ASH 2024 preview – more challenges to the BTK order

Nurix and BeiGene's BTK degraders, which went toe to toe at ASH 2023 and then put up impressive data at this year's European Hematology Association meeting, are about to face off again. Both feature among the oral presentations due to be discussed at next month's ASH conference, recently unveiled abstracts reveal.

Of course, more traditional BTK inhibitors abound too, with BeiGene's Brukinsa and AstraZeneca's Calquence, for example, being tested alongside BCL-2 inhibitors. And some investors will keep a close eye on the results of Lilly's high-profile Jaypirca, especially given the threat that degraders might pose to such non-covalent BTK inhibitors.

These data will feature among the most advanced presentations concerning clinical trial results to be discussed at ASH. Most of the meeting's regular abstracts have been unveiled, while plenary presentations remain under wraps, and late-breakers go live on 25 November.

Non-covalent

Lilly's Jaypirca has accelerated US approvals for BTK inhibitor-pretreated mantle cell lymphoma and chronic lymphoblastic leukaemia (CLL), and as a non-covalent BTK inhibitor it is claimed to remain active even in patients who relapse via C481S and other mutations – common escape pathways in treatment with covalent drugs like Imbruvica, Brukinsa and Calquence.

However, because of the way BTK degraders work these are claimed also to remain active in C481S and other mutations of the BTK protein. And, from the limited data available so far, there is evidence that this is indeed the case: at EHA Nurix's NX-5948 and Beigene's BGB-16673 both yielded responses in C481S-mutant disease and in post-Jaypirca patients.

From the ASH 2024 abstracts these two degraders again seem to have similar activity, with ORRs in the high 70% range across the board, though BGB-16673 has previously looked to be more toxic than NX-5948, so this will be something to look out for. Nurix is also developing NX-2127, a BTK degrader also said to be cereblon-recruiting; this spent four months on clinical hold, and at ASH will only have in vivo data.

For Lilly's Jaypirca the ASH focus will be data from Bruin CLL-321, which acts as the confirmatory study for the drug's CLL approval. Bruin CLL-321 was toplined positive for PFS a year ago, but no data have been released from it until now; the ASH abstract reveals PFS hazard ratios (0.58 versus Rituxan combos), but relates to a February 2024 cutoff, with Lilly promising data as of August.

First generation

Among first-generation, covalent BTK inhibitors, Brukinsa has already beaten Imbruvica on overall survival in the Alpine CLL study, which also suggested cross-trial superiority versus Calquence.

At ASH these two drugs will be aiming to bolster their first-line CLL labels, with readouts of trials combining them with BCL-2 inhibition. The more advanced study here is Astra's phase 3 Amplify, testing Calquence plus Venclexta, with or without Gazyva, against chemo; Amplify was toplined positive in July, and the ASH abstract reveals statistically significant PFS hazard ratios for the doublet and triplet alike.

For Brukinsa the focus is a phase 1 study combining the drug with BeiGene's own BCL-2 inhibitor sonrotoclax. Data from this had already been presented at ASH a year ago, and the combo has entered phase 3.

Selected ASH 2024 oral presentations on BTK

ASH will take place on 7-10 December in San Diego.