ASH 2023 | First-in-human study of the menin-KMT2A inhibitor JNJ-75276617 in R/R acute leukemias

There’s been a lot of work over many, many years on the mechanisms by which a gene called MLL causes leukemia. It’s been a common gene rearrangement in both lymphoid leukemia in children and in myeloid leukemia in children and adults. And, after a lot of work, a key gene that mediates the leukemogenic activity of MLL was identified and it’s called menin. And then subsequent work showed that also, it is a key gene in identifying some of the leukemic actions of a gene called NPM1, which is also mutated in about 30% of adults with acute myeloid leukemia. So together the MLL, or KMT2A, and NPM1 alterations are common in adult AML, in childhood AML, but also in childhood ALL. And a number of companies have developed small molecule inhibitors, oral small molecule inhibitors, i.e. tablets to target menin.

At ASH this year there was an update both on the Syndax data some of the Kura compound data. But I’ll talk a little bit about the compound that has been made by Johnson and Johnson. It’s called 617 for short. And we presented data on a Phase I monotherapy trial in relapsed/refractory acute leukemia. And so a number of clinical investigators throughout the world collaborated on this trial in the United States, in Europe, and in the United Kingdom. And in all data was presented on 86 patients, median age of 59 years. These are individuals who mainly had AML, 91% of them, though there were four patients treated with ALL. There was a median of three prior lines of therapy, so they were often heavily pretreated. 20% of them had a prior transplant and just over half of them, 58% of them, had a KMT2A alteration and 42% of them had an NPM1 alteration. And not surprisingly, with NPM1 mutations patients often had a FLT3 mutation as well. So this is a compound which is safe, like the other menin inhibitors. It does have some side effects. The most notable side effects is differentiation syndrome, and that was observed in a total of ten patients. The drug can also cause a reduction in blood counts, neutropenia, and thrombocytopenia. And finally it’s associated with a small degree of nausea. But on the whole, compared to intensive chemotherapy, it’s very well-tolerated. And of the 66 patients who are evaluable, we saw an overall response in 50% of patients with a reduction in leukemia, with patients achieving less than 5% blasts in just under 50% of patients. And in those patients who had not only a reduction in blasts, but a recovery of their blood counts, so if you combine complete count recovery with incomplete count recovery, CRh and CRi, 27% of patients achieve that kind of response.

So this is similar to the responses that have been seen with the other menin inhibitors and the toxicity profile is similar to what’s been seen with the other menin inhibitors. And, in conclusion, 617 as a monotherapy is well-tolerated. It’s got a very safe profile in terms of side effects. It has activity in terms of antileukemic activity and other work showed that its mechanism of action is really to encourage leukemia cells to differentiate. So it’s very distinct from chemotherapy which kills cells. And I think this class of compound, there are multiple companies in the clinic now, I think this class of compound will likely be licensed for use in the United States and relapsed/refractory acute leukemia next year, initially in the MLL-rearranged group, KMT2A-rearranged group, but then also for NPM1 at a later stage. It’s also been combined with other drugs, so it’s been combined with venetoclax and azacitidine. It’s been combined with intensive chemotherapy. And this will be an important addition to the armamentarium of drugs that patients can access. So I think it’s an important advance.