The FDA has granted a priority review to a supplemental new drug application for bosutinib for the first-line treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia.
Mace Rothenberg, MD
The FDA has granted a priority review to a supplemental new drug application (sNDA) for bosutinib (Bosulif) for the first-line treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). The agency is scheduled to make a final decision by December 2017.
According to Pfizer and Avillion, the co-developers of the tyrosine kinase inhibitor (TKI), the European Medicines Agency (EMA) is also reviewing an application for use of bosutinib in the same patient population.
The FDA and EMA applications are based on data from the phase III BFORE trial, in which bosutinib was associated with a significantly higher rate of major molecular response at 12 months compared with imatinib (47.2% vs 36.9%; odds ratio [OR], 1.55; P = .02), in patients with newly diagnosed Ph+ CML.
“As physicians gained experience with Bosulif, they have come to appreciate its favorable risk-benefit profile in patients with Ph-positive CML who no longer responded to or could not tolerate prior TKI therapy,” Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development, said in a press release. “At the 400-mg dose, we believe that the BFORE study demonstrates a similarly favorable risk-benefit in previously untreated patients with Ph-positive CML.”
In the multicenter, multinational, open-label BFORE trial, patients with newly diagnosed chronic phase CML were randomly assigned to 400 mg once daily of bosutinib (n = 268) or 400 mg once daily of imatinib (n = 265). Investigators lowered the bosutinib dose from 500 mg daily that was used in a previous study in an attempt to reduce toxicity.
Efficacy was assessed in a modified intent-to-treat population of 487 Ph+ patients, 246 in the bosutinib group and 241 in the imatinib group. The safety analysis included all patients treated.
The arms were well balanced. Median age was 52 years in the bosutinib arm (range, 18-84) and 53 years in the imatinib arm (range, 19-84). Roughly 20% of patients in the both arms were in the Sokal high-risk group. In both groups, all patients had an ECOG performance score of 0 or 1.
At 3 months, after achieving BCR-ACL transcript levels of <10%, early response was significantly superior for bosutinib (75% vs 57%).
Complete cytogenetic response (CCyR) by 12 months was also statistically significant in favor of bosutinib (77.2% vs 66.4%; OR, 1.74; P <.01). Cumulative incidence of CCyR was also superior in the bosutinib group (hazard ratio [HR], 1.35; 95% CI, 1.13-1.69; P = .001).
At 12 months, 82% of patients in both groups completed the full course of treatment and 18% in both groups discontinued within 12 months. In the bosutinib arm, 13% discontinued due to treatment-related adverse events compared with 9% in the imatinib arm.
More patients in the bosutinib arm experienced treatment-related dose interruptions (55% vs 36%) and reductions (35% vs 17%). Median dose intensity was 392 mg per day with bosutinib and 400 mg per day with imatinib.
All-grade diarrhea (70% vs 34%) and grade ≥3 diarrhea (8% vs 1%) were significantly higher with bosutinib. 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%).
Bosutinib is currently indicated in the United States for the treatment of adult patients with Ph+ CML who have resistance or intolerance to prior therapy. In Europe, Bosutinib has conditional marketing authorization for the treatment of adult patients with Ph+ CML previously treated with 1 or more TKIs and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.
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 35, 2017 (suppl; abstr 7002).