Outcomes With Experimental Neoadjuvant T-VEC in Resectable Stage IIIB-IVM1a Melanoma

According to the results of the largest randomized neoadjuvant trial in resectable stage IIIB–IVM1a melanoma to date (abstract 9520), patients who received talimogene laherparepvec (T-VEC) monotherapy plus surgery had superior improvements in R0 surgical resections and 1-year recurrence-free survival (RFS) compared with those who received surgery only.

The results were presented by Reinhard Dummer, MD, of the University Hospital Zürich Skin Cancer Center in Switzerland, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

T-VEC is a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy designed to preferentially replicate in tumors, produce granulocytic-macrophage colony-stimulating factor, and stimulate an antitumor immune response,” according to the study poster.

The prospective, randomized, open-label phase II study evaluated the effect of T-VEC in high-risk, resectable stage IIIB–IVM1a melanoma (NCT02211131). At last year’s ASCO meeting, the team reported (abstract 9508) that, when comparing T-VEC plus surgery with upfront surgery in patients with resectable stage IIIB/C/IVM1a melanoma, the T-VEC plus surgery treatment resulted in a pathologic complete remission (CR) rate of 21% and an overall response rate of 14.7%. This year, Dummer presented the updated 1-year interim analysis results.

“[One] rationale for a neoadjuvant is avoiding surgery all together,” said Joshua Mammen, MD, of the University of Kansas, who was a discussant of the study.

Patients (n = 150) with resectable stage IIIB/C/IVM1a melanoma with at least one injectable cutaneous, subcutaneous, or nodal lesion (≥ 10 mm) who had not received any systemic treatment within the previous 3 months were randomized to receive 6 doses of T-VEC for 12 weeks followed by surgery at weeks 13 to 18 (n = 76) or upfront surgery from weeks 1 to 6 (n = 74). The primary endpoint was relapse-free survival, and the secondary endpoints included overall survival, the rate of histopathologic tumor-free margin (R0) resection, and safety.

“We do T-VEC injections until week 13, and then we do the surgery. So, we delay surgery,” explained Dummer.

The investigators reported a pathologic complete response rate of 22.8% (13 of 57 patients) in the efficacy analysis set compared with 17.1% (13 of 76 patients) in the intention-to-treat (ITT) analysis set of patients who received T-VEC plus surgery. The R0 resection rates were 56.1% (32 of 57 patients) in the T-VEC plus surgery arm vs 40.6% (28 of 69 patients) in the surgery-only arm.

“It’s interesting that the R0 resection rate was better in the TVEC arm, suggesting there may be a benefit for making those resections easier,” said Mammen.

There was a between-group difference in the ITT relapse-free survival per protocol (hazard ratio [HR], 0.73; 80% CI, 0.56–0.93; P = .048) and in a sensitivity analysis (HR, 0.63; 80% CI, 0.47–0.83). Overall survival was 95.9% in the T-VEC plus surgery arm compared with 85.8% in the surgery-only arm (HR, 0.47; 80% CI, 0.27–0.82).

“After 1 year, we already see a separation of the [overall survival] curves. This is not yet significant, but there is a clear trend and the difference is huge,” said Dummer. “Now, the key question is how stable is this? Because this is only 1 year, and this is not driven by the second-line [adjuvant treatments] because the surgery-alone patients have more additional treatments after surgery. This difference is from the effect of the neoadjuvant [therapy],” said Dummer.

The percentage of patients who received subsequent adjuvant treatment after surgery was 11% (8 of 73 patients) in the T-VEC plus surgery arm compared with 29% (20 of 69 patients) in the surgery-alone arm. The authors report no unexpected toxicities in the T-VEC plus surgery arm, and no treatment-related deaths occurred.

“We did see progression on TVEC therapy in a substantial percentage of patients, nearly a quarter. So, there are a couple of different ways to look at that. Did we lose the opportunity for surgical resection in patients that perhaps could have benefited from surgical resection? Or perhaps more likely, did we improve patient selection for surgery? Meaning that we really only resected from those patients who may have benefited from surgery,” said Mammen. “Obviously, we need a longer follow-up regarding melanoma-specific survival, and the authors have mentioned that the 2-year data will be out later this year.”