T-VEC Shows Promise in Combinations and as Monotherapy in Unresectable Melanoma

Robert H. I. Andtbacka, MD, CM

The intratumoral injection talimogene laherparepvec (T-VEC) demonstrated promise in combinations and utility as a monotherapy in certain subsets of patients with unresectable melanoma, according to results discussed by Robert H. I. Andtbacka, MD, CM, at the 2014 ASCO Annual Meeting.

"I do think that there are patients who benefit from talimogene laherparepvec as monotherapy," Andtbacka, one of the study's authors, and a surgeon and investigator with Intermountain Healthcare and Huntsman Cancer Institute, said in an interview withTargeted Oncology. "Moving forward though, I think that—similar to many of these other immune therapies that we have—combination study is the way to go for many patients. I think that the fact that the toxicity with talimogene laherparepvec is very low really bode well for combination with other agents."

In the phase III OPTiM study,¹436 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 granulocyte macrophage-colony-stimulating factor (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.

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.

"Clinically, I think that the 4.4-month difference [in survival] is important for our patients," Andtbacka said. "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 endpoint of durable response rate 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.

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, Andtbacka said.

"We do know that patients with a slightly later stage tend to do worse compared with the patients with an earlier stage," Andtbacka noted. "We also found that the functional status with the patient, the ECOG status, was more ECOG 1 compared to 0 in the talimogene laherparepvec group versus in the GM-CSF group, and these may potentially have impacted the differences in survival as well."

A phase Ib study added T-VEC to the CTLA-4 inhibitor ipilimumab (Yervoy) for patients with previously untreated, unresectable melanoma.²Overall, this study demonstrated promising efficacy without inducing dose-limiting toxicity, according to preliminary reports presented in a poster highlight session at ASCO.

In the study, 19 patients with stage IIIB—IV melanoma were enrolled and 18 received treatment with the combination. In this analysis, T-VEC was administered at ≤ 4 mL of 10⁶PFU/mL at week 1 then 10⁸PFU/mL at week 4 followed by once every 2 weeks. In the study, ipilimumab was administered at 3 mg/kg every 3 weeks. Altogether, 58% of patients in the trial had stage IV M1b/M1c disease.

The ORR for ipilimumab plus T-VEC was 56%, with 33% of patients experiencing a complete response. The disease control rate was 72%. In an analysis of CD8 T cells, which may indicate response to T-VEC treatment, a higher increase in the number of activated CD8 T cells by flow cytometry was observed in patients with disease control.

No dose-limiting toxicities were reported during the evaluation period. Grade 3/4 adverse events occurred in 32% of patients, with the most common T-VEC-related event being pyrexia. Two patients experienced immune-related grade 3/4 adverse events. One patient experienced grade 3 hypophysitis, adrenal insufficiency, and diarrhea. The other patient had grade 4 elevated amylase and lipase. There was one death attributed to brain metastases.

"There was no added toxicity by combining talimogene laherparepvec with ipilimumab compared to agents alone," Andtbacka said. "Most of the toxicity appears to be related to ipilimumab rather than to talimogene laherparepvec, since the toxicity, and grade 3/4 toxicities, with that are very low."

A phase II randomized study is ongoing that will evaluate the safety and efficacy of T-VEC in combination with ipilimumab versus ipilimumab alone. Additionally, other ongoing clinical trials are planned that will investigate T-VEC in combination with other immune checkpoint inhibiting antibodies, such as those targeting PD-1. One such study, recently announced by Merck, will examine the combination of T-VEC with the PD-1 inhibitor MK-3475 in previously untreated advanced melanoma.

"We are actually going to start, very soon within a month or so, a trial with T-VEC and MK-3475 to explore the idea that maybe a PD-1 will be a better partner for T-VEC than ipilimumab," combination trial lead author, Igor Puzanov, MD, a medical oncologist at the Vanderbilt-Ingram Cancer Center, said in an interview withTargeted Oncology. "However, having both these trials will allow us to glean what is the better partner for T-VEC. And maybe, we may be surprised."

1. Kaufman HL, Andtbacka RHI, Collichio FA, et al. Primary overall survival (OS) from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol. 2014;32:5s (suppl; abstr 9008a).
2. Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.J Clin Oncol. 2014;32:5s (suppl; abstr 9029).

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