Novartis shifts focus as CAR T-cell therapy fails to add benefit in non-Hodgkin lymphoma

Pharma News: Novartis’ chimeric antigen receptor (CAR) T-cell therapy was not found to improve event-free survival over what was seen with standard of care as a second-line treatment for patients with aggressive non-Hodgkin lymphoma, according to phase III trial data presented during the recent American Society of Haematology (ASH) congress.

The results from this Kymriah (tisagenlecleucel – tisa-cel) study, which come as a surprise after previous CAR-T trials have shown improved clinical outcomes, may reflect variability in the patient population, timing and administration of tisa-cel and stem cell transplants, and use of chemotherapy in real-world settings, according to researchers.

The new study sought to determine whether tisa-cel could offer benefits earlier in the course of treatment as a second-line therapy before attempting a stem cell transplant.

“We were surprised that event-free survival was identical in both study arms,” said Dr Michael R. Bishop, The David and Etta Jonas Centre for Cellular Therapy, University of Chicago. “This suggests there is still a lot to be learned about the proper administration of CAR-T therapies. As this field progresses, we’re learning that there may be more variables to consider as we seek to optimize CAR-T therapies.”

The trial enrolled 322 patients with aggressive B-cell non-Hodgkin lymphoma who did not respond to initial chemotherapy or relapsed within 12 months. The majority of patients randomised to receive tisa-cel also received chemotherapy before their CAR T-cell therapy, a treatment strategy known as “bridging,” at their physician’s discretion.

The results showed no significant difference between study arms for the primary endpoint of event-free survival, defined as death at any time or progressive or stable disease at or after 12 weeks. Twenty-eight percent (28%) of patients in both study arms showed a complete response to treatment, and the overall response rate was also similar (46% in those receiving tisa-cel versus 43% in those receiving standard of care).

Researchers identified several factors that may have potentially contributed to the current results. As an international trial conducted in 18 countries, researchers observed some real-world variability in the treatment strategies used in different regions and countries. Use of bridging therapy was not uniform, and this led to more patients with progressive disease at infusion, which was associated with a worse outcome.

“These findings show the importance of doing randomised trials and comparing their results to help improve outcomes for patients,” said Dr. Bishop. “It gives us tremendous insights into the biology of these very aggressive diseases and points to an opportunity to more closely examine many factors, in particular the role and timing of bridging therapy.”

The investigators of this Novartis study are now performing additional analyses to determine factors that may have affected outcomes in both treatment arms.

“Instead of repeating the same experiment with our first-generation Kymriah, we’re really focusing on conducting our next experiment,” said Dr Jeff Legos, Novartis’ global head of oncology and haematology development. “And we will move YTB323 into definitive pivotal registration trials in 2022, looking at a similar patient population of patients who’ve failed first-line chemoimmunotherapy.”