Discussion
first-ever, CML, CML-CP, upper respiratory tract infection, musculoskeletal pain, PD, GI toxicity, hypersensitivity
UPPER RESPIRATORY TRACT INFECTIONS, PANCREATIC TOXICITY, CML, EVENTS, HYPERSENSITIVITY, DISEASE CHARACTERISTIC
Updated analysis of this phase 1 trial in heavily pretreated patients with CML-CP without T315I demonstrates the continued safety, tolerability, and substantial, durable efficacy of asciminib; with a median exposure of ≈4 years, most patients (69.6%) remained on asciminib. No new safety signals arose in this patient population. A significant proportion of patients achieved MMR or DMR, and very few lost MMR. The cumulative rate of MMR and DMR continued to increase with additional patients achieving responses even 3 years after initiation of treatment. Discontinuation due to PD (6.1%) and AEs (11.3%) occurred infrequently; 2 patients died on treatment, unrelated to asciminib. In studies of other TKIs (including nilotinib, dasatinib, bosutinib, and ponatinib) in heavily pretreated patients, 24%–62% remained on treatment [The most frequently reported AEs grouped by common pathophysiological features were GI toxicity (72.2%), musculoskeletal pain (59.1%), hypersensitivity (mainly dermatologic events [44.3%]), and upper respiratory tract infection (41.7%); these events were generally mild and manageable. AEs (including hematologic) generally occurred early after treatment initiation, a pattern also observed in the phase 3 ASCEMBL trial, where most first-ever AEs (including hematologic) occurred in the first 6 months [Pancreatic toxicity, including pancreatic enzyme elevations, is a broad safety concern for patients with CML receiving TKIs [CV toxicity is observed with all ABL kinase inhibitors, including ponatinib, and warrants a personalized approach for optimal CV risk management in patients with CML [MMR is a well-established treatment goal [In this updated analysis, the cumulative MMR rate continued to increase with longer asciminib treatment duration regardless of line of therapy or baseline disease characteristics, with two-thirds of patients (61.6%) achieving MMR by data cutoff; rates ranged from 52.5% to 75.0% by treatment line, confirming the benefit of asciminib in this heavily pretreated population for whom options are very limited. These data compare favorably with those in other later-line TKI studies [Compared with lesser depth of response, DMR is associated with improved outcomes, including better OS, EFS, and failure-free survival and reduced risk of progression to AP/BC [This longer-term follow-up demonstrates the durability of response achieved with asciminib; only 5 of 53 patients who achieved MMR lost this response (2 of 5 remain in Newly emerged In conclusion, asciminib, with its novel mechanism specifically targeting the ABL myristoyl pocket, is safe, well tolerated, and provides durable longer-term responses, including DMR in heavily pretreated patients with CML-CP without T315I. With a median treatment duration of ≈4 years, more than two-thirds of patients remained on therapy. These extended safety and response data from the phase 1 study complement results from ASCEMBL, which demonstrated superior efficacy and favorable safety with asciminib compared with bosutinib [