FDA Approves Bosutinib for Newly-Diagnosed Ph+ CML

Jorge Cortes, MD

The FDA has granted an accelerated approval to bosutinib (Bosulif) as a first-line treatment for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), based on findings from the phase III BFORE trial.

In the open-label study, 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).

“Among patients with CML today, with the various treatment options available, it is important to recognize the unique needs of each of my CML patients and prescribe treatments that best meet those needs,” Jorge E. Cortes, MD, The University of Texas MD Anderson Cancer Center, said in a statement. “The efficacy and distinct tolerability profile of Bosulif make it an important and useful treatment option for newly diagnosed CML patients.”

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%).

Bosutinib was initially approved in the United States for the treatment of adult patients with Ph+ CML who have resistance or intolerance to prior therapy in September 2012. The frontline approval was granted under the FDA's accelerated approval program. Continued approval is contingent upon findings from long-term follow up.

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).