FDA Schedules Hearing for T-VEC in Metastatic Melanoma

Sean E. Harper, MD, executive vice president of Research and Development at Amgen

Sean E. Harper, MD

The FDA has scheduled a hearing to discuss the biologics license application (BLA) for the immunotherapy talimogene laherparepvec (T-VEC) as a treatment for patients with metastatic melanoma. The joint committee meeting is scheduled for April 29, 2015, and will include input from ODAC and the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC).

The BLA for T-VEC was based on findings from the phase III OPTiM study, which demonstrated a significant extension in durable response rates (DRR) with the immunotherapy compared with GM-CSF. DRR was the primary endpoint of the OPTiM study, with overall survival (OS) as a secondary endpoint. In the final analysis for OS, a 4.4-month extension was noted; however, this was not deemed statistically significant (P= .051).

"The incidence of melanoma has continued to rise in recent years, and even with recent additional options in treatment, there is an important unmet medical need," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a press release. "We look forward to discussing the efficacy and safety profile of talimogene laherparepvec with the advisory committees, and we are committed to working closely with the FDA during its review of the BLA."

Prior to announcing the advisory committee meeting, the FDA had extended the review period for T-VEC by 3 months to allow time for Amgen to submit additional information on the treatment. The FDA is currently scheduled to act on the BLA for T-VEC by October 27, 2015.

T-VEC is engineered through the genetic alteration of the herpes simplex 1 virus to secrete the cytokine GM-CSF within the tumor, causing cell lysis. The treatment is among a new class of agents known as oncolytic immunotherapies. At this point, a therapy in this class has not yet been approved.

In the phase III OPTiM study, 436 patients with unresected stage IIIB/C and IV melanoma were randomized in a 2:1 ratio to receive intralesional T-VEC (n = 295) or subcutaneous GM-CSF (n = 141). The median age of patients in the study was 63 years. T-VEC was administered initially at ≤ 4 mL x10⁶PFU/mL for 3 weeks followed by ≤ 4 mL x10⁸PFU/mL every 2 weeks. GM-CSF was administered daily at 125 µg/m²every 14 days in a 28 day cycle.

The primary endpoint of DRR was 16% with T-VEC compared with 2% for GM-CSF. The objective response rate (ORR) was 26% versus 6% and the complete response rate was 11% compared with 1%, for T-VEC and GM-CSF, respectively.

At the primary survival analysis, the median OS was 23.3 months with T-VEC compared with 18.9 months for GM-CSF (HR = 0.787; 95% CI, 0.62-1.00;P= .051). This examination occurred after 290 events and was powered to detect an HR of 0.67, with aPvalue of .05 representing significance.

Following progression on the trial patients received similar therapies, between the two arms. However, more patients with advanced disease were randomized to the T-VEC arm compared with GM-CSF, lead investigator Robert H. I. Andtbacka, MD, CM, said in an interview withTargeted Oncologywhen the data were presented at the 2014 ASCO Annual Meeting.

"Clinically, I think that the 4.4-month difference [in survival] is important for our patients," Andtbacka, a surgeon and investigator with Intermountain Healthcare and Huntsman Cancer Institute, explained. "However, I think it's also important to recognize that this is a secondary endpoint, and the study clearly was not powered to look at a small difference, such as this. For me though, clinically, I look at more of what the median survival was for these patients and I also look at the durability of that response."

The most frequently reported all grade adverse events for the T-VEC arm were fatigue (50.3%), chills (48.6%), and pyrexia (42.8%). Grade 3/4 adverse events were limited, with cellulitis affecting 2.1% of patients in the T-VEC arm.