Patients with large B-cell lymphoma which are primary refractory or relapse within 12 months of receiving frontline chemotherapy containing anthracycline and a CD20 antibody, these are the patients who have exceptionally poor outcomes with the existing current standard of care which has been salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant. These high-risk patients very rarely go into remission with salvage chemotherapy, besides the fact that they have undue toxicity from salvage chemotherapy. As a result, this remains pretty much a critical unmet need for this high-risk group where new therapies are important that we develop so that these patients can also enjoy better outcomes in the long run.
The fact remains that these high-risk patients at this point in time, based on the current standard of care, all of us go ahead and give them salvage chemotherapy. Although about a third of patients are eligible to receive salvage chemotherapy, only about a quarter actually achieve durable long-term remission. So there is a lot more work that needs to be done in this high-risk subset.
Lisocabtagene maraleucel, or liso-cel, is an autologous CD19 directed CAR T product and this product has actually shown in the third line setting, in the TRANSCEND NHL 001 study, that it has not just excellent efficacy but also a manageable safety profile. Based on that study, liso-cel was moved to the second-line setting in this clinical trial. What I am presenting at ASH this year is a pre-specified interim analysis of the TRANSFORM study. This is a head-to-head comparison of patients with primary refractory or relapse within 12 months with large cell lymphoma. They are randomised to either receiving liso-cel or standard of care in the second-line setting. What we are evaluating here is the efficacy and safety of liso-cel versus standard of care.
What was the design of the study?
The study design in terms of the key eligibility criteria, patients had to be between the age groups of 18 and 75; they had to have aggressive non-Hodgkin lymphoma that was primary refractory or relapse within 12 months of receiving frontline chemoimmunotherapy. Their ECOG had to be at 1 or under 1 and they had to be eligible for autologous stem cell transplantation. The one thing to highlight in terms of the study – eligibility was that secondary CNS lymphoma was allowed. Patients also did not need to have a minimum absolute lymphocyte cut-off for enrolment.
About 232 patients were screened of which 184 patients were leukopheresed. This formed the intention to treat analysis set. They were subsequently randomised to either getting liso-cell infusion or standard of care. On the liso-cel arm they were allowed to get bridging therapy; bridging therapy consisted of salvage chemotherapy that was available in the standard of care arm. On the other hand, on the standard of care arm the patients could be treated with either R-DHAP, RICE or RGDP for three cycles and then the responders, which would include complete response or partial response, were followed by high dose chemotherapy with BEAM and autologous stem cell transplant.
Randomisation was further stratified based on response to first-line chemotherapy as well as secondary age-adjusted IPI score. Response assessments were then done at weeks 9, 18 and then months 6, 9, 12, 18, 24 and 36. The primary endpoint of the study was event free survival and event free survival was defined as time from randomisation to either death due to any cause, progression of disease, failure to achieve a response nine weeks post-randomisation or start of an anti-neoplastic therapy.
There were key secondary endpoints of the trial which were complete response rate, progression free survival and overall survival as well as patient reported outcomes, so PROs. That data will also be presented by Dr Abramson in a poster at ASH.
What were the key findings?
The study met its primary endpoint which was event-free survival and the median follow-up at this point is 6.2 months. The event-free survival in the liso-cel arm was 10.1 months; event-free survival in the standard of care arm was 2.3 months. The stratified hazard ratio is 0.349 and the p-value is less than 0.0001. So it’s highly statistically significant. Important to highlight that the 6 month EFS as well as 12 month EFS rate in the liso-cel arm was nearly doubled compared to the standard of care arm.
In terms of the key secondary endpoints, the complete response rate was also statistically significantly higher in the liso-cel arm compared to the standard of care arm. The CR rate in the liso-cel arm was 66% and the CR rate in the standard of care arm was only 39%. Progression free survival was also a key secondary endpoint and the liso-cel arm median PFS is 14.8 months and in the standard of care arm the median PFS is 5.7 months. This is at a stratified hazard ratio of 0.406, again the p-value is statistically significant.
It’s also important to highlight that one of the other key secondary endpoints, which is the overall survival, at this point the median overall survival in the liso-cel arm is not reached, in the standard of care arm it’s only 16 months. This is at a p-value of 0.02 and the p-value that was set for analysis in the TRANSFORM study was at less than 0.012. However, when you look at the curves, the Kaplan-Meier curves have clearly separated. They are more going towards liso-cel, preferring the liso-cel arm, so it will be interesting to see at the next data cut and with a little more follow-up what happens to the overall survival. But right now it looks like it’s trending towards liso-cel and this is despite a crossover. So patients on the standard of care arm, if they did not respond to standard treatment, had the ability to cross over to the liso-cel arm. Despite that, the overall survival looks like it’s favouring the liso-cel arm. So we are very excited to see what the overall survival looks like on further follow-up.
In terms of safety, the treatment emergent adverse events in both arms were comparable and there was one death in the liso-cel arm. There were two deaths in the standard of care arm. In terms of febrile neutropenia the chances of developing febrile neutropenia was only 15% in the liso-cel arm, it was 24% in the standard of care arm. This is important to highlight that in terms of TEAEs of special interest, because CAR T-cell therapy comes with its unique share of toxicity, which is cytokine release, or CRS, or neurological toxicity, and some of the other products do demonstrate higher toxicity. It’s important to highlight that in our study, in the TRANSFORM study, there were very few grade 3 CRS and neurological events. It was also extremely impressive to note that there were no grade 4 or grade 5 CRS or neurological events reported in the liso-cel arm.
Prolonged cytopenia was higher in the liso-cel arm at 43% as compared to standard of care, however, this did not translate into a higher grade 3 infection which was actually higher in the standard of care arm at 21%.
In terms of the cellular kinetics, patients that were treated on the TRANSFORM study, they had cellular kinetics that were very similar to those patients who crossed over to receive liso-cel as third-line treatment. The persistence of liso-cel was observed up to 11 months after infusion.
So overall I can say that in conclusion liso-cel demonstrated a clear superiority over standard of care with a highly significant and clinically meaningful event free survival, complete response rate, as well as progression free survival. Impressive to note that the overall survival curves are separated and they are really going towards the liso-cel arm. This is despite a crossover. Also interesting to highlight that the safety profile is very similar to what was, or consistent with what was, reported in the third-line setting. Again, very impressive to note that there were no grade 5 or grade 4 events reported in terms of CRS or neurological events on the liso-cel arm.
So at this point, at a median follow-up of 6.2 months, in this phase III randomised controlled study liso-cel improved outcomes as compared to salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant. It not just met its primary endpoint but some of the key secondary endpoints and it exhibited an extremely favourable safety profile. So this study serves as a potential to change the standard of care that has been existent for nearly two decades, which is salvage chemotherapy and autologous transplant. We hope that this study provides support for liso-cel to be the new standard of care for patients with high risk large B-cell lymphoma who have relapsed in the second line setting.