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For CAR-T Cancer Fighters in the Real World, Two Roads Diverge

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often have experience with bone marrow transplants, which are also fraught with complications. They have steroids and other drugs at hand to tamp down an immune system threatening to run amok, and the intensive care unit is at the ready.

In ZUMA-1, it’s now been more than two years since many patients received their one-time treatment. In an update last month, Yescarta helped shrink the tumors of 83 percent of patients with 58 percent showing no sign of cancer. (Median follow-up of 27.1 months.) Some observers say it takes three to five years of remission to start using the “C” word—cure—but these types of results, two years after a one-time treatment, are remarkable.

In the real-world reports released last month, patients were not followed nearly as long. But the results were promising:

–For 112 patients treated across 17 medical centers, including MD Anderson and the University of California, San Francisco, the one-month outcomes were 79 percent showing some response; 50 percent were showing no sign of cancer. In the same study, 163 patients were available for safety evaluation. There are two main types of serious side effects with CAR-T, which receive a grade 3 or higher: an overheated immune system response known as cytokine release syndrome (CRS); and neurological problems. CRS occurred in 7 percent of patients. Neurological problems occurred in 31 percent. Those numbers were very similar to those seen in ZUMA-1 (11 percent and 32 percent).

—For 76 patients treated across a different set of centers, including Dana-Farber Cancer Institute in Boston and the Seattle Cancer Care Alliance, 57 percent of patients had some type of response, with 36 percent showing no sign of cancer. The median follow-up after receiving the CAR-T cells was four months. Thirteen percent of patients had grade 3 or higher CRS, and 38 percent had grade 3 or high neurological problems. There were no 4-month data from ZUMA-1, but at the six-month check-in two years ago, about 35 percent of patients had seen their cancers essentially disappear.

More than 60 percent of the patients in the study would not have met the bar to enter ZUMA-1, at least in part because they were too sick. The similar results “may mean that the data from ZUMA-1 is an accurate portrayal of the safety of Yescarta,” regardless of a patient’s status, said Jacobson, the first author of the study and medical director of Dana-Farber’s immune cell therapy program.

CAR-T For Free

Kymriah, meanwhile, has been dogged by manufacturing troubles. The main problem: After genetic engineering outside the patient, not enough have been converted into active cancer killers. “When final product does not meet specification, it is usually due to lower than expected percentage of viable cells,” says Novartis spokesman Eric Althoff. (Manufacturing problems also occurred with nearly 8 percent of enrolled patients in Novartis’s two key clinical trials.)

The firm’s top cell and gene therapy official told Biopharmadive last month that many patients were receiving Kymriah for free, because Novartis can’t charge for a product that doesn’t meet the specifications on its commercial label.

On an earnings call late last year Novartis executives tried to put the situation in a positive light. “We’re actually above our expectations given the manufacturing challenges that we’ve had,” said Elizabeth Barrett, the former head of the Novartis oncology division. “Centers have continued to order Kymriah despite this.”

On the same call, Novartis CEO Vas Narasimhan said Kymriah’s safety record has encouraged Novartis to expand manufacturing in France, Switzerland, and China. (The real-world evidence for Kymriah is only anecdotal. No studies have yet emerged. Long-term results from Kymriah’s clinical study in NHL were released late last year.)

Narasimhan was also optimistic that CAR-T could treat patients in earlier stages of disease, not just end-of-the-line cases. “We really see this as a long-term play, and we are quite confident in the profile of the medicine,” he said.

For others to feel the same confidence, however, more data are necessary, and not just for this first generation of CAR-T products. “Watch the safety data of next-generation CAR-T closely,” says Morris Paterson of Group H, a biopharma consulting group. Several companies, including Novartis and Gilead, have experimental CAR-Ts in development for blood cancers and more. “If they have a better safety profile, using them in a broader setting becomes more feasible.”

More CAR-T, Cheaper CAR-T?

One of Novartis’s biggest critics also wants to see the cutting-edge medicine become an option for patients in earlier stages of disease. David Mitchell, a public-relations executive and multiple myeloma patient, is the founder of Patients for Affordable Drugs, a drug-price watchdog. He slammed Novartis when it announced Kymriah’s $475,000 price tag, noting how U.S. taxpayers had shouldered more than $200 million to fund the research that led to CAR-T.

The federal agency overseeing the Medicare and Medicaid insurance programs has been weighing how much to pay for CAR-T—a final decision could come this spring. Mitchell’s group has suggested a pay-for-performance scheme that rewards drug makers with milestone payments based on the patient’s condition one, six, and 18 months after infusion.  Mitchell has a personal stake in his advocacy. Several companies are racing to develop CAR-T products for multiple myeloma. (Celgene is in the lead—another reason to watch the proposed acquisition closely.)

The cancer, which affects cells in the bone marrow, almost always progresses, even after long remissions. Patients cycle through several treatment regimens. If CAR-T becomes safer to give to patients who aren’t nearly as sick, and it proves to be durable, Mitchell argues that higher prices might be justified if they replace several levels of regimens. “I don’t want to go through two or three lines of treatment and millions of dollars,” he says. His current regimen cost $450,000 the first year and $300,000 each year thereafter. “The difference between ‘my cancer is going to progress, I’m going to run out of drugs and die,’ and ‘I have at least 10 more years because of CAR-T,’ is a big deal,” Mitchell says.

Even with last month’s release of promising real-world results for Yescarta, no one knows yet if it or Kymriah can deliver the same longterm remissions that they have in leukemia and lymphoma clinical studies. Until then, the argument for moving them and perhaps other CAR-T products into earlier-stage cancer will be tough to make at their current prices, and one of the most promising medical advances in decades could end up solely as a last-ditch treatment for handfuls of patients. Good for those patients, but disappointing for those expecting CAR-T to make a major dent in cancer.

Image of a T cell attacking cancer courtesy of the National Cancer Institute/Duncan Comprehensive Cancer Center at Baylor College of Medicine.

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