T-VEC Approved by FDA for Advanced Melanoma Treatment

Advanced Melanoma

Sean E. Harper, MD

Approval for first-in-class oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) has come down from the FDA based on the results from the phase III OPTiM study.

T-VEC is used for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Based on the data from the study, members of the FDA’s ODAC and CTGTAC panels voted 22-1 to recommend approval of T-VEC following a joint committee meeting in late April.

"IMLYGIC is the first clinical and regulatory validation of an oncolytic virus as a therapy, which Amgen is proud to bring to patients with a serious form of skin cancer. Not all melanoma patients currently benefit from available therapies, and IMLYGIC represents an important new option that can provide meaningful durable responses for patients with this aggressive and complex disease," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. "Immunotherapy is an exciting area for cancer research, and we are currently studying IMLYGIC in combination with other immunotherapies in advanced melanoma and other solid tumors."

In the trial, T-VEC significantly extended durable response rates (DRR) compared with GM-CSF. DRR was the primary endpoint, with overall survival (OS) as a secondary endpoint. In the final OS analysis, a 4.4-month extension with T-VEC was observed; however, this was not deemed to be statistically significant (P= .051).

OPTiM randomized 436 patients with unresected stage IIIB/C and IV melanoma 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.

DRR was 16.3% with T-VEC compared with 2.1% for GM-CSF. The objective response rate 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 a Pvalue of .05 representing significance.

Following progression on the trial, patients in the two arms received similar therapies. 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 Huntsman Cancer Institute at the University of Utah, 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 primary safety analysis for the approval was based on findings from 292 patients in the T-VEC arm and 127 patients in the GM-CSF arm of the OPTiM study. The median treatment duration in the treatment versus control arms was 23 versus 10 weeks, respectively.

Incidence of all-grade adverse events (AEs) was 99.3% versus 95.3% in the two arms. The most frequently occurring all-grade AEs for patients receiving T-VEC included fatigue (50.3% vs 36.2% with GM-CSF), chills (48.6% vs 8.7%), pyrexia (42.8% vs 8.7%), nausea (35.6% vs 19.7%), influenza-like illness (30.5% vs 15%), and injection site pain (27.7% vs 6.3%).

Serious AEs occurred in 25.7% and 13.4% of the T-VEC and GM-CSF arms, respectively. Disease progression (3.1% vs 1.6%) and cellulitis (2.4% vs 0.8%) were the most commonly reported serious AEs in the treatment versus the control arm. Six immune-mediated AEs occurred in the T-VEC group compared with three in the GM-CSF group.

There were 12 patient deaths within 30 days of the last dose of T-VEC, including 10 in the primary OPTiM study and 2 in an extension of the study. Nine of the deaths were associated with progressive disease, with the remaining three attributed to myocardial infarction, cardiac arrest, and sepsis. There were four patient deaths in the GM-CSF arms, two each in the primary and extension analyses.

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.