Amgen's regulatory team for talimogene laherparepvec (T-Vec) was grilled by a group of outside FDA experts who picked up on some major questions regarding the Phase III melanoma study that was used to back its new drug application. A vigorous defense of the drug, though, helped make a winning case for the therapy, which was ultimately supported by all but one member of the panel.
There was considerable sentiment in favor of restricting the drug to certain patient groups, with some of the panelists expressing their frustration that they couldn't register a vote regarding the low likelihood that the drug would work for visceral (internal) tumors or later-stage patients.
At the end of the day, though, the expanded panel voted 22 to 1 that the drug has a favorable risk/benefit profile. T-Vec is injected directly into tumors, where it replicates and then ideally ruptures the tumor cells. The rupture causes the release of antigens which in turn spur the immune system response--a kind of one-two punch that represents a different approach to treating melanoma.
|UT's Patrick Hwu|
"There are clearly patients in my clinic I'd like to use this for," noted Patrick Hwu, a professor in the department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center who voted to support T-Vec. A number of the experts noted that the more "arrows" they had in their therapeutic quiver, the better off patients would be.
The final decision is being left in the hands of the FDA, though today's vote would make T-Vec an odds-on favorite for approval. If so, Amgen ($AMGN) is on track to score several possible approvals this year, marking some advances after analysts like Geoffrey Porges have criticized the Big Biotech's development strategy and heavy research costs.
The day started with FDA reviewers offering some skeptical remarks about their interpretation of the late-stage data.
"The evidence that talimogene has a systemic effect was limited and difficult to calculate," FDA reviewer Robert Le told the committee. In particular, committee members noted that there were widely different response rates among different subgroups in the study. For Le, "first line or less advanced patients may have responded better."
"Subjects with small lesions may be more likely to respond," he added, "larger lesions less likely."
Abigail Luo, who specifically focused on mixed survival benefits, also raised concerns about the removal of 7 patients from the control arm. That change may have skewed the results in favor of the drug arm, raising the prospect that investigator bias may have played a role in shaping the results. And her review "increases uncertainty of overall survival benefits" for the drug arm, though patients in the drug arm did live more than 4 months longer on average than the comparator arm.
Another concern was viral "shedding," in which healthcare workers and others could be exposed and infected by the live herpes simplex virus used in T-Vec.
Amgen applied for full approval of T-Vec based on durable response.
Amgen execs noted that the comparator treatment in the study, GM-CSF, has some effect, which may have influenced results as well. So overall, the observed results do give an idea of who benefits the most from T-Vec, they noted. Subgroup analysis--which tends to raise all sorts of issues related to statistical significance--also showed some dramatic differences in response, with first-line patients, for example, doing better than second-line patients.
Amgen had some big factors playing in its favor. The experts, like the agency, lean heavily on the side of providing physicians and patients as many treatment choices as possible, particularly in the absence of serious toxicity issues. Treating late-stage cancer patients isn't an ideal world, and attitudes to safety and efficacy can be far more flexible in oncology than, say, chronic diseases. The agency also keeps an open mind when it comes to last-ditch efforts, after other treatments have failed.
"Metastatic melanoma continues to be a major challenge to patients and caregivers," Amgen stated after the vote Wednesday. "It is a complex and heterogeneous disease that often requires the use of multiple treatment modalities. Despite recent advances, the five-year survival rate for metastatic melanoma is still unacceptably low and nearly 10,000 patients are expected to die in the U.S. this year. It is clear from today's discussion that the committee recognized the importance of the need for new therapeutic options for patients with metastatic melanoma. We look forward to talking with the FDA about how to best make talimogene laherparepvec monotherapy available to patients as they complete their review of the Biologics License Application."