Making a Match

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.

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.

Baker’s health care providers had told her about the risks of side effects, and trial administrators gave her up-to-date information. “It was scary,” Baker says. “At one point, they brought me a form saying people had died from complications on the trial.”

Baker’s experience illustrates what Ryan Sullivan, a cancer researcher at Massachusetts General Hospital Cancer Center in Boston, identifies as one of the biggest hurdles facing combination therapies: toxicity. Emerging combination therapies have led to promising patient survival in trials, but they have also brought serious side effects.

Toxicity derailed one of the first studies to look seriously at a combination therapy involving immunotherapy. Until 2011, patients diagnosed with metastatic melanoma had no reliable options that might help them live longer. In that year, the FDA approved Yervoy (ipilimumab) and Zelboraf (vemurafenib), both of which extended overall survival by a few months, on average. The two drugs’ approvals, within months of each other, spurred researchers to investigate combining them. A small clinical trial began in 2012.

“There was a tremendous amount of support for this trial, because if one [drug] is good, then two has to be better,” says Sullivan. “But it really was a disaster.”

Most patients taking the combination suffered side effects, especially severe liver toxicity. The phase I trial, designed to find a safe and effective dose of the combination, was shut down.

Yet over the past few years, the FDA has approved several other immunotherapies, including PD-1 inhibitors like Opdivo, which Baker took for lung cancer. In 2013, Wolchok helped launched a phase III clinical trial combining Yervoy with Opdivo. Both are immunotherapies, but they work in different ways. “They’re like two different braking mechanisms being released,” he says, which allows the immune system to react to the cancer.

Researchers are finalizing survival data on the study, but Wolchok says the combination caused tumors to shrink in about 60 percent of patients with advanced melanoma. According to clinical trial data presented in April 2016 at the American Association for Cancer Research Annual Meeting, 69 percent of patients with metastatic melanoma who were treated with the combination were still alive after two years, compared with 53 percent treated with Yervoy alone.

“It’s a good example of how knowledge of the science underlying the pathways can drive the development of more potent therapies,” Wolchok says of the drug combination. At the same time, he cautions that not all cancer types respond in the same way: A treatment that works for melanoma patients may be toxic for patients with lung cancer, for example.

Despite the positive results in clinical trials that combine these drugs, health economists warn of another kind of toxicity: the high costs of these treatments. Many clinical trials, including the one that benefited Baker, provide drugs at no cost to the patients. Once the treatment is approved for use in clinical practice, however, cost can be a major issue for patients and their insurance companies.

Wolchok presented earlier promising findings on the Yervoy-Opdivo combination at the 2015 annual meeting of the American Society of Clinical Oncology. At the same meeting, oncologist Leonard Salz, also from Memorial Sloan Kettering Cancer Center, made a startling observation: The combined annual cost for these two celebrated immunotherapy drugs is more than 4,000 times the price of the same weight of gold. Treating a person weighing about 175 pounds would cost nearly $300,000 a year, Salz claimed.

“When we’re talking about combinations of expensive medicines, cost becomes a more pressing dialogue,” says Wolchok. “It’s not going away.”

Expanding the Combination Pipeline

The cancer drug pipeline includes more than 1,000 experimental drugs. Researchers know some combinations of these drugs are likely to prolong survival more effectively than single agents acting alone—so what’s the best way to find those mixes?

In March 2016, 40 cancer researchers and pharmaceutical company leaders gathered in Boston to address the question. They had been invited by oncologist Keith Flaherty of Massachusetts General Hospital in Boston. Flaherty, who is known for innovative approaches to oncology clinical trials, noted that out of nearly 1,500 clinical trials testing drug combinations launched in 2014 and 2015, only 80 investigated combinations of experimental drugs. Only nine of those trials tested drugs made by different companies, a “dismally low” fraction, Flaherty wrote.

Flaherty had a remedy in mind. The March meeting marked the beginning of a nonprofit project called Collaborative Novel-Novel Combination Therapies, or CoNNCT, designed to combine cutting-edge biology with smart trial designs while boosting cooperation among companies to identify promising combinations of experimental drugs.

“Historically, combinations aren’t used until both agents are approved,” says Dennis Chang, a principal at Boston-based Clarion Healthcare, a consulting firm to the life-sciences industry. Clarion signed on after Chang heard Flaherty describe his vision for the project in 2015. “We found it incredibly exciting,” Chang says. “We didn’t expect Keith to have a solution in mind.” The researchers are still hammering out legal and financial details, but CoNNCT plans to start clinical trials in early 2017.

Other initiatives have also encouraged synergy. In fall 2015, pharmaceutical giant AstraZeneca, with headquarters in Cambridge, England, and the Sanger Institute, a genetic research institution also based in Cambridge, launched a competition in which entrants submitted computer models to predict the effectiveness of drug combinations. Participants had to write programs that searched among 10,000 different combinations.

Yuanfang Guan, a computational biologist at the University of Michigan in Ann Arbor, led the team that developed the winning computer model. She says the model could be used to predict how different cancers will respond to treatment, and potentially indicate patient responses as well. She thinks bioinformatics approaches that predict patient responses will become an essential tool in finding effective combinations. “Bioinformatics can help us prioritize these drug combinations,” she says. “If you just prescribe the same drug to everybody, that’s not the best solution.”

The best solution for Baker so far has been a series of treatments that keep her lung cancer at bay. She knows firsthand the pendulum swings of optimism and disappointment, of going from promising early effects to the detection of new metastases. Since the end of the nivolumab and Tarceva trial, she has participated in other clinical trials and had a small brain tumor surgically removed—a metastasis from the primary lung cancer. She has been taking Tagrisso (osimertinib), a targeted drug similar to Tarceva, since January 2015. So far her disease is not progressing.

“For people who are living longer and want to go on, you have to look at everything,” she says.

​Wolchok says exploring combinations, especially those involving immunotherapies, has just begun. “There will be combinations of immunotherapies with other [immunotherapies], or with targeted inhibitors or chemotherapy,” he says. “In cases where one drug is not producing satisfactory results, this really is the next dimension.”

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