Immunotherapy Combos: Will Cost Put Them out of Reach?

Kerry Dooley Young

October 18, 2018

WASHINGTON — New classes of cancer medicines that activate the immune system may be used in combinations, just as more traditional chemotherapies have been, specialists said here at the 2018 annual meeting of the National Academy of Medicine.

However, the prospect of using combinations of these immunotherapies will exacerbate already intense concerns about the cost of treatment.

Immunotherapy is a rapidly growing field within oncology. Last year saw approval by the US Food and Drug Administration (FDA) of two more checkpoint inhibitors, durvalumab (Imfinzi, AstraZeneca) and avelumab (Bavencio, EMD Serono Inc). The drugs join about a half dozen others of that class now available for a growing number of indications. More are on their way — the Pharmaceutical Research and Manufacturers of America has estimated that about 295 immuno-oncology medicines and vaccines are in development.

Last year also saw a major leap in personalized medicine, with FDA approvals of the first two chimeric antigen receptor (CAR) T-cell therapies, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Gilead Sciences' Kite Pharma). These treatments use genetically engineered versions of patients' own cells to treat blood cancers.

The keynote address at the meeting was delivered on October 15 by Laurie H. Glimcher, MD, chief executive of the Dana-Farber Cancer Institute. She talked about a future when these various ways of manipulating the immune system will be used in combination.

"We need to not just do checkpoint blockade or just CAR-T cells or vaccines," Glimcher said. "We need to combine them in various ways without causing excessive toxicity."

She illustrated the point with some recently reported results from work on a personalized melanoma vaccine from her own institution.

This project was headed by Catherine Wu, MD, and was published last year in Nature. For melanoma patients who were considered to be at high-risk of recurrence after surgery, the team developed a vaccine to target "neoantigens" derived from the patients' tumors.

At the 2-year mark, 4 of the 6 patients who were treated had not experienced a recurrence of their tumors. The other two patients, whose cancer had spread to their lungs, did experience disease recurrence, and they began treatment with a checkpoint inhibitor. For both patients, the tumors completely resolved.

This is a better result than could be expected, because in only about 5% of people who take PD-1 inhibitors for metastatic melanoma do tumors disappear completely, according to a commentary about the research published in Science.

At the NAM meeting, Glimcher said that this work "raises the obvious theme that you will hear through the day, that what we are really looking for is combination immunotherapy."

Scientists at the NAM meeting also noted the need for varied therapies to keep ahead of cancer, which has been shown to have an ability to outwit treatments over time.

"Most patients treated with single-target therapy develop drug resistance, so we have to start paying attention to the potential for combinations," said Elaine R. Mardis, PhD, co—executive director of the Institute for Genomic Medicine at Nationwide Children's Hospital in Columbus, Ohio, during a panel discussion.

Charles Sawyers, MD, who was involved in the development of the breakthrough targeted therapy imatinib (Gleevec, Novartis), recalled how resistance to the drug developed fairly quickly. Sawyers, now chairman for human oncology and pathogenesis at Memorial Sloan Kettering Cancer Center, New York City, argued for moving to combinations of new medicines earlier in the course of treatment.

There are concerns about increasing side effects from this approach, but cancer specialists "have managed toxicity in the past," he said, referring to the multidrug combinations used for older drugs.

The Path Ahead

The successes seen in fighting HIV infection offer a good example for the path ahead for oncology, even given the far more complex nature of cancers, Sawyers said.

"We can't get away with single-drug therapy," Sawyers said. "We need to leverage the insights that have come from infectious diseases and come up with rational combinations."

However, using combinations will drive up cost, and the immunotherapies are already very expensive. As previously reported by Medscape Medical News, in one melanoma trial, single immunotherapies were compared with a combination, and the combination showed impressive results. The cost of using ipilimumab (Yervoy, Bristol-Myers Squibb) alone was $158,282, the cost of nivolumab (Opdivo, Bristol-Myers Squibb) alone was $103,220, and the cost of the combination was $295,566.

The tab jumps ever higher for personalized medicine, with the cost of tisagenlecleucel (Kymriah, Novartis) pegged at about $475,000 for a one-off treatment.

"What you have heard through today is that we will be moving toward combination therapy, which adds then tremendously to the cost," commented Carl June, MD, director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia.

Out of Reach?

The spiraling prices for cancer drugs may prevent patients from using these new therapies, experts said at an earlier NAM session on policy challenges.

Mary C. Beckerle, PhD, director of the Huntsman Cancer Institute at the University of Utah, in Salt Lake City, said half of new cancer drugs cost more than $100,00 a year, exceeding the average family's annual income.

"The cost of cancer care is rising out of control," Beckerle said. "We have this amazing science, but it's becoming more out of reach."

Lee Newcomer, MD, MHA, a former top executive at insurer UnitedHealth, pointed to coverage mandates and hospital consolidation as key contributors to the high cost of cancer medicines. Newcomer has been working for some time to draw attention to these issues. He says hospital executives have told him that they need to charge more for oncology services provided by the physicians in their networks to make up for losses in other departments, including emergency departments.

He asked the audience at the NAM meeting to consider this situation from the view of the individual cancer patient.

"Why are we overcharging her to fix someone else's problem?" Newcomer said.

Peter B. Bach, MD, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center, also argued for a need to address the prices of oncology drugs. As with Newcomer, Bach has been a leading voice in the debates over the high cost of cancer care.

At the NAM meeting, Bach urged a broader look at how the United States as a nation spends money fighting cancer. With rare exceptions, the costs of newer cancer therapies are drawn from shared pools of funds, whether these are state and federal funds or money paid to insurers by their customers, Bach noted. The high cost of certain cancer drugs means that there will be less money for other purposes, such as education or infrastructure or public health initiatives, he said.

Bach compared the revenue generated by one immunotherapy, pembrolizumab (Keytruda, Merck), to the amount that the government is spending to prevent tobacco use, including cigarette smoking.

Pembrolizumab is now used for a number of different cancers, including lung cancer, and it is a "fabulous" drug, Bach said.

In a regulatory filing, Merck reported that US sales of Keytruda was $959 million over a 3-month period that ended in June 2018. That figure annualizes to $3.59 billion.

In contrast, annual government spending on major antitobacco initiatives may run short of $1 billion, he said. States are expected to spend about $722 million in fiscal 2018 on tobacco prevention and cessation programs, according to the Centers for Disease Control and Prevention. In a recently enacted spending bill, congressional appropriators directed $210 million in fiscal 2019 for tobacco work as part of federal efforts to prevent chronic diseases and promote public health.

Put another way, a single quarter's worth of sales of Keytruda — just one of many drugs used to treat lung cancer — rivals annual US government spending on major programs intended to prevent the disease from happening.

"That's a social decision, and I think it's not optimal," Bach said, and the comment drew a sudden and strong burst of applause from the audience at the NAM meeting.

During the closing session of the NAM conference, Merck Chief Executive Kenneth C. Frazier acknowledged that there are "significant issues of affordability" with newer cancer medicines. But he focused his remarks on the advances that have been seen in oncology.

Cancer "strikes a primal fear in patients unlike anything else. When these patients hear that word, their fundamental concern is the malignancy itself, the tumor growing inside their bodies," Frazier said. "For them, the fundamental hope is for their survival, and those hopes, I think, have never been as well founded as they are today."

Dr Bach has received grants from the Laura and John Arnold Foundation and Kaiser and honorarium from Yale. Dr Beckerle has served on the board of Johnson & Johnson. Dr Glimcher has financial holdings in GSK Plc, Waters Corp, and Quentis Therapeutic. Dr June has received grants from Novartis and Tmunity Therapeutics and has financial holdings in Tmunity. Dr Newcomer has financial holdings in UnitedHealth. Dr Sawyers serves on the board of directors of Novartis.

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