Kymriah CAR-T therapy: a journey of controversy to clinical success in Korea

Two years ago, Novartis’ Kymriah (ingredient: tisagenlecleucel) became Korea’s first CAR-T treatment to receive health insurance coverage.

While Kymriah presents a one-time cure for blood cancer patients facing recurrence, its steep price tag of 360 million won ($266,785) per dose ignited considerable debate well before its debut.

Even though being hailed as a miracle drug, Kymriah initially faced criticism in Korea due to early reports indicating that 75 percent of treated patients did not respond, a stark contrast to global clinical trial results.

However, this controversy has since subsided as early performance data focused on terminally ill patients with poor prognoses, naturally resulting in lower success rates.

Real-world evidence now shows outcomes aligning closely with international clinical data. Additionally, with a 2022 out-of-pocket cap of approximately 6 million won, patient financial burdens are significantly mitigated.

Kymriah continues to demonstrate its clinical value through real-world evidence, paving the way for various CAR-T therapies across different cancer types.

Against this backdrop, Korea Biomedical Review met with Stephen J. Schuster, Director of Lymphoma Translational Research at the Abramson Cancer Center of the University of Pennsylvania, who shared his extensive knowledge and experience in the field of blood cancers, particularly Diffuse Large B-cell lymphoma (DLBCL).

Schuster has been instrumental in pioneering CAR-T cell therapy and has played a pivotal role in the development and clinical trials of Kymriah.

DLBCL is the most common type of lymphoma in the U.S., accounting for one-third of all lymphoma cases and ranking among the top five cancer types.

“Before the advent of innovative therapies like CAR-T, we had been treating DLBCL with traditional aggressive therapies, often with limited success in older patients or those with poor overall health,” Schuster said. “The introduction of CAR-T therapy has revealed a much higher prevalence of DLBCL than previously thought, as it became accessible to a broader range of patients who were previously deemed untreatable.”

One of the most notable aspects of CAR-T therapy, according to Schuster, is its potential for single-treatment efficacy.

"Traditional chemotherapy requires repeated cycles, but CAR-T offers a one-time treatment solution," he said. However, he acknowledged that CAR-T therapy is not a panacea, with some patients requiring additional therapies like bispecific antibodies to achieve meaningful results.

Schuster played a pivotal role as the lead author of the JULIET clinical trial, which was instrumental in the development and commercialization of Kymriah.

“Our initial research began at the University of Pennsylvania and laid the groundwork for Kymriah's commercialization,” he said. “Despite concerns about replicating our early results on a larger scale, the expanded JULIET trial across four continents confirmed our initial findings."

The JULIET trial demonstrated a complete response rate of approximately 40 percent among DLBCL patients, a significant milestone.

Schuster emphasized the importance of achieving complete remission (CR) in DLBCL treatment stating that patients who reach CR generally see the best survival outcomes, with 80-85 percent remaining disease-free for over a year.

“Achieving CR means they can live as though they never had the disease,” he said.

Schuster also addressed the unique advantages of Kymriah, particularly for elderly patients. "Kymriah's excellent tolerance profile means it can be used in older, more frail patients, some as old as 90 years," he explained. “Compared to other therapies like Lisocabtagene, which can have significant neurotoxic side effects requiring hospitalization, Kymriah's safety allows for outpatient treatment.”

Addressing challenges and future directions for CAR-T therapy

In discussing real-world evidence (RWE) from clinical practice, Schuster pointed out that selection bias might explain higher CR rates observed outside clinical trials.

"These clinical outcomes depend heavily on patient characteristics,” the UPenn Professor said. “Younger, healthier patients typically fare better, but we must interpret RWE results with caution.”

He also noted that the durability of CAR-T therapy's effects, particularly in long-term survival, remains a critical measure of success.

Addressing concerns raised by the U.S. FDA about secondary malignancies following CAR-T treatment, Schuster referenced a study of 407 patients, which identified only one case of T-cell lymphoma, ultimately deemed unrelated to CAR-T therapy.

The FDA had published a safety advisory in November of last year, stressing the need for caution regarding CAR-T cell therapies after receiving reports of adverse events of T-cell malignancies following administration of CAR-T cell therapies.

"While secondary malignancies are a known risk with any cancer therapy, the benefits of CAR-T in DLBCL treatment far outweigh these risks,” Schuster said.

When asked about some concerns from local physicians regarding the manufacturing and administration timeline for CAR-T, which typically takes around six weeks in Korea, Schuster emphasized the importance of not just reducing manufacturing time but also streamlining the process within hospitals to ensure timely treatment.

"In the U.S., it takes about four weeks from the manufacturing of Kymriah to its administration to the patient, which is not significantly different from the process in Korea,” he said. “During the JULIET clinical trial, it initially took six weeks from manufacturing to administration, but this time has been significantly reduced.”

However, the problem lies not only in the manufacturing time but also in the fact that in some hospitals, it took an additional two weeks from the arrival of the therapy at the hospital to its administration to the patient, he added.

Therefore, Schuster stressed that while reducing manufacturing time is important, it is also crucial to ensure that the therapy is administered as soon as it is available.

Looking to the future, Schuster sees potential in combining CAR-T with bispecific antibodies, but he cautions against viewing them as outright replacements for CAR-T therapy.

"Bispecific antibodies and other novel therapies are not yet ready to replace CAR-T therapy,” he said. “They play a complementary role, stabilizing and improving patient conditions until they can undergo CAR-T treatment.”

This is particularly relevant for patients whose disease progresses rapidly or who require additional management to maintain their condition, he added.

Schuster highlighted the importance of selecting the right therapeutic targets.

"Current bispecific antibodies target CD20, which has a higher likelihood of being lost by cancer cells compared to CD19,” he said. “Recent studies show that if CD20 isn't present, the treatment's efficacy drops to zero.”

Thus, it's critical to confirm the presence of CD20 before proceeding with bispecific antibody therapy, he emphasized.

Addressing the challenges specific to Korea, Schuster recognized the limited access to alternative therapies as a significant obstacle.

"In environments where access to other therapies is restricted, it’s essential to strategically time the administration of CAR-T therapy,” he said. “If a patient’s condition isn’t conducive to immediate treatment, it’s better to manage the disease with bridge therapies first.”

He shared that at his hospital, they have successfully treated patients by stabilizing their conditions for up to a year before administering CAR-T therapy.

On the issue of cost-effectiveness, Schuster acknowledged the high price of Kymriah but suggested that prices might decrease as more therapies enter the market.

He stressed the importance of selecting the right patients for CAR-T therapy to maximize its value. "Developing protocols to determine which patients will benefit the most and educating healthcare providers based on these results can help improve outcomes and justify the costs," he said.

Schuster remains optimistic about the future of CAR-T therapy and its integration with new treatment modalities.

"The trend is moving towards using CAR-T therapy earlier in the disease progression,” he said. “The development of next-generation CAR-T therapies, which may not require lymphodepleting chemotherapy, shows great promise.”

These advancements could further enhance the effectiveness and accessibility of CAR-T therapy, he concluded.