EHA 2025 | Initial results from the GOlDiLOX trial of pirtobrutinib and glofitamab in MCL

So Goldilox is pretty close to my heart. It’s one of the investigator-initiated trials which we’ve been leading from Australia. And this is a phase two study of the CD20-CD3 bispecific T-cell engaging antibody glofitamab with the non-covalent BTK inhibitor pirtobrutinib. So I think two best-in-class agents for relapsed mantle cell lymphoma. The target population is patients with covalent BTK inhibitor refractory disease which is a high unmet need in mantle cell lymphoma at the moment. We also allowed patients with prior CAR-T failure. This is the first data presentation for Goldilocks and I think it’s been pretty heavily anticipated because it’s to my knowledge the first study with any data presented combining a bispecific and a BTK inhibitor and you know we’ve presented data on 16 patients at this meeting. We’ve explored three different dosing strategies, and the early dose levels were, we did have some issues with cytokine release syndrome in the early dosing. And initially we were wondering whether that was due to the dosing strategy that we were using, having a pirtobrutinib lead-in followed by the glofitamab introduction. But as it turns out, I think it was more due to the optimising the steroid prophylaxis regimen. What we’re increasingly seeing is that not all patient populations treated with bispecific antibodies have exactly the same safety profile. And there are some patients, there are some patient groups, and mantle cell lymphoma in particular, seems to be a particularly high-risk subgroup of patients for cytokine release syndrome. And I think that that problem is not unique to glofitamab and has actually been seen across other agents in the class as well. But after we sort of made some adjustments on the fly and optimised the steroid dosing, our troubles with CRS were largely mitigated, not completely, but substantially ameliorated, such that we were able to get through glofitamab dose escalation reasonably safely. So look, follow-up is very short. We’re only reporting on 16 patients and CRS has been the main toxicity observed, but the efficacy has been remarkable. Of course, glofitamab has high efficacy with a CR rate of about 70% as a single agent, but the issue with glofitamab as a single agent in mantle cell lymphoma is that the PFS curves do not look quite as good as in, for instance, diffuse large B-cell lymphoma, where patients tend to maintain their responses if they attain a complete response. With mantle cell lymphoma in the 179 phase two trial we did see that even patients who attained a CR with glofitamab therapy tended to experience subsequent disease progression so our hypothesis when adding in pirtobrutinib was that we could sort of prevent those late later relapses from happening and get some durable disease control in this patient population is often unsuitable for procedures like allogeneic stem cell transplantation and we’ve seen some remarkable responses. I mean the complete response rate in the study in the patients we’ve seen so far is still approximating you know high 60s 70% but probably the most impressive thing is that we’ve seen ultra high risk patients go on. TP53 mutations, people with CAR T-cell failure, very high tumor burden, leukemic disease, heavy marrow involvement, massive spleens, having really encouraging results. So I think this combination is highly potent and very promising and enrolment continues but yeah really excited to present some of the initial data at this meeting

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