Novartis' CAR-T Therapy Kymriah Fails to Outperform Standard Care in Phase III BELINDA Trial for Second-Line B-NHL

News Event

Today, Novartis announced the results of a Phase III clinical trial evaluating its CAR-T cell therapy, Kymriah, as a second-line treatment for B-cell non-Hodgkin lymphoma (NHL). The BELINDA trial was designed to enroll 318 patients aged 18 years or older who were refractory to first-line therapy or experienced disease progression within 12 months of initial treatment. It compared Kymriah with the standard of care (SOC), high-dose chemotherapy followed by autologous stem cell transplantation, in terms of event-free survival (EFS). The results showed that the CAR-T therapy demonstrated comparable efficacy to SOC. Kymriah is already approved for the treatment of third-line NHL and relapsed/refractory acute lymphoblastic leukemia (r/r ALL) in patients aged 25 years or younger.

Drug Source Analysis

Kymriah is the first CAR-T cell therapy to receive regulatory approval, securing its initial indication for pediatric relapsed/refractory acute lymphoblastic leukemia (r/rALL) in 2017 and its label for third-line treatment of B-cell lymphoma in 2018. In this refractory r/rALL patient population, Kymriah demonstrated a 3-month response rate of 83% and a 1-year response rate of 79%. Its first trial patient, Emily Whitehead, has since become an iconic figure in immunotherapy. This product not only established CAR-T cell therapy as a distinct therapeutic modality and triggered intense competition within the CAR-T development landscape, but also propelled CD19 to become one of the most sought-after targets in the pharmaceutical industry. Consequently, the field has seen an influx of diverse modalities, including bispecific antibodies, antibody-drug conjugates (ADCs), and immunotoxins, all competing in this highly targeted therapeutic space.

The persistence of CAR-T therapy has consistently been a challenge. One factor is the limited survival time of CAR-T cells within patients; additionally, tumor cells can bypass their dependence on CD19 or downregulate CD19 expression, thereby causing CAR-T cells to lose their target. That said, for last-line patients, Kymriah’s duration of response of approximately one year remains quite satisfactory. It has been eight years since Whitehead was critically ill, yet the cost of CAR-T therapy, which exceeds $400,000, continues to drive higher expectations from both patients and payers. Furthermore, while CAR-T carries significant toxicity risks, the industry has now accumulated substantial experience in managing cytokine release syndrome (CRS). Considerable progress has also been achieved in the manufacturing and distribution of CAR-T therapies.

Approximately half of patients with B-cell non-Hodgkin lymphoma (NHL) are refractory to first-line therapy or experience disease progression within 12 months. The standard treatment following progression is high-dose chemotherapy followed by stem cell transplantation. However, only about half of these patients are eligible for stem cell transplantation, and among those who undergo the procedure, only half achieve a durable response. Kymriah has been approved as a third-line treatment for relapsed/refractory (r/r) lymphoma after progression on second-line therapy; however, this approval was granted via the accelerated approval pathway based on results from a single-arm, uncontrolled trial. Safety requirements are more stringent for patients in the second-line setting. Although early trial data indicate that 30–40% of responders in this population can achieve durable responses with Kymriah, the overall response rate still appears inadequate. Recently, Fate Therapeutics’ CAR-NK cell therapy FT596, administered as monotherapy or in combination with rituximab, has demonstrated a 70% response rate in a similar patient population. It holds promise as a novel cell therapy to save the lives of these patients.

The market approval of CAR-T therapy was primarily based on its remarkable response rates; however, these rates may have been inflated due to the uncontrolled nature of the initial trials. The main issue is that patients with severely compromised immune status may fail to provide viable T cells for CAR-T manufacturing, and some may succumb to their disease during the manufacturing lead time prior to infusion. These critically ill patients are occasionally excluded from ORR calculations. In controlled trials, however, all enrolled patients must be compared against the control arm, which can consequently lower the observed response rates. The BELINDA trial implemented pre-randomization T-cell collection, thereby mitigating, to some extent, the risk of T-cell ineligibility due to post-enrollment disease progression; nevertheless, its efficacy remained comparable to that of standard therapy. While many, including some professionals, argue that RCTs should not be conducted when patients face a near-certain fatal prognosis or when a drug exhibits exceptionally high response rates—as it would harm patients in the control arm—the BELINDA trial once again reaffirms that randomized controlled trials remain the gold standard for establishing drug efficacy.