[Corrected, 1/4/19, 3:55pm ET. See below.] A generation ago, cancer treatments made from a patient’s own living immune cells would have been science fiction. Now they’re here. The first two products, approved in 2017 and known in shorthand as CAR-T, have brought some people with otherwise untreatable blood cancers back from the brink of death.
“Often these patients have survival measured in weeks to months,” says David Maloney, medical director of the Bezos Family Immunotherapy Clinic in Seattle, which at any given time is treating more than 30 patients with both experimental and approved CAR-T products.
The experimental results that led to approval for each product were remarkable. But outside the cautious, tightly controlled bubble of clinical studies, the products and their owners have had different experiences in the real world.
One CAR-T, axicabtagene ciloleucel (Yescarta) from Gilead Sciences (NASDAQ: [[ticker:GILD]]), has provided surprising real-world results so far that hew closer to the successful clinical studies than doctors typically expect. The safety record in particular is “reassuring,” says Caron Jacobson, who treats leukemia and lymphoma patients at Dana-Farber Cancer Institute in Boston, one of the top country’s top CAR-T centers. Side effects from the aggressive cancer-killing cells have been a major concern for doctors.
The other approved CAR-T, tisagenlecleucel (Kymriah) from Novartis (NYSE: [[ticker:NVS]]), has hit major snags. While its clinical results were also strong, Kymriah has been used far less in the real world. Novartis has had problems manufacturing the complicated product, which, like Yescarta, requires a patient’s T cells to be extracted, genetically modified in a lab, nurtured so the cell population expands, and shipped back to the patient.
(CAR-T stands for chimeric antigen receptor T cell, a reference to the genetic engineering that programs the killer cells to seek out specific proteins on tumors. Yescarta and Kymriah are autologous CAR-T products, which take about three weeks to produce and administer to the patient.)
Kymriah was first approved in August 2017 for pediatric acute lymphoblastic leukemia (ALL), a rare blood cancer. Novartis officials said at the time they expected 600 eligible patients a year. In May 2018, Kymriah received approval for adults with the most common form of non-Hodgkin lymphoma (NHL).
Yescarta was approved in October 2017 for several types of adult NHL.
Both are allowed only after other treatments, including chemotherapy and bone marrow transplant, have been exhausted or ruled out. And both come with price tags that have raised serious concerns about affordability, from health policy experts to the FDA commissioner.
Kymriah has a one-time price of $475,000 for ALL, with a refund if it doesn’t work after one month, and $373,000 for NHL (no refund). Gilead has priced Yescarta at $373,000, with no refund. [Correction: The price of Kymriah for NHL is $373,000, not $375,000.]
(A third CAR-T for NHL could be on the way. If the megamerger of Bristol-Myers Squibb (NYSE: [[ticker:BMY]]) and Celgene (NASDAQ: [[ticker:CELG]]) is consummated, Bristol’s large experimental CAR-T portfolio will include JCAR017, which was developed by Celgene division Juno Therapeutics. It remains to be seen if Bristol will push JCAR017 aggressively in NHL after hints last month that Celgene’s enthusiasm might have waned.)
Still Struggling
Maloney of the Bezos Clinic says Kymriah’s experimental record suggests it could have less intense side effects, thanks to a difference in the engineering. But he prefers Yescarta for lymphoma patients for a simple reason: “Novartis is still struggling to produce Kymriah. I can’t get it from them.”
At University of Texas MD Anderson Cancer Center in Houston, one of the top CAR-T treatment centers in the country, the number of patients treated with Kymriah as of late November were “in the single digits,” says Sattva Neelapu, a blood cancer specialist. At Dana-Farber in Boston, another major CAR-T center, the total is two.
Those figures are reflected in the financial statements of the product’s owners. Yescarta garnered $183 million in revenue the first three quarters of 2018 for Gilead, which bought Yescarta’s developer Kite Pharma for nearly $12 billion a few weeks before the product’s October 2017 approval.
Kymriah tallied $48 million in revenue through the first three quarters of 2018. (The timing of its approvals, first in ALL, a tiny patient population, then in the larger NHL, is one factor but not a full explanation.)
Neither company would give an exact count of their real-world patients. But it’s safe to say a couple hundred if not more have received Yescarta in a real-world setting, enough for oncologists to start analyzing its performance. Two studies were presented at the American Society of Hematology’s annual meeting last month. Patients receiving Yescarta commercially fared a bit worse than patients in the 101-patient study known as ZUMA-1, which Kite Pharma used to gain FDA approval.
That may not sound praiseworthy at first. But once a drug is available commercially, a wider swath of patients, often closer to death or with other layers of health problems, can receive treatment; conditions are less predictable, less tightly controlled.
In Yescarta’s case, the performance gap between experimental conditions and the real world has been narrow so far. “There is a drop-off of results in every oncology drug, but here, I am surprised,” says Neelapu of MD Anderson, who is a co-leader of the extended ZUMA-1 study.
Neelapu is particularly pleased that the real-world safety numbers across two studies and 188 patients were similar to ZUMA-1: “I expected higher toxicity because of sicker patients.”
Across the Bridge
One potential factor in the better-than-expected results, says Neelapu, is short-term “bridging” therapy for patients who have only weeks or months to live. CAR-T production takes three weeks; some patients might not survive that long, so doctors give them a burst of radiation or other treatment as a temporary bridge to CAR-T. The quick hit might be shrinking tumors enough to decrease the CAR-T side effects, which can be amplified by the amount of cancer in a patient’s body. Think of the killer T cells as sharks at a feeding frenzy, and the cancer is the food. The less there is to eat, the less collateral damage during the attack.
There are still side effects, to be sure. But patients can only be treated with CAR-T in centers where staff receive special training and
