ASH 2024 | COALITION trial: glofitamab-R-CHOP or glofitamab-pola-R-CHP in young patients with high-risk LBCL

The COALITION clinical trial is an investigator-initiated clinical trial which we ran through my hospital, Peter MacCallum Cancer Centre in Melbourne, Australia, at sites across Australia. A very committed group of investigators, we ran the trial through the COVID-19 pandemic. And the question that we had is, can we address the area of need in diffuse large B-cell lymphoma for younger patients with high-risk disease? This is a difficult patient population to study. As clinicians we’ve all been familiar with the situation where a patient presents with very high burden disease, particularly younger patients, and we wonder whether delivering a standard chemotherapy such as R-CHOP on a 21-day cycle is sufficient to treat what appears to be very poor prognosis disease. The IPI tells us that patients with IPI 3 and above disease or NCCN IPI 4 and above disease who are treated with standard treatments really do poorly with long-term cure rates in the order of about 50 percent and we wanted to address this at-risk population and ask ourselves the question can we develop a regimen or show that a novel regimen might perform better particularly in the population where people consider using intensified chemotherapy regimens like dose-adjusted EPOCH or hyper-CVAD or CHOEP to address that area of need in younger patients. We were aware at the time that glofitamab, a CD20 x CD3 bispecific, was highly active as a monotherapy in diffuse large B-cell lymphoma. And we were also aware that it would be developed as a first-line therapy and wanted to develop a trial that would evaluate its use as a first therapy for young patients with high-burden disease. So at the time we designed the trial, we weren’t aware of the outcome of the POLARIX clinical trial and since then as this audience will know, POLARIX has shown that polatuzumab significantly improves progression-free survival in diffuse large B-cell lymphoma and that effect may also be greater in patients with high IPI disease. We designed a trial for younger patients up to the age of 65 with an NCCN IPI of 4 or 5 or an IPI of 3. Patients were randomized to receive either R-POLA-CHP in case of 40 patients together with glofitamab or glofitamab together with R-CHOP for the other 40 patients. So an 80 patient study really evaluating could glofitamab add something to this high-risk population. Now one of the challenges in this population is that often the highest risk patients don’t go on to clinical trials because they need urgent treatment. So what we did is we allowed investigators to recruit patients in cycle 2. For this reason cycle 1 was given as R-CHOP regardless of which arm you were randomized to and then the remaining five cycles were given with glofitamab and we gave two glofitamab consolidation treatments at the end. 75% of patients who were recruited to the clinical trial actually came on on cycle 2 which really showed investigative preference that to get these high burden high risk patients onto a trial it’s really difficult to get organized to get all of your screening done and get the logistics done and this opportunity to recruit patients at cycle 2 is a feature of our study which we think meant that we recruited the highest risk patients. Now, if you think about the IPI you get a score for age and you get a score for performance status, even patients with high burden disease who are young will often have a good performance status. So as a consequence, we really did recruit patients with high burden disease. Unlike any study I’ve seen before, we had a total tumour metabolic volume of over 800 centimeters cubed for the patients who were recruited. I can tell you as a clinician looking after many of these patients, we saw a lot of high burden disease here. We also saw about 11% with double-hit lymphoma were recruited to the clinical trial. And what we found from the regimen whether patients were given R-CHOP with glofitamab or R-POLA-CHP with glofitamab was that the regimen was really well tolerated. All of the studies that look at R-CHOP plus X have to ask the question is the chemotherapy backbone compromised and in this patient population there was no compromise to the chemotherapy backbone with more than 90% of patients receiving a relative dose intensity of more than 90%, which is really the bar that we look to achieve with this clinical trial. We saw a very high complete response rate, but what was interesting was the time that we saw the complete response rate. Traditionally with R-CHOP chemotherapy or R-POLA-CHP chemotherapy, we do a PET scan at the end of the chemotherapy backbone and look at the response there. That’s the time point that we look at. And in this clinical trial we looked at that that moment but did give a further two cycles of glofitamab consolidation. Now the complete remission rate at the end of induction treatment was a little disappointing roughly 80% overall which was not hugely different from what we see with R-CHOP. But when we looked at the complete remission rate and the overall response rate as best overall response. In fact 100% of patients responded and 98% of patients had a complete remission on this clinical trial which is quite remarkable. So there was an evolution of response between the end of treatment and the best response to treatment. In fact all the patients who had a partial response at the end of induction converted to a complete remission. So this was a novel finding that PET scans need to be interpreted with care in patients who are on immunotherapy combinations with chemotherapy backbone. We were able to present follow-up in this patient population of over 20 months, which is a clinically important time point in diffuse large B-cell lymphoma, and the retention of complete response at that time point was 86% in both arms. This is strikingly different from what would have been expected historically with R-CHOP chemotherapy, or probably with R-POLA-CHP chemotherapy as well. So this really suggests that the addition of glofitimab in this ultra-high-risk patient population is feasible without compromise of the chemotherapy backbone. And probably the days of opting for chemotherapy intensification will be over. Now, we’re very proud of having an 80 patient clinical trial in this population. We have a lot of confidence in these results, extra confidence because the time to treatment between diagnosis and treatment was just 12 days. In comparable studies, it’s usually about a month. That suggests to us that we didn’t select out good risk patients, so this gives us a lot of confidence. But it is essentially a trial with no control that doesn’t have glofitimab in it. And so we feel this is a very important piece of information for sites that are currently recruiting to the SkyGlo clinical trial. SkyGlo is a clinical trial that explores R-POLA-CHP with or without glofitamab in a very large, international randomized trial. That trial continues to recruit. There are many sites open in America. And I hope that this data from the coalition trial gives investigators confidence that in recruiting patients to that trial, they may be providing patients with a better outcome for their poorer risk lymphoma. Above all things, this was a trial that was run by PhD student Adrian Minson, who really did all of the very hard work in leading the investigators. And it was an amazing collaboration between Australian investigators. Despite the pandemic, it recruited on time. We have a lot of translational work that we’re working on. We look forward to presenting in future meetings.

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