Blinatumomab (Blincyto, Amgen) may offer benefit for patients who have only minimal residual signs of a certain aggressive form of leukemia, but significant doubts remain about whether the evidence is sufficient for US Food and Drug Administration (FDA) approval of a new indication, federal advisers said.
On March 7, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8-4 in Amgen’s favor on the question of whether current research demonstrated a potential benefit for a new use of blinatumomab. The panelists did not vote directly on whether blinatumomab should be approved for treatment of minimal residual disease (MRD)–positive B-cell precursor acute lymphoblastic leukemia (BCP ALL) after intensive chemotherapy.
The drug has been approved for the treatment of relapsed or refractory BCP ALL in adults and children.
Amgen is seeking FDA approval for use of blinatumomab in patients whose disease would appear to be in remission, as determined through use of older morphologic measures.
The proposed new indication is “paradigm shifting” because it would allow use of blinatumomab in patients for whom there is molecular evidence of leukemia, said Donna Przepiorka, MD, PhD, a cross-discipline team leader in FDA’s Division of Hematology Products, at the meeting’s opening.
If granted regulatory approval, blinatumomab would become the first treatment for which MRD positivity is a selection criterion and MRD negativity an endpoint for ALL.
At the meeting, ODAC panelists openly wrestled with questions about balancing the pressing need for a new option for ALL patients against concerns about the clinical impact of the supporting data. FDA staff highlighted several potentially confounding factors, including the inclusion of records for patients whose hematologic recovery was incomplete and whose disease was thus not in true complete remission (CR), and inconsistency in the use of hematopoietic stem cell transplant.
ODAC Chairman Bruce J. Roth, MD, who voted “yes” on the FDA’s question, said he also could have presented arguments for a “no” vote or for abstaining. Like the FDA staff, he expressed reservations about the evidence.
“I am not convinced of clinical benefit from what was presented,” said Roth, a professor of medicine at Washington University School of Medicine in St. Louis, Missouri. “I’d be very interested to see the results of the upcoming randomized trials to confirm that MRD conversion actually does end up resulting in improved clinical benefit.”
I am not convinced of clinical benefit from what was presented.
The academics serving as FDA reviewers noted that the lack of a control arm made it “difficult to interpret” results from the pivotal trial that was used to support Amgen’s application. Amgen said that in this trial, known as Study MT 103-203, 77.9% of patients experienced a complete MRD response after cycle 1 of treatment. Two additional patients achieved this status during cycle 2 of treatment, for an overall complete MRD response rate of 79.6%.
This single-arm, open-label trial investigated blinatumomab for the treatment of patients with BCP ALL in CR or in CR with partial platelet recovery and with MRD >0.1%. The adult patients in the study were judged to have MRD-positive B-cell precursor ALL in hematologic CR, meaning there were fewer than 5% blasts in the patients’ bone marrow after they had undergone at least three intense chemotherapy blocks. Eligibility requirements including an MRD level of 1 x 10-3 on either polychrome chain reaction (PCR) assay or flow cytometry, with a minimum sensitivity of 1 x 10-4.
The FDA staff also found fault with Amgen’s retrospective examination of the prognosis for patients with ALL.
“Although the retrospective analyses appeared to confirm that patients with ALL in remission with MRD >0.1% had a poor prognosis, all were confounded by the inclusion of patients with marrow remission but incomplete hematological recovery, which may not reflect a true” CR, the agency staff said in the briefing document for the meeting.
In its briefing document, Amgen emphasized the need for increasing treatment options for ALL.
Almost 50% of adult patients and 25% of pediatric patients with B-cell ALL eventually experience relapse or their condition is refractory to initial treatment, said the company. It also argued for paying more attention to “submicroscopic leukemic cells in the bone marrow below the detection of conventional morphological methods.”
Amgen said that patients who achieve hematologic CR by morphologic assessment (ie, <5% blasts in bone marrow) can still have MRD. Furthermore, approximately 30% to 50% of adult and 10% to 20% of pediatric ALL patients who achieve hematologic CR following multiagent therapy are MRD positive, said the company.
Maybe I can do something else to stop this train.
ODAC Chairman Roth said that one of the factors that led him to vote “yes” was that the prospects are dim for these patients “who don’t have transplant as an option.” Several other panelists raised this point. Grzegorz S. Nowakowski, MD, from the Mayo Clinic in Rochester, Minnesota, compared these patients, who are likely to experience relapse, to someone who is tied to a railroad track and who can see a train coming.
“Maybe I can do something else to stop this train,” he said, referring to blinatumomab.
Will Outcomes Improve?
The FDA determined that of the 116 patients treated in the MT103-203 study, there were only 87 who were in true CR and whose results on MRD assay met the required cutoffs for assay sensitivity or MRD level. The agency’s efficacy analysis indicated that 79.3% of patients achieved a complete MRD response within the first cycle. The FDA also noted two fatal treatment-emergent adverse events, one case of atypical pneumonia, and one case of subdural hemorrhage at the site of a prior hemorrhage. The safety profile appears “no worse than that established in the patients” with relapsed and refractory ALL, the FDA said in the briefing document.
ODAC panelist Philip C. Hoffman, MD, a professor of medicine from the University of Chicago, questioned Amgen presenters as to whether the “holy grail” of their efforts would be to someday avoid transplants for many ALL patients. Aaron Logan, MD, PhD, of the University of California, San Francisco, who represented Amgen, said that if blinatumomab is approved for MRD-positive patients, “the most common usage will be as a bridge to transplant.
“There are, however, patients who are not medically fit or not socially fit to undergo an allogeneic transplant, and they may simply receive” blinatumomab along with other therapies, he said.
David M. Reese, MD, Amgen’s senior vice president of translational sciences and oncology, focused on the “positive vote” from the panel in a statement about the meeting. Blinatumomab is a leader in a new class of drugs called bispecific T-cell engagers (BiTEs). These drugs are designed to prompt T cells to target cancer cells that express the protein CD19. This protein is present on B-cell-derived ALL cells.
“We are pairing Blincyto, the first-in-class BiTE, with state-of-the-art understanding of disease at the molecular level to improve outcomes in patients with MRD-positive ALL,” Reese said in the statement. “If approved, an indication for the treatment of MRD-positive ALL will add an important, earlier treatment option for physicians and patients.”
The FDA’s target action date on the application for the new use of blinatumomab is March 29. The agency weighs the deliberations of its advisory committees in deciding on drug applications, but it is not bound to reflect their committees’ views. Blinatumomab has been a fast-growing product for Amgen. Its domestic sales rose by 34%, from $85 million in 2016 to $114 million in 2017.
The 2017 guidelines from the influential National Comprehensive Cancer Network (NCCN) recommend consideration of blinatumomab for the treatment of persistent or late-clearance MRD-positive ALL, Amgen noted in its briefing material. The NCCN, a nonprofit alliance of cancer centers, does not define a specific threshold for MRD positivity in such cases. But the NCCN did note that MRD positivity can be detected with flow cytometry or PCR with a minimum sensitivity of <1 x 10-4, Amgen said.
The NCCN tends to be “a little bit looser” than the FDA, observed ODAC panelist Andy Chen, MD PhD, a lymphoma specialist from the Oregon Health and Science University in Portland.
Chen, who was among the four naysayers on the March 7 vote, said the research on blinatumomab that was presented “is promising,” but he questioned whether it is “actually strong enough to merit an FDA label” change.
Another naysayer, David Harrington, PhD, a professor of statistics and biostatistics at Dana-Farber Cancer Institute, Boston, Massachusetts, noted that different analyses indicated varying levels of benefit for blinatumomab before transplant.
“For me, it doesn’t quite reach the level of labeling evidence,” Harrington said. He noted that there was a notion that reducing residual disease before a transplant would improve outcomes in ALL, “but that remains to be shown.”
Dr Logan is paid consultant for Amgen.
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