I’d like to highlight for you our work on the association of metabolic tumour volume and clinical outcomes in second line relapsed/refractory large B-cell lymphoma in the randomised ZUMA-7 clinical trial comparing axicabtagene ciloleucel CAR T-cell therapy to the existing standard of care of second-line chemotherapy with consolidative autologous stem cell transplant.

Axi-cel is a CD19 directed CAR T-cell therapy and based upon ZUMA-7, a phase III global randomised trial, it is now approved as a second line therapy for patients with large B-cell lymphoma who relapse within 12 months of initial therapy. We know from the ZUMA-1 trial, which led to the approval as a third or later line in large B-cell lymphoma, in ZUMA-1 we found that tumour size was associated with outcome. In fact, patients with larger tumours, as measured by the sum of the product of the diameters, or SPD, and up to six reference lesions, those patients had worse outcomes in ZUMA-1. So when we looked on ZUMA-7, a randomised trial, we were surprised to find that that wasn’t the case – patients with larger tumours were treated earlier with CAR T, at least as measured by SPD, did not have worse outcomes, although patients who got the standard of care treatment with large tumours did have worse outcomes. So that was a little bit surprising.

We also had studied metabolic tumour volume, or MTV, which can be calculated from a PET scan. This MTV has been shown to correlate with outcomes of CAR T-cell therapy in the third or later line setting, so we thought to look at MTV in the setting of the ZUMA-7 clinical trial.

ZUMA-7 is a randomised 1:1 clinical trial, as I mentioned, with a primary endpoint of event free survival. The MTV was measured from the baseline PET scan prior to CAR T-cell therapy or standard of care therapy. We looked at associations of MTV with clinical characteristics. One of the interesting things we found is that, yes, patients with a high LDH had a higher metabolic tumour volume and patients who were younger had higher metabolic tumour volume, larger tumours, than older patients over 65.

We also found a correlation between the sum of the product of diameters I mentioned, SPD, and metabolic tumour volume but it was not a strong correlation, it was a moderate correlation. So MTV is measuring more than that SPD. Similarly, LDH was a moderate correlation so MTV really is capturing more granularly this tumour size in these patients.

What we found, though, is basically that with axicabtagene ciloleucel, whether patients had large metabolic tumour volume or small metabolic tumour volume they did better than standard of care patients. However, patients with small metabolic tumour volume did better with axi-cel than those with large metabolic tumour volume. So it does stratify patients by event free survival and progression free survival but, interestingly, patients with large metabolic tumour volume who got the standard of care did dismally, they did horribly across the board with really low event free survival and progression free survival.

We also found an association between response – patients who were responders had a lower metabolic tumour volume than those who were non-responders. In addition, metabolic tumour volume was lower in patients who were complete responders compared with others.

Then finally we found an association between toxicity – patients with grade 3 or higher neurologic events or grade 3 or higher cytokine release syndrome were more likely to have high metabolic tumour volume. There was no association with toxicities in the standard of care arm.

So really we concluded that, to our knowledge, this is the first examination of metabolic tumour volume, or MTV, in a large randomised prospective trial of CAR T-cell therapy in relapsed/refractory large B-cell lymphoma. Similar to prior analysis with SPD and LDH, axi-cel was superior to standard of care for both high and low MTV, but while tumour burden by SPD didn’t predict for axi-cel outcomes in ZUMA-7, low MTV was associated with improved outcomes with axi-cel versus high MTV as well as high MTV was associated with toxicities. Again, patients did better in the axi-cel treatment arm whether they had high or low MTV compared to standard of care patients. So, taken together, we think that metabolic tumour volume is a better prognostic marker than the sum of the product of the diameters.