Match

Oncologists and researchers are looking for new drug combinations that extend patient survival without worsening side effects, but it's a daunting task By Stephen Ornes

In the summer of 2012, Carole Baker’s oncologist told her she was eligible to join a clinical trial just getting underway after earlier treatments for her stage IV non–small cell lung cancer (NSCLC) had failed to stem the disease. Baker, 55, a learning specialist and mother of three school-age children, was being treated at Memorial Sloan Kettering Cancer Center in New York City.

Finding Clinical Trials
Is a combination therapy clinical trial right for you?
The phase I clinical trial was investigating an experimental treatment that combined an approved targeted drug called Tarceva (erlotinib) with a then-experimental immunotherapy drug called nivolumab. (In March 2015, the U.S. Food and Drug Administration [FDA] approved nivolumab to treat some lung cancer patients under the brand name Opdivo.) Baker didn’t hesitate to sign up for the small trial, which began in August 2012 and was intended for patients who, like Baker, had been treated previously. The combination of the two drugs kept her lung cancer from progressing for over a year, when severe side effects forced her to drop out of the trial.

Oncologists have long known that combining therapies can potentially deliver greater benefits to patients than using one treatment alone. As far back as the 1960s, combinations of chemotherapy drugs that successfully treated patients generated hope for an eventual cure for cancer. Other treatment combinations since then have brought together chemotherapy, radiation and surgery.

The latest experimental combination therapies are taking advantage of a flood of new kinds of drugs developed in the past decade or so, treatments spurred by deepening knowledge of tumor biology—namely the genes, mutations, processes and pathways that drive cancer’s growth. These treatments include targeted drugs that block or disrupt a particular receptor or process in cancer cells, as well as immunotherapies that rally the body’s immune system against cancer. They also include epigenetic drugs that target cellular processes involved in activating cancer-causing genes.

For some cancers like melanoma and breast cancer, the FDA has already approved combinations. The first therapy to include more than one targeted drug, approved in 2012 to treat HER2-positive breast cancer, brought together two monoclonal antibodies, Perjeta (pertuzumab) and Herceptin (trastuzumab), with the chemotherapy drug docetaxel. Clinical trials are now investigating additional combinations of newer drugs to treat other cancers, including lung, ovarian and kidney cancers.
The logic is clear: If an assortment of precise drugs target cancer in different ways, they may produce better outcomes when used together. In the best-case scenario, the combination will lead to synergy—an outcome greater than the sum of its parts, in which patients live longer, suffer fewer side effects, and have fewer recurrences.
“This is where we’d like to be,” says medical oncologist Jedd Wolchok at Memorial Sloan Kettering Cancer Center in New York City about such a scenario, “but we’re not there yet.” Wolchok, who researches combination immunotherapies in melanoma patients, says part of his job is explaining treatment options honestly and in a balanced way so patients who hear the hype about immunotherapy have realistic expectations. The truth is that, while combination treatments can extend survival for some people, for others, they may not be effective. The logic of combination therapies is clear, but the reality is complicated.

Finding the right combination isn’t simply a matter of matching the right drug mix to a particular cancer type. Researchers want to identify patients who are most likely to respond to a combination while avoiding serious and potentially fatal side effects. The quest to find effective combinations, which has yielded successes and failures, is being undertaken by a variety of researchers, including biologists and clinicians, as well as bioinformatics experts who are developing algorithms to search through large quantities of data to identify the needles of a promising combination in a haystack of possibilities.

Combination Treatments: A Mixed Bag
Baker’s journey has been long and rocky. In April 2011, she sought medical attention for severe back pain and, to the nonsmoker’s surprise, was diagnosed with metastatic lung cancer. Genetic tests identified a mutation in her cancer cells in the epidermal growth factor receptor (EGFR) gene, which is relatively common in nonsmoking NSCLC patients like Baker. She was prescribed Tarceva, a first-line drug for patients with EGFR-positive NSCLC, but after nine months, the disease began to spread. She then joined a clinical trial combining two experimental EGFR inhibitors, but the drugs didn’t work for her and she experienced severe side effects.

Next came the clinical trial combining Tarceva with nivolumab. Baker took Tarceva in pill form every day and received an IV infusion of nivolumab, the immunotherapy drug, every two weeks. About a year into the trial, in mid-summer 2013, the side effects of the treatment became drastic. Baker began having diarrhea as often as 25 times daily and lost a lot of weight. Hormone production in her adrenal gland dropped precipitously. She was removed from the trial in October 2013 because of the side effects. Further tests suggested the nivolumab had brought on immune-related colitis, which had led to the diarrhea.


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