ASH 2025 | Mosunetuzumab + zanubrutinib for newly diagnosed high-burden FL: first results of MITHIC-FL2

Here at ASH, we’re also presenting the first look, early look, at our MITHIC-FL2 trial program. This is a series of academic trials we’re putting together for patients with newly diagnosed high-burden follicular lymphoma. In years past, we presented the results of MITHIC-FL1 study testing mosunetuzumab as a single agent subcutaneously administered drug for patients with high burden follicular lymphoma. And we really observed very encouraging results with high response rates and a good duration of response with the available follow-up. 

In MITHIC-FL2, we’re trying to test whether the addition of an oral agent, an oral BTK inhibitor, zanubrutinib, could improve these results. And the rationale for that is that we’re seeing that after administration of mozonetuzumab in patients in the MITHIC-FL1 study, we see an expansion of CD8-positive T cells that may start exhibiting some signs of exhaustion. And we saw an opportunity to potentially mitigate or reverse that exhaustion as a means to improving clinical results. So in this trial, we added zanubrutinib given orally continuously at 320 milligrams daily for a total of 12 months. And then the rest of the study remains similar to MITHIC-FL1 with mosunetuzumab given on a step-up dosing schedule in cycle one, and then every three weeks for eight cycles, which is roughly six months. Patients in a complete response would only continue on the zanubrutinib, those with a partial response continue both drugs, and obviously patients with less than that response will be taken off study because they wouldn’t benefit from the program. 

We enrolled so far 54 patients, 51 were evaluable for efficacy. Most patients are still on treatment, so the follow-up is short, 6.5 months. But we saw very good deliverability of the treatment. Very few cycles were delayed. No patient really interrupted treatment permanently or discontinued treatment permanently. So the safety of and the deliverability of the treatment is really good. And we started to see an early good efficacy signal. 92% of the patients had an objective response. 82% of the patients had a complete metabolic response. Obviously, we can’t speak about durability, as I mentioned, the follow-up is short. On the safety side, we certainly didn’t see any safety signals. The CRS profile or cytokine release syndrome profile was quite consistent with a single-agent study. Other adverse events of special interest, you know, neurotoxicity, injection site reactions, skin manifestations on the mosunetuzumab side, or bruising or bleeding or atrial fibrillation on the zanubrutinib side, were really consistent with the safety profile of each individual single agent. So again, an early look, but very promising early results for this combination.

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