Bosutinib Nears EU Approval for Frontline Ph+ CML

Mace Rothenberg, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of bosutinib (Bosulif) as a first-line treatment for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), according to Pfizer, the developer of the third-generation tyrosine kinase inhibitor.

The CHMP recommendation is based on data from the phase III open-label BFORE trial, in which the major molecular response (MMR) at 12 months was 47.2% with bosutinib (95% CI, 40.9-53.4) compared with 36.9% (95% CI, 30.8-43.0) for imatinib (P = .02). The complete cytogenetic response (CCyR) rate by 12 months was 77.2% (95% CI, 72.0-82.5) with bosutinib compared with 66.4% (95% CI, 60.4-72.4) for patients treated with imatinib (P = .0075).

Based on these findings, the FDA approved bosutinib in this setting in December 2017. Bosutinib is currently approved in the EU for previously treated patients with CML. The positive CHMP opinion will now be sent to the European Commission for a final regulatory decision.

“The potential expansion of the approved use of Bosulif to include first-line therapy expands the treatment options for adult patients with newly diagnosed chronic myelogenous leukemia,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

In the BFORE trial, patients with newly-diagnosed chronic phase CML were randomized to bosutinib (n = 268) or imatinib (n = 265). A 400-mg dose of bosutinib was utilized in the phase III study to avoid adverse events (AEs) reported in prior studies that explored a 500-mg dose. Imatinib was given at 400 mg. Efficacy was evaluated specifically in those with Ph+ CML, which accounted for 246 patients in the bosutinib group and 241 in the imatinib arm.

Patient characteristics were well balanced between the 2 arms. The median age of patients was 53 years (range, 18-84), with 18.5% being ≥65 years. The median time since diagnosis was 24 days. The Sokal risk group was intermediate and high for 40.2% and 20.9% of patients, respectively, and the ECOG performance score was 0 (70.6%) and 1 (29.2%). Extramedullary disease was present for 4.5% of patients.

MMR rates favored bosutinib at 6 and 9 months. The 6-month MMR was 35.0% with bosutinib and 18.3% with imatinib and the 9-month MMR was 42.3% for bosutinib and 29.5% for imatinib. The cumulative incidence function of MMR was more favorable with bosutinib, indicating a shorter time to response (HR, 1.34; 95% CI, 1.06-1.69; P = .0173). At 3 months, bosutinib led to BCR-ACL transcript levels of <10% in 75.2% of patients compared with 57.3% of those in the imatinib group.

In those with high Sokal scores, the 12-month MMR rate with bosutinib was 34.0% compared with 16.7% with imatinib. In the intermediate group, the 12-month MMR was 44.9% and 39.1% with bosutinib and imatinib, respectively. In the low Sokal group, the MRR rates were 58.1% and 46.3%, for bosutinib and imatinib, respectively.

More patients in the bosutinib arm experienced treatment-related dose interruptions (55% vs 36%) and reductions (35% vs 17%). The median dose intensity was 392 mg in the bosutinib group compared with 400 mg in the imatinib arm. At 12 months, 82% of patients in both groups had completed the full course of treatment and 18% in both groups discontinued treatment within 12 months. In the bosutinib arm, 13% discontinued due to treatment-related adverse events (AEs) compared with 9% in the imatinib arm.

All-grade diarrhea (70% vs 34%) and grade ≥3 diarrhea (8% vs 1%) were significantly higher with bosutinib versus imatinib. Patients in the experimental arm were also much more likely to experience all-grade liver toxicity (40% vs 14%) and grade ≥3 liver toxicity (24% vs 4%). The most common treatment-emergent AEs (TEAEs) of any grade with bosutinib were diarrhea (70.1%), nausea (35.1%), thrombocytopenia (35.1%), increased ALT (30.6%), and increased AST (22.8%). Grade ≥3 TEAEs occurred in 56.3% of patients receiving bosutinib, most commonly ALT increase (19.0%) and thrombocytopenia (13.8%).

Cortes JE, Gambacorti-Passerini C, Deininger MWN, et al. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): Initial results from the BFORE trial. J Clin Oncol. 2017;35 (suppl; abstr 7002).