Can CAR T-cell therapy now move to 2nd line treatment in lymphoma?

Blood cancers

By Mardi Chapman

10 Jan 2022

A/Prof Manali Kamdar

CAR T-cell therapies are showing huge promise as the future standard of care in hard-to-treat patients with relapsed or refractory large B cell lymphoma (LBCL) – but not every product wins.

Speaking at the 63rd ASH Annual Meeting and Exposition, Associate Professor Manali Kamdar presented the results of the phase 3 study of lisocabtagene maraleucel (liso-cel) versus the standard of care – three cycles of salvage chemotherapy followed by ASCT – as second line treatment in relapsed or refractory LBCL.

Associate Professor Kamdar, from the University of Colorado, said there was a high unmet need for additional therapy options given only a quarter of transplant-intended patients achieve a durable remission.

The TRANSFORM study of 184 patients found the primary end point of event-free survival (EFS) was a median of 10.1 months with liso-cel versus 2.3 months with the standard of care (HR 0.349; p <0.0001).

As well, secondary endpoints demonstrated the liso-cel had superior efficacy to the standard of care.

The complete response rate was 66% with the CAR T-cells compared to 39% with the standard of care (p <0.0001); PFS was 14.8 versus 5.7 months (HR 0.406; p=0.0001); and OS was not reached with liso-cel compared to 16.4 months with standard of care (HR 0.509; p=0.0257).

Dr Kamdar said the safety profile of liso-cel was consistent with previous studies.

“A very low incidence of grade 3 cytokine release syndrome and neurological events were seen with liso-cel. These adverse events were manageable with treatments as per standard practice.”

“It is important to highlight that there were no grade 4 or 5 events reported.”

She concluded that liso-cel was a “breakthrough therapy” which had shown highly significant and clinically meaningful superiority over the current standard of care.

“We are thus extremely excited about the potential of this study to change the existing standard of care in [these] high risk patients with LBCL.”

Axi-cel shows similar benefit

Dr Frederick Locke, from the Moffitt Cancer Centre in Tampa, Florida presented similarly positive findings from the phase 3 study of axicabtagene ciloleucel (axi-cel) versus standard of care in 359 patients with relapsed or refractory LBCL.

The ZUMA-7 study found the primary endpoint of EFS was 8.3 months with axi-cel versus 2.0 months with standard of care and the 24-month EFS rate was 40.5% versus 16.3% (HR 0.398; p=0.0001).

Patients in the axi-cel arm also had a 33% higher objective response rate (ORR) and double the CR rate compared with patients receiving standard of care.

Dr Locke said the safety profile of axi-cel was manageable and consistent with prior studies in refractory LBCL.

“The definitive therapy-related mortality, meaning the investigator attributed mortality either to axicabtagene ciloleucel or autologous haematopoietic stem cell transplant, were 1% and 3% respectively for patients that received those therapies.”

Dr Mahmoud Elsawy, from Dalhousie University in Canada, presented patient-reported outcomes (PRO) from the ZUMA-7 study.

He said there was a significant and clinically meaningful difference in the mean change of scores from baseline at day 100 on all prespecified PRO measures in favour of axi-cel over standard of care.

These included the EORTC QLC-C30 physical functioning and global health status /quality of life domains as well as the EQ-5D-5L.

As well, patients treated with axi-cel had statistically significant lower mean absenteeism and lower mean activities impairment on the Work Productivity and Activity Impairment – General health (WPAI) measure.

“The superior clinical outcomes and patient experience with axi-cel over standard of care should help inform treatment choices in second line relapsed or refractory LBCL,” he said.

Outlier in the CAR-T race

However the BELINDA trial of tisagenlecleucel versus standard of care in relapsed or refractory aggressive B-cell NHL found no difference in EFS between the two arms (median 3 months for both arms; HR 1.07; p = 0.69).

Professor Michael Bishop, director of the HSCT program at the University of Chicago, told an ASH press meeting that the comparison with the other CAR T-cell trials kept him awake at night.

“All of us are excited to see that the other two trials were positive and we were hoping that ours would be as well. Unfortunately, BELINDA did not meet its primary endpoint of event-free survival.”

He said it was possible that differences in the trial design and implementation including the definition of EFS, allowed bridging chemotherapy, and time from randomisation to infusion, may be contributing factors to the results.

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