FDA advisory committees consider T-VEC for metastatic melanoma

Two FDA advisory committees convened today to review Amgen’s biologic license application for its oncolytic virus, talimogene laherparepvec, as a treatment for metastatic melanoma.

In a preliminary document released Monday, FDA reviewers questioned the design and results of a key phase 3 trial designed to evaluate talimogene laherparepvec, commonly referred to as T-VEC. The reviewers concluded there was not enough evidence to suggest the agent improves OS for patients with metastatic melanoma.

Amgen representatives, thus, adjusted their presentation of results of the phase 3 study to address many of the questions raised in the FDA review.

Members of the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee and its Oncologic Drugs Advisory Committee are expected to vote this afternoon about whether to recommend approval of T-VEC for this indication. Although the FDA is not required to follow the recommendations of its advisory committees, it often does.

T-VEC is a systemically active oncolytic immunotherapy derived from herpes simplex virus type-1.

Upon injection directly into tumor tissue, T-VEC selectively infects and replicates in tumor cells. The virus replication leads to tumor cell lysis and exposure of tumor-specific antigens to the immune system, resulting in a local and systemic immune activation and an immune-mediated destruction of tumor cells throughout the body.

T-VEC also is engineered to produce GM-CSF to enhance the local and systemic antitumor immune response.

Phase 3 trial results

Howard Kaufman, MD, FACS, chief surgical officer, associate director for clinical science, and co-leader of the clinical investigations and precision therapeutics program at Rutgers Cancer Institute of New Jersey, and colleagues presented data from the phase 3 OPTiM trial to the advisory committees. They also tried to address concerns raised by the FDA about potential investigator bias, clinical meaningfulness of the observed responses and evidence of systemic response.

Howard Kaufman

The OPTiM trial compared T-VEC with GM-CSF in patients with unresectable stage IIIb, stage IIIc or stage IV melanoma.

Results showed patients assigned T-VEC experienced significantly longer median OS (23.3 months vs. 18.9 months; HR = 0.79; 95% CI, 0.62-1). More than one-third (38.9%) of patients assigned T-VEC survived at least 3 years.

Results also showed a considerably reduced risk for death among patients who achieved durable response by 9 months (HR = 0.07; 95% CI, 0.01-0.48), 12 months (HR = 0.05; 95% CI, 0.01-0.33) and 18 months (HR = 0.11; 95% CI, 0.03-0.44). A Cox proportional hazards model showed a consistent association between survival and achievement of durable response (HR = 0.08; 95% CI, 0.03-0.26).

Seventeen percent of patients assigned T-VEC achieved a complete response, and 82% of those patients remain in complete response.

“The patient’s journey with this disease is a very challenging one and, when it becomes unresectable and patients develop what is often a very large, difficult, locoregional disease — the population where T-VEC belongs — it has a really acceptable benefit-to-risk ratio in this population,” Kaufman said. “If I didn’t have this agent available, I’m not sure what I would do with these patients, and it would be a great agent to add to armamentarium as we strive to combat this terrible disease.”

Following Amgen’s presentation, FDA representatives continued to express concerns about the phase 3 study’s design, which they suggested may have led to inflated study data.

“We identified several concerns, which included the appropriateness of GM-CSF as a study control,” said Ramjay Vatsan, PhD, a biologist in the office of cellular tissue and gene therapies for the FDA. “The [Endpoint Assessment Committee] did not review data for all subjects in the intent-to-treat population, potentially leading to assessment bias. The small lesion size potentially influenced the reliability of outcome assessments, and the primary basis for effectiveness comes from a single phase 3 study.”

Vatsan also questioned the clinical meaningfulness of durable response rate as a primary endpoint, as well as the limited evidence of a systemic effect of T-VEC since it was given as a local intralesional therapy for melanoma in a systemic disease setting, which may make it difficult to quantitatively measure evidence of response in uninjected lesions. There also is a lack of certainty regarding T-VEC’s association with improved OS, Vatsan said.

The FDA reviewers also expressed concern with dosing inconsistencies in the trial and their potential effect on safety and efficacy.

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Q&A session

After the initial presentation of the phase 3 trial results, members of the two FDA advisory committees sought additional information from Amgen officials during a Q&A session. The concerns raised during this portion of the meeting focused primarily on the wording of the proposed indication compared with the design of the OPTiM study, as well as on the use of GM-CSF as a control rather than placebo.

Elliott M. Levy, MD, senior vice president of global development for Amgen, said “unresectable” was left out of the proposed indication — although the phase 3 trial evaluated patients with unresectable melanoma — to provide clarity for the prescriber.

“We recognize that recently approved products have all had the word ‘unresectable’ in their indication statement and the protocol for our trial also required that the patients have a disease that was not treatable by surgical resection,” Levy said. “It is our intention that is where the product would be used. However, in speaking with people who have experience with the product in their patient population, they tell us that the word ‘unresectable’ is, in practice, difficult to apply … and that it doesn’t provide meaningful, clear instruction to the prescriber.”

T-VEC should not be used when patients have the option for surgical resection, and Amgen is open to discussing with the FDA how best to include this indication in product labeling, Levy said.

Jennifer Gansert, MD, PhD, executive director and global development lead for Amgen, explained that GM-CSF was used as the control rather than placebo because when the trial was designed in 2008, GM-CSF was considered a valid treatment option and a promising and tolerable cytokine-based agent for adjuvant therapy.

“We chose GM-CSF because it’s another potentially active immunologic agent that is well tolerated,” she said. “At the time of the study, and even today, there’s not much data available on the intralesional administration of GM-CSF, but it was being studied in a large trial and thought to be a more acceptable comparator. Other agents, such as chemotherapies, cannot be continued through progression like we have to do with T-VEC.

“Direct intralesional injections of other agents that aren’t oncolytic viruses would probably have a different appearance in the patient,” Gansert added. “In all practicality, if we used some other injectable comparator, [the trial] would have been, to some degree, unblinded.”

The advisory committee members will discuss Amgen’s application this afternoon. They then will render a decision about whether to recommend for or against approval of T-VEC.

Stay tuned to Healio.com/HemOnc for continued updates. – by Anthony SanFilippo