Complexities of Immunotherapy Highlighted at New Drugs Seminar

Complexities of Immunotherapy Highlighted at New Drugs Seminar

In the past 5 years, cancer immunotherapy has captured the attention of not only the medical community but also the general public. Numerous reports in peer-reviewed literature and the lay press have detailed clinical successes with immunotherapy, and a recent cover story in Time highlighted the promise of this therapeutic approach. This year, ASCO’s annual report on the progress against cancer, Clinical Cancer Advances 2016, named immunotherapy the Clinical Cancer Advance of the Year.

Yet for all the attention, many questions remain about the challenges of successfully integrating immuno-oncology (IO) into current models of cancer care. The annual New Drugs in Oncology Seminar kicked off on June 2 with the session “Novel Direction of Clinical Trial Design,” at which speakers addressed some of the issues involved in realizing the promise of immunotherapy.

Immunotherapy Bubble?

Chair Anthony W. Tolcher, MD, FRCPC, FACP, of the South Texas Accelerated Research Institute (START), began the session with a provocative question: Does the current proliferation of clinical trials in immunotherapy represent “a period of growth or a worrisome bubble?” He compared the present era, with multiple emerging immunotherapeutic drugs, to the proliferation of cytotoxic chemotherapies following the success of cisplatin in the 1970s.

“We spent the next 30 years developing more than 25 new cytotoxic agents, many of which were disappointing,” Dr. Tolcher said. “Many of them brought incremental improvement, but none had the same single-agent curative effect as cisplatin. So it’s important to remember that we have seen transformational therapies come before, but afterward we may not be able to build on that for many years.”

PD-1 inhibitors, such as pembrolizumab and nivolumab, have been transformative in a way that other immunotherapies had not, Dr. Tolcher said. Although other checkpoint inhibitors are now in development, they are not, for the most part, expected to achieve the same levels of single-agent activity as the PD-1 inhibitors.

To demonstrate that any new immunotherapeutic agent has efficacy superior to that of an existing agent, a large-scale clinical trial is needed, on the order of 300 to 600 patients, Dr. Tolcher said. But with multiple agents in development, patient recruitment becomes a challenge. A recent search of for the terms “immunotherapy” and “cancer” returned more than 450 results, with many trials pursuing the same few indications where immunotherapy has shown efficacy to date: melanoma, non–small cell lung cancer, renal cancer, bladder cancer, and head and neck cancers.

“With so many people pursuing the same indications, there are very soon not going to be enough patients to sustain that large number of studies,” Dr. Tolcher said. In addition, patients with many types of cancers have not seen benefit from treatment with PD-1 inhibitors, he said, including most patients with colon cancer, sarcoma, and esophageal cancer.

The economic definition of a “bubble” is a market cycle characterized by rapid expansion followed by contraction. The most recent example of an economic bubble was the collapse of the housing market in 2008, which destroyed the wealth of many investors, large and small. Other examples include the stock market bubbles that burst in 1929 and 1987, and the dot-com bubble of the 1990s that burst in 2001.

Dr. Tolcher asserted that oncology has seen several bubbles of its own, including the multiple platinum “look-alikes” that appeared following the development of cisplatin, a spate of doxorubicin look-alikes, and the development of more than 25 agents targeting EGFR and more than 25 agents targeting VEGFR. Keeping in mind that fewer than one in 10 drugs entering clinical trials reach regulatory approval, Dr. Tolcher suggested that the current atmosphere surrounding immunotherapy constitutes a bubble. He borrowed the phrase “irrational exuberance,” used by Alan Greenspan, chairman of the Federal Reserve Board during the dot-com bubble, to describe the recent phenomenon of multiple large pharmaceutical companies spending up to $1 billion to acquire a new immunotherapy or a company developing one.

To bring this market back down to earth, Dr. Tolcher suggested that a number of pragmatic steps are necessary. He cautioned against the “herd mentality” in which multiple agents and combinations of drugs are being assessed in clinical trials in the same narrow group of indications in which immunotherapy has been shown to work. He said clinical trials should be directed at what he called “real phase I patients”—those who have exhausted other therapies or who have some organ dysfunction and comorbid illness, rather than healthier patients. He advised leading clinical researchers, the so-called key opinion leaders, to avoid cheerleading and self-interest, and he counseled pharmaceutical firms to resist pressure from Wall Street analysts to be “in the IO space.”

There are a number of reasons clinicians should wish for the IO bubble to end safely, he said. First, after a bubble collapses, funding dries up, even for worthy ideas, and funders become cynical. Second, IO research is still in its infancy, and clinicians must better understand why some patients respond to immunotherapy and some do not, and why their chosen target might or might not be superior to other targets. Third, clinical trial participants are not an unlimited resource. “Unless somehow change occurs, clinical trials are going to become a zero-sum game,” he said. And finally, the cost of failed research and development in oncology is directly reflected in the price of newly approved agents, and the best way to reduce those prices is to reduce the number of failures and speed drug approvals.

To promote rationally rather than irrationally exuberant drug development, Dr. Tolcher said, investors must be more skeptical, biotech and pharma companies must have realistic goals, investigators must be efficient, and key opinion leaders must be objective.

“Honest appraisal, even if painful, is priceless in a bubble,” Dr. Tolcher said.

Combination Trials

Howard A. Burris III, MD, of Sarah Cannon, spoke about how the population of patients benefitting from immunotherapy might be increased through the use of combination therapies. Like Dr. Tolcher, he stressed that clinical trials of combination therapies must be well designed, rationally developed, and efficiently run.

Dr. Howard A. Burris III

The goals for combining therapies with immunotherapy include broadening the group of responders, improving the response rate and duration of response, overcoming resistance to single-agent therapy, and modifying the toxicity profile of existing regimens.

Hundreds of immunotherapy combination trials are ongoing, addressing almost every type of cancer, Dr. Burris noted. In a search for open trials on, he identified 85 assessing combinations with ipilimumab, 149 with pembrolizumab, 104 with nivolumab, and 42 with atezolizumab. Last year, for the first time, the U.S. Food and Drug Administration approved an immunotherapy combination, ipilimumab plus nivolumab, for the treatment of metastatic melanoma.

Multiple types of immunotherapy combinations are possible, Dr. Burris said, not simply dual checkpoint blockade. Other potential combinations include checkpoint plus costimulatory receptor agonists, checkpoint plus IDO pathway inhibition, checkpoint plus innate immunity potentiators, checkpoint plus oncolytic viruses, checkpoint plus adoptive T-cell transfer or T-cell engineering, checkpoint plus small molecules that create an immune-active environment (such as HDAC, EGFR, VEGF, or BRAF), checkpoint plus cancer vaccines, checkpoint plus chemotherapy, and checkpoint plus radiation.

Challenges in developing immunotherapy combinations will include identifying preclinical models and further elucidating the mechanisms of action of immunotherapies. Determining appropriate regimens requires setting multiple parameters, including dose levels, administration frequencies, durations of treatment for each drug in the combination, and sequence of administration.

“Those parameters all need to be worked out as rationally as possible before we begin to put patients on these trials,” Dr. Burris said. Other challenges will include discovering fitting biomarkers for efficacy and safety; selecting appropriate diseases; designing suitable endpoints; and identifying apt patients, potentially with the use of immunoprofiling.

Managing overlapping toxicities of multiple drugs, especially if chemotherapy is involved, will be a particular challenge. Toxicities with immunotherapies can involve inflammatory conditions such as hepatitis, colitis, thyroiditis, pneumonitis, and nephritis. “The toxicities seem to be managed in one of two ways, either steroids or stopping the drug, neither of which is an attractive option,” Dr. Burris said. “There is a possibility that we can dial back on one of the drugs and then be able to retreat the patients who have these side effects.”

A number of abstracts reporting positive results with combination immunotherapy will be presented throughout the 2016 ASCO Annual Meeting, Dr. Burris noted, including some in cancers that are not often thought of with immunotherapy, such as small cell lung cancer. With an abundance of agents available, he said, future combination trials must be developed rationally, with attention to choice of tumor type and patient immune status, identification of appropriate biomarkers, and effective management of toxicities.

Good trial design is important, Dr. Burris said. Patients are precious, he said, “so let’s be very smart about how we develop these combinations.”

– Tim Donald, ELS