Tolerability and Clinical Activity of Novel First-in-Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma
Dose escalation cohorts have enrolled 48 RRMM pts to date with a median age of 68 yrs (range 41-82). Median prior lines of therapy was 6 (range 2-10), all were triple-class exposed, 39 pts (81%) were triple class refractory, and 16 pts (33%) received prior BCMA therapy. In addition, 31 pts (65%) were pomalidomide-refractory.
Median duration of treatment for 36 evaluable patients to date was 177 days (range 35-601), with a median of 6 cycles (range 1-21). Over 1/3rd of the patients continue on treatment. Almost 1/3rd of patients have died in the survival follow-up, mainly due to disease progression, but a number of patients remain in follow-up for overall survival.
At the data cut-off (4th June 2024), Grade (gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 35 of 48 (73%) pts. The most frequent gr 3/4 events were hematological (56%); neutropenia (27%: 19% gr 3, 8% gr 4), thrombocytopenia (27%: 21% gr 3, 6% gr 4) and anemia (13%, all gr 3). Frequency of gr 3/4 infections was 29%. This is in line with the anticipated profile of pom/dex only. The main potential for overlapping toxicity is thrombocytopenia however no significant increase in frequency or severity has been seen with the triplet. Inobrodib as monotherapy has not been shown to cause neutropenia. One patient died due to an unrelated cardiac event at the end of cycle 2. Five pts (10%) discontinued due to TEAEs. The pattern of TEAEs considered related to study treatments is consistent with the known safety profile of the individual agents, with the majority of events gr 1/2 and the most common gr 3/4 events being hematological toxicities.
Objective responses were seen across all dose levels tested with best ORR (6/8 evaluable patients, 75%) in the highest dose cohort. In general responses start rapidly after initiation of treatment and deepen with time on treatment.
Among pom-refractory pts, 7 had progressed on a pom-containing regimen as the last prior therapy and 5 of these achieved OR, providing clinical proof of concept on published non-clinical data regarding the exquisite synergy of this combination (Welsh et al. 2024). Responses were also seen in patients exposed to anti-BCMA and/or TCE therapies; further recruitment is ongoing in this population.
In the initial sample of pom-naïve pts (12), there is a trend for deeper response with 2 patients achieving CRs (17%) and 2 patients having MRD negativity 10-5 .