EHA 2025 | The GOlDiLOX trial: pirtobrutinib plus glofitamab in MCL with previous covalent BTKi exposure

Mantle cell lymphoma that progresses after exposure to a BTK inhibitor is a very difficult to treat condition. In this population we know that patients are enriched for high molecular risk factors and are often refractory to chemotherapy and this is where immunotherapies like the bispecific antibodies and CAR T-cell treatment can be very effective. Unfortunately, CAR T-cell therapy has more toxicity in the setting of mantle cell lymphoma than what we see in diffuse large B-cell lymphoma, meaning that it’s not suitable for all patients. In the GOLDILOX clinical trial, we wanted to combine two agents that we know are effective in patients who’ve progressed after traditional BTK inhibitors and chemotherapy. One, pirtobrutinib, which is approved in the United States in this context, is clearly active and induces a significant overall response rate in this population and is extremely well tolerated as a monotherapy. And the other, glofitamab, a CD20, CD3 bispecific antibody, which is very potent in mantle cell lymphoma and induces a complete remission rate in about 80% of patients when used as a monotherapy, but which comes with a cost of cytokine release syndrome, which is a key issue with the delivery of bispecific antibodies in this population. So in GOLDILOX what we wanted to do is take these two active agents and use it in this high risk patient population, patients who’ve been exposed to BTK inhibitors and in the Australian environment that’s usually patients who’ve received BTK inhibitors in the second or subsequent line of therapy. We don’t have routine access in the first line apart from the trial setting. And so these patients are quite enriched for poor molecular risk factors and poor cytological appearances suggesting that they would be very unlikely to respond well. We recruited patients who were also thought to be, while it wasn’t a formal inclusion criteria, it was likely that these patients had either already received tecartus or were not being considered for tecartus for either practical reasons or age or fitness, which meant that we recruited a high-risk population with a high burden of disease. We did two strategies in this trial. The first strategy was to use pirtobrutinib first and then introduce glofitamab later. And then after we treated some patients with that, we decided on the basis of some of the safety signals to change the way that we were using glofitamab and explore an alternative dosing regimen. In the first cohort, we saw probably about as much cytokine release syndrome as one would expect from the glofitamab monotherapy data that was recently seen in the JCO article. But we felt that the rate of grade 2 CRS and the practical elements of delivering the treatment in this way were not good enough for this frailer population. So we made these two changes. Firstly, we switched to delivering glofitamab first to induce the response because we know that patients who are already progressing after a BTK inhibitor need something different quickly. And secondly, we augmented the corticosteroids that we use around the introduction of glofitamab in line with some of the changes that are being made to the glofitamab program in mantle cell lymphoma. And that led to a dramatic change in tolerability. We found that we’ve been seeing no more CRS than we would have expected with glofitamab monotherapy, and that the grade of CRS is significantly less. Overall, in the 16 patients that we’ve recruited with these two dosing strategies, we saw a CRS rate of around 50% and a higher grade CRS rate of around 25%. But importantly, we saw really remarkable clinical responses. We had 14 patients who were evaluable at the primary endpoint, which is measured at 16 weeks, and 70% were in a complete remission, and they were all MRD-negative complete remissions, despite a fairly high proportion of patients having mutations in P53 and unfavourable cytologic features. So it’s really quite a remarkable clinical response to treatment there that we’ve seen. Now the study is ongoing and we’re recruiting to this second strategy at the moment of giving glofitamab first and then introducing the pirtobrutinib and so far so good we plan to expand it out to around 40 patients and we look forward to presenting that data.

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