Bosutinib for newly diagnosed chronic phase chronic myeloid leukaemia: final 5-year follow-up of the phase III BFORE trial
At ASH 2020, the final efficacy and safety results from the BFORE trial after five years of follow-up were presented. In this analysis, first-line bosutinib continued to demonstrate superior efficacy over imatinib, with bosutinib-treated patients achieving earlier and deeper molecular responses compared to patients treated with imatinib. Although bosutinib was more effective than imatinib in all risk groups, this benefit was particularly pronounced in patients with a Sokal high-risk profile.
Background
The approval of first line bosutinib for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) who are resistant or intolerant to prior therapy and for patients with newly diagnosed Ph+ chronic phase (CP) CML was based on the primary results of the pivotal BFORE trial. In this open-label phase III study, 536 patients with newly diagnosed CP CML were randomly assigned (1:1) to receive bosutinib or imatinib, both at 400 mg once daily. Baseline demographics and patient characteristics were well-balanced between treatment arms. Early results showed superior efficacy of bosutinib vs. imatinib in the modified intent-to-treat population (Ph+ with e13a2/e14a2 transcripts) after at least twelve months of follow-up. At ASH 2020, the final efficacy and safety results from the BFORE trial after five years of follow-up were presented.
Results
Five years after the last enrolled patient, 59.7% of patients in the bosutinib arm and 57.4% of patients in the imatinib arm were still on treatment. In total, 86.6% and 86.2% of patients on bosutinib and imatinib completed the complete five years of follow-up. Overall, the cumulative major molecular response (MMR) rate by 60 months was higher with bosutinib versus imatinib (73.9% vs. 64.6%; OR[95%CI]: 1.57[1.08-2.28]), as was the cumulative molecular response (MR)4 (58.2% vs. 48.1%; OR[95%CI]: 1.50[1.07-2.12]) and MR4.5 rate (47.4% vs. 36.6%; OR[95%CI]: 1.57[1.11-2.22]). Moreover, these molecular responses also occurred earlier with bosutinib than with imatinib (time to MMR: HR[95%CI]: 1.34[1.10-1.64]). Superior MR rates with bosutinib vs. imatinib were consistently seen across all Sokal risk groups, with the greatest difference seen in patients with high Sokal risk (MR4.5: 46.4% vs. 24.6%; OR[95%CI]: 2.66[1.20-5.92]). Among evaluable patients, a higher percentage of patients achieved BCR-ABL1 transcripts ≤10% at three months in the bosutinib vs. imatinib arm (80.6% vs. 60.5%; OR[95%CI]: 2.72[1.82-4.08]). These early responses translated into deeper molecular responses such as MMR later on. For bosutinib and imatinib there were no significant differences regarding event-free survival (EFS). If patients achieved a complete cytogenetic remission or a major molecular remission, these responses were typically durable for both bosutinib and imatinib. A numerically larger proportion of patients had a two-year sustained MR4 with bosutinib compared to imatinib (32.5% vs. 26.5%; OR[95%CI]: 1.33[0.92-1.93]). An ECOG performance status score of 0 versus >0 and time to BCR-ABL1 transcript ≤10% vs. >10% at three months were predictive of achieving a sustained MR4. The cumulative incidence of transformations to accelerated/blast phase by 60 months was 2.2% for bosutinib and 2.6% for imatinib (HR[95%CI]: 0.86[0.29-2.54]) while the cumulative incidence of progression or death by 60 months was 6.7% and 9.3% (HR[95%CI]: 0.70[0.38-1.27]), respectively. No new transformation occurred after the 24-months follow-up. The 60-months overall survival rates were similar (94.5% and 94.6% for bosutinib and imatinib, respectively) with 14 deaths in each treatment arm.
Treatment-emergent adverse events (TEAEs) of special interest (any grade) were in line with the previous experience with both drugs. The most frequent AEs observed under bosutinib as compared to imatinib were gastrointestinal (79.9% vs. 61.5%), liver toxicity (44.0% vs. 15.5%) and rash (39.2% vs. 26.0%), whereas musculoskeletal events (35.4% vs. 59.6%) and oedema (15.7% vs. 43.4%) were more frequently reported in the imatinib arm. In total, 16 cases of effusion in the bosutinib arm and 6 cases in the imatinib arm were reported. Out of these 16 cases of effusion in the bosutinib arm, treatment had to be temporarily interrupted for 11 patients. However, in nine of these patients treatment could be rechallenged successfully. For bosutinib, more than half of the AEs leading to treatment discontinuation were observed during the first year of treatment, whereas the vast majority of AEs that led to discontinuation in the imatinib arm occurred during the first year of treatment. The most frequent AE leading to permanent treatment discontinuation was increased ALT (4.9% vs. 0%) with bosutinib versus imatinib. Vice versa, muscle spasms and myalgia led to discontinuation in 1.1% and 1.1% of patients under imatinib whereas this was not reported in the bosutinib arm. Interestingly, diarrhoea, thrombocytopenia and neutropenia led to discontinuations in similar rates of patients across both arms.
Conclusions
After five years of follow-up, bosutinib continued to demonstrate superior efficacy compared to imatinib, as evidenced by earlier and deeper MR. The greatest improvement in MR with bosutinib was observed in Sokal high-risk patients. In addition, a higher percentage of patients achieved BCR-ABL1 transcripts ≤10% at three months in the bosutinib vs. imatinib arm and a substantial proportion of patients receiving bosutinib or imatinib achieved a two-year sustained MR4. Finally, long-term AEs were generally manageable and consistent with the known safety profile of both drugs. Final results of the BFORE trial thus confirm the use of bosutinib as a standard of care in patients with newly diagnosed CP CML.
Reference
Brümmendorf TH, Cortes JE, Milojkovic D, et al. Bosutinib (BOS) Versus Imatinib for Newly Diagnosed Chronic Phase (CP) Chronic Myeloid Leukemia (CML): Final 5-Year Results from the Bfore Trial. Presented at ASH 2020; Abstract 46.
