ASH 2024 | The tolerability and clinical activity of inobrodib plus pomalidomide and dexamethasone in RRMM

Okay, so I presented this in the future therapies and myeloma session on Monday evening, just as ASH was starting to wrap up. And this data concerns a novel first-in-class agent, called inobrodib, or CCS1477. I’d previously presented some monotherapy data in poster form at ASH. But this, the data that I presented at ASH 2024 was the first in combination data with pomalidomide and dexamethasone. And the reason we’d honed in on this combination was because of preclinical data that suggested that we were likely to have synergy with immunomodulatory drugs and that you could potentially rescue IMiD responsiveness. So when I presented the monotherapy data, we’d found that the overall response rates were, you know, there was monotherapy activity, which is always exciting to see, but the overall response rates were modest at around 25%. And in this combination portion, I presented data from 40 patients treated with a range of doses from 3mg of pomalidomide with inobrodib, 25mg twice daily, through to 4mg of pomalidomide with inobrodib, 35mg twice daily. It’s worth noting that we dosed the inobrodib on a four-days-on, three-days-off regimen because of our experience in the monotherapy study, which showed that thrombocytopenia occurs, but recovers very briskly when you pause treatment so an interrupted schedule helps to manage that. The pomalidomide was dosed on a standard 21 day out of 28 day schedule and the dexamethasone was given at doses appropriate to age as a single dose weekly. I showed that the pharmacokinetic data showed proportional linear pharmacokinetics with a short half-life of 46 hours, which is how we settled on the twice-daily dosing. And this PK is not altered by the addition of the other agents, so the pomalidomide and the dexamethasone. And as you’d expect for a study of this type with a completely novel agent, the patients were predominantly, particularly heavily treated with a median prior lines of therapy of five. And there was, although this study started as kind of an all-comers haematological malignancy study, so it didn’t have myeloma-specific imaging built into it in its early stages, there was certainly a sense from the data that we had that these patients had a high disease burden because we saw high rates of marrow infiltration and high rates of elevated LDH and increased ISS stage. So 70% of the patients had already had pomalidomide before, and just under a third of patients had received a BCMA-targeted approach, such as a T-cell engager. And getting down to the key observations in terms of safety, we didn’t see anything we weren’t expecting. We understand the safety profile of Ino pretty well now. The main side effect, as stated, was thrombocytopenia, though that was mitigated by the interrupted schedule. We did see some low-grade bleeding events. And then, as expected, when you’re using pomalidomide and dexamethasone, particularly in heavily pretreated patients, we did see some neutropenia, which was manageable with G-CSF. And there were some low-grade gastrointestinal side effects, such as constipation. We did see some infections. As I said, these patients were very heavily pretreated, but there were no deaths from infection within this study. In terms of overall response rates across all of the dosing cohorts assessed, we saw a 49% overall response rate with a median duration of response of 6.3 months. But excitingly, in that highest dose in cohort, we saw a 75% overall response rate. A bit early to talk about duration of response when we’re assessing such limited patient numbers, but that did come up at 9.7 months. Interestingly, in the pomalidomide refractory patients, and particularly the patients who’d received pomalidomide as their last line of therapy, we saw half of the patients responding to the combination. So really mirroring what we’d hoped to see given the laboratory data that you can recapture responses in patients even who are pomalidomide refractory. But certainly in this early data, there’s a sense that the pomalidomide naive patients achieved the deepest responses with two out of the 12 pomalidomide naive patients achieving a stringent CR which was MRD negative. So again another tool in our armory we’re all starting to wonder what to do with these patients particularly who’ve had BCMA or other T-cell engaging antibodies. This is an all oral combination which makes it very manageable for patients who don’t want to spend significant time in hospital. And this study is now moving on to randomised expansion, assessing different doses with pomalidomide, dexamethasone and inobrodib in patients with relapsed refractory multiple myeloma.

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