Experts Endorse Amgen’s Immunotherapy for Advanced Melanoma

Source: Life Scieces Connect, May 2015

Progress toward immunotherapy treatments for melanoma advanced another step with near-unanimous support from FDA advisors for Amgen Inc’s talimogene laherparepvec (T-VEC). An oncolytic virus immunotherapy, T-VEC has been developed for patients with injectable regionally or distantly metastatic melanoma. If approved, it will be the first product in a new class of drugs, oncolytic immunotherapies.

In late April, the FDA convened two of its advisory committees, the Cellular, Tissue and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee, tasking them with a review of the T-VEC biologics license application (BLA). The agency requested feedback on several issues related to the OPTiM study, the sole phase 3 clinical trial submitted to support the BLA. Ultimately, committee members voted 22 to 1 in support of T-VEC’s benefit-to-risk profile for the proposed melanoma indication.

The most lethal form of skin cancer, melanoma is expected to kill nearly 10,000 Americans in 2015, and nearly 74,000 new melanomas will be diagnosed in the US this year, according to American Cancer Society (ACS) estimates. Metastatic melanoma has spread through the lymph nodes to distant sites and/or organs; metastases most often affect the liver, lungs, bones, and brain, according to the Melanoma Research Foundation.

Immunotherapies use the body’s immune system to fight disease. T-VEC is derived from herpes simplex virus type-1 (HSV-1), the virus responsible for most cold sores. It is engineered to produce a white blood cell growth factor, granulocyte-macrophage colony stimulating factor (GM-CSF). When injected into a tumor, T-VEC infects only tumor cells, replicating within them and inducing tumor-cell lysis; cells rupture, releasing tumor-specific antigens and GM-CSF. According to Amgen, this stimulates a system-wide immune response that kills tumor cells elsewhere in the body.

Amgen’s phase 3 OPTiM study was the primary source of safety and efficacy evidence for the T-VEC BLA. Study subjects had been diagnosed with unresectable stage IIIB, IIIC, or IV melanoma that was suitable for injection, and were randomized (2:1) to receive either T-VEC or the control (GM-CSF). The FDA characterized the OPTiM primary endpoint as “novel”: statistically significant improvement in durable response rate (DRR), defined as the rate of complete response or partial response lasting continuously for at least 6 months. While OPTiM clearly met the primary endpoint (FDA analysts calculated a 15.6% DRR for T-VEC versus 1.4% for GM-CSF), the FDA raised several concerns about the trial and the data it yielded, including:

• The appropriateness of the GM-CSF control.
• The potential for investigator bias in several areas of the study, including patient dosing.
• Bias may have influenced which study subjects were assessed and, ultimately, DRR determinations.
• Uncertainty over T-VEC’s systemic effect.
• An absence of a clear effect on overall patient survival.
• Limited data on T-VEC “shedding,” which could put healthcare providers and others with close patient contact at risk for viral transmission.

While committee members discussed the FDA’s concerns at length, they overwhelmingly agreed that OPTiM data supported T-VEC’s efficacy for shrinking and, in many cases, eliminating melanoma tumors. Like the FDA, most committee members were uncertain about a T-VEC systemic effect.

Members debated at length about whether the proposed indication should be modified to specify patients who do not have visceral disease. While some asserted vehemently that T-VEC would be inappropriate for patients with visceral metastases, others stressed that modifying the indication could severely restrict T-VEC access to patients who could benefit – for example, someone with significant cutaneous disease who also has a single liver lesion. Oncologists should decide T-VEC suitability on a case-by-case basis, they said. There was also lengthy discussion about whether the proposed indication should refer specifically to patients with “unresectable” melanoma, since OPTiM enrolled only subjects with unresectable stage IIIB, stage IIIC, or stage IV melanoma.

If approved by the FDA, T-VEC would be the seventh new treatment approved for advanced melanoma since 2011.

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