Sprycel Approved for Resistant CML and Ph+ ALL

ATLANTA—The FDA has granted accelerated approval to Bristol-Myers Squibb's Sprycel (dasatinib) Tablets for the treatment of adults in all phases of chronic myeloid leukemia (CML) (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy, including imatinib (Gleevec). Sprycel also received regular FDA approval for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

The approval came shortly after the FDA's Oncologic Drugs Advisory Committee (ODAC) signaled its support for the agent in a meeting held in Atlanta to coincide with ASCO's annual conference.

Dasatinib is an oral inhibitor of multiple tyrosine kinases, including BCR-ABL, SRC family, c-KIT, EPHA2, and PDGFRβ. It is promising because it is several hundred times more potent than imatinib at inhibiting the growth of cells harboring the BCR-ABL fusion gene and is effective in nearly all cells that have imatinib-resistant mutations, according to the sponsor.

Sponsor Evaluation

At the ODAC meeting, Claude Nicaise, MD, vice president, global development, Bristol-Myers Squibb, said, "We focused the development of dasatinib on the treatment of CML patients who failed imatinib because of
resistance or intolerance. These patients have limited therapeutic options, and dasatinib has the potential to fulfill this important unmet medical need."

Data on the drug come from six trials conducted at about 75 institutions worldwide in patients with all phases of CML who had imatinib resistance or intolerance and in patients with Ph+ ALL who had resistance or intolerance to prior therapy: a phase I dose-escalation trial, four single-arm phase II trials, and a randomized phase II trial pitting dasatinib against high-dose imatinib. (Data for the entire population in the randomized trial were presented at ASCO, see page 62.)

Efficacy analyses were based mainly on 529 patients enrolled in the phase I and single-arm phase II trials, which have a planned follow-up of 2 years. Most of these patients had CML in chronic phase (226 patients), accelerated phase (118), or myeloid blast phase (97); fewer had CML in lymphoid blast phase (47) or had Ph+ ALL (41). Only 94 patients (18%) overall had imatinib intolerance, and the majority of these were in the chronic phase CML group. Based on findings of the phase I trial, a dose of 70 mg twice daily was selected for use in the phase II trials, Dr. Nicaise said.

Efficacy results showed that among patients with chronic phase CML, 31% to 38% of imatinib-resistant patients and 73% to 75% of imatinib-intolerant patients had a major cytogenetic response, depending on the trial. Additionally, data from the first 36 patients enrolled in the randomized phase II trial, which was restricted to patients with chronic phase CML with imatinib resistance, showed a major cytogenetic response rate of 45% with dasatinib, compared with 21% with high-dose imatinib.

Among patients with advanced phases of CML or with Ph+ ALL, 30% to 59% had a major hematologic response. Moreover, responses were durable, according to Dr. Nicaise.

Safety results, based on 511 patients, showed that myelosuppression and fluid retention were the most noteworthy toxicities of dasatinib, Dr. Nicaise said. Some 47% to 84% of patients developed severe thrombocytopenia and 50% to 86% developed severe neutropenia, depending on disease phase. However, he noted, in a separate trial, patients with solid tumors treated with dasatinib have not developed myelosuppression, and preclinical data show that dasatinib targets bone marrow progenitor cells from patients with CML, but not those from healthy individuals. "This strongly suggests that the myelosuppression in the CML program is linked to the [drug's] activity in this population," he commented. Likely related to myelosuppression, 10% of patients had gastro intestinal hemorrhage, 1% had CNS hemorrhage, and 5% developed severe infections.

Fluid retention occurred in 44% of patients; it was most commonly superficial edema (28%) or pleural effusion (21%). The fluid retention was grade 3 to 4 in 8% of patients overall.

The majority of patients needed a dasatinib dose reduction or dose interruption, with such adjustments occurring more commonly in patients with chronic phase CML, Dr. Nicaise said; in that group, the mean dose actually received was 108 mg daily. Some 14% of patients discontinued trial participation because of treatment-related toxicity.

The safety profile in imatinib-intolerant patients was similar to that in the safety population overall, Dr. Nicaise noted; moreover, none of the imatinib-intolerant patients had a recurrence of their imatinib-related hepatotoxicity or skin toxicity while taking dasatinib, and only 3% of had a recurrence of grade 3 nausea, diarrhea, or fatigue.

FDA Questions Dosing

"The FDA reviewers have not detected major issues with this [new drug] application," Edvarda Kaminskas, MD, a medical officer in the FDA's Division of Drug Oncology Products, said at the ODAC meeting. The agency did seek ODAC's input on two issues. First, although the sponsor recommending approval of dasatinib at a starting dose of 70 mg twice daily, should a lower one be studied? "We think lower starting doses should be evaluated," Dr. Kaminskas commented, noting that the phase I data suggested that response rates with 50 mg twice daily were similar to those with 70 mg twice daily. [The FDA-approved dose is 70 mg twice daily.] Second, are the data provided sufficient in magnitude and duration for imatinib-intolerant patients, given their small number?

ODAC Deliberations

Taking up the first issue—recommended starting dose—ODAC member Maria Rodriguez, MD, of M.D. Anderson Cancer Center, asked the sponsor to clarify the rationale for selecting 70 mg twice daily. In addition, she noted that the response rates achieved despite the often prolonged duration of dose interruptions suggested that an intermittent dosing schedule might also be possible.

In response, Dr. Nicaise said that dose selection was based in part on pCRKL inhibition, and although both the 50 and 70 mg twice daily doses were effective in this respect, inhibition "was more complete and more reproducible from one patient to another at 140 mg per day."

Furthermore, he noted, the company took a different approach to the phase I analyses than did FDA. "We did not look at the starting dose, but rather at the dose patients were receiving when the cytogenetic response was documented," he said, and the results slightly favored the higher dose. To further explore the dose issue, the company has recently completed a trial comparing four dosing schedules—50 mg twice daily, 70 mg twice daily, 100 mg daily, and 140 mg daily—and the data are currently maturing, he said.

ODAC member S. Gail Eckhardt, MD, of the University of Colorado Health Sciences Center, asked whether, given the response rates observed even in light of the frequent dose reductions and interruptions, it might be possible to start patients at the 50 mg twice daily schedule and escalate the dose. In response, Neil P. Shah, MD, of the University of California, San Francisco, investigator of the randomized trial, said, "Thinking forward about what we might face with dasatinib and dasatinib resistance down the line, it's entirely possible there will be mutations that cause resistance to dasatinib that may be sensitive to a higher dose, and one could almost make the argument that we should be trying to dose closer to its MTD, which has not even yet been established." He noted that his clinical experience suggests that individualizing the dose is also important, and some patients will need an even higher dose to achieve a response. "Given the complexities, I feel that 70 mg twice daily is a very reasonable starting point," he concluded.

Turning to the second issue—the limited data in patients with imatinib intolerance—Dr. Eckhardt pointed out that there are few treatment options for truly intolerant patients, at least when it comes to orally active agents. In terms of patients with imatinib intolerance in the accelerated, myeloid blast, or lymphoid blast phases of CML, ODAC member Alexandra M. Levine, MD, of the USC/Norris Cancer Hospital, pointed out that the committee was being asked to give an assessment based on data from fewer than 30 patients. "That makes it exceedingly difficult in a scientific sense. In a human sense and a practical sense, yes, we're going to use [the drug] in those patients," she said. Committee members further noted that despite the small numbers of patients with CML in these phases, the response rates were favorable.

ODAC Votes

After deliberating on these and other issues, ODAC gave affirmative responses to five questions put to a vote, as follows:

•Has the sponsor provided sufficient evidence of dasatinib's effectiveness, based on the magnitude and duration of major cytogenetic responses and major hematologic responses, for chronic phase CML? Accelerated phase CML? Myeloid blast CML? Lymphoid blast CML? (Excludes Ph+ ALL.) (vote: 14-0)

•For accelerated approval—in the imatinib-resistant population, excluding Ph+ ALL. Based on the phase II data, does the risk-benefit profile support dasatinib's approval for chronic phase CML? Accelerated phase CML? Myeloid blast CML? Lymphoid blast CML? (vote: 14-0)

•For accelerated approval—in the imatinib-intolerant population, excluding Ph+ ALL. Has the sponsor provided evidence of an effect on a surrogate endpoint (major cytogenetic response) for chronic phase CML patients intolerant to imatinib? (vote: 13-0, 1 abstention)

•For accelerated approval—in the imatinib-intolerant population, excluding Ph+ ALL. Has the sponsor provided sufficient evidence to warrant accelerated approval in CML patients intolerant to imatinib in accelerated, myeloid blast, or lymphoid blast phases? (vote: 14-0)

•For regular approval—in the Ph+ ALL population. Has dasatinib demonstrated sufficient evidence to warrant regular approval in either the imatinib-resistant or intolerant Ph+ ALL populations? (vote: 12-1, with 1 abstention).