A phase I study of the safety and efficacy of talimogene laherparepvec in Japanese patients with advanced melanoma

Abstract Talimogene laherparepvec (T‐VEC) is approved for the treatment of unresectable melanoma in the USA, Europe, and Australia. This phase I, multicenter, open‐label, dose de‐escalation study evaluated the safety and efficacy of T‐VEC in Japanese patients with unresectable stage IIIB–IV melanoma. Eligible adult patients had histologically confirmed stage IIIB–IVM1c cutaneous melanoma, may have received prior systemic anticancer therapy, must have had ≥1 injectable lesion, serum lactate dehydrogenase ≤1.5x upper limit of normal, ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. T‐VEC was injected intralesionally (first dose, ≤4.0 ml of 106 PFU/ml; after 3 weeks and then every 2 weeks thereafter, ≤4.0 ml of 108 PFU/ml). Primary endpoints were dose‐limiting toxicities (DLTs) and durable response rate (DRR). Of 18 enrolled patients (72.2% female), 16 had received ≥1 prior line of therapy. Ten patients discontinued T‐VEC due to disease progression. Median (range) follow‐up was 20.0 (4–37) months. No DLTs were observed; 17 (94.4%) patients had treatment‐emergent adverse events (AEs). Fourteen (77.8%) patients had treatment‐related AEs; the most frequent were pyrexia (44.4%), malaise (16.7%), chills, decreased appetite, pruritus, and skin ulcer (11.1% each). The primary efficacy endpoint was met: 2 (11.1%) patients had a durable partial response ≥6 months. The DRR was consistent with that observed in a phase III trial of T‐VEC in non‐Asian patients. The safety profile was consistent with the patients' underlying disease and the known safety profile of T‐VEC.

The prognosis for metastatic melanoma is poor, with a median OS of 6.2 months. 9 The 5-year survival rates vary widely depending on the disease stage, ranging from 99% for localized melanoma to 66% and 27% for melanoma with regional and distant metastases, respectively. 2 In Japan, the 10-year OS rates for stage III and stage IV disease were reported as 54% and 7%, respectively. 10 The application of checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab) and small molecule inhibitors of BRAF and MEK (vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, encorafenib) has transformed the outcomes for patients with advanced melanoma. 3,11 According to the 2019 Japanese Dermatological Association guidelines, the current treatment regimen for Japanese patients with melanoma comprises dabrafenib plus trametinib, encorafenib plus binimetinib, pembrolizumab monotherapy, and nivolumab alone or in combination with ipilimumab. 3,12 Vemurafenib (December 2014), dabrafenib plus trametinib (March 2016), and encorafenib plus binimetinib (January 2019) were approved in Japan following trials that demonstrated their efficacy and safety in melanoma patients. [13][14][15][16][17] Ipilimumab showed acceptable tolerability in a phase II trial in Japanese patients with advanced melanoma, with best ORR and disease control rate of 10% and 20%, respectively. 18 Phase II trials of nivolumab have been conducted in previously untreated and treated Japanese patients with advanced melanoma; the ORR and median OS in these trials were 35% and 33 months, and 29% and 18 months, respectively. [19][20][21][22] Moreover, a phase Ib trial of pembrolizumab in patients with cutaneous melanoma demonstrated a confirmed ORR of 24%. 23 Despite these recent approvals, additional treatment options are needed to further improve outcomes with minimal toxicity in patients with metastatic melanoma in Japan. Vemurafenib, dabrafenib, and trametinib are associated with early development of resistance in most cases, leading to short DORs. Furthermore, these treatments are associated with severe and long-lasting toxicities. T-VEC is an intralesional oncolytic viral immunotherapy designed to produce GM-CSF in tumors to enhance antigen release, presentation, and antitumor immune responses. 24,25 T-VEC is the first FDAapproved oncolytic viral therapy for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. 26  treatment-related AEs; the most frequent were pyrexia (44.4%), malaise (16.7%), chills, decreased appetite, pruritus, and skin ulcer (11.1% each). The primary efficacy endpoint was met: 2 (11.1%) patients had a durable partial response ≥6 months. The DRR was consistent with that observed in a phase III trial of T-VEC in non-Asian patients. The safety profile was consistent with the patients' underlying disease and the known safety profile of T-VEC.

K E Y W O R D S
immunotherapy, Japanese, melanoma, phase I clinical trial, talimogene laherparepvec  T-VEC administration continued until the patient achieved a CR, had a DLT during the DLT evaluation period, had no injectable lesions, had clinically relevant disease progression beyond 24 weeks of treatment per modified WHO response criteria, had a safety concern, or had a maximum treatment duration of 48 months, whichever occurred first.

| DLT evaluation
Dose-limiting toxicities were defined as any of the following treatmentrelated toxicities occurring during the DLT evaluation period: grade 4 nonhematologic toxicity; grade 3 nonhematologic toxicity lasting >3 days despite optimal supportive care (except grade 3 fatigue); grade ≥3 nonhematologic laboratory value requiring medical intervention/hospitalization or abnormality persisting >1 week; grade 3/4 febrile neutropenia; thrombocytopenia <25 × 10 9 /L associated with a bleeding event requiring intervention; serious herpetic event; grade 5 toxicity; or any toxicity requiring permanent discontinuation of T-VEC.
Initially, six DLT-evaluable patients were enrolled and treated with dose 1. The incidence of DLTs in the first six DLT-evaluable patients and additional safety data from all patients were evaluated by a doselevel review team comprising investigators and representatives of Amgen study teams. The dose level would be declared tolerable if the incidence of DLTs was <33% during the DLT evaluation period.

| Endpoints and assessments
The primary endpoints were the incidence of DLTs and DRR using modified WHO response criteria. 28 DRR was defined as the rate of CR or PR lasting continuously for ≥6 months and onset within 1 year of treatment. Secondary endpoints included ORR, TTR, DOR, and PFS using modified WHO response criteria, and OS.
Safety endpoints, in addition to DLTs, included the patient incidence of the following: all TEAEs, grade ≥3 TEAEs, SAEs, clinically F I G U R E 1 Patient disposition. DLT, dose-limiting toxicity; qPCR, quantitative polymerase chain reaction; T-VEC, talimogene laherparepvec. No patients (n = 0) were included in the qPCR analysis set. The DLT analysis set included all enrolled patients who were followed for ≥35 days on treatment from initial dosing (unless discontinued due to DLT) and had received ≥1 dose of T-VEC, and was used to summarize the patient incidence of DLTs for the study. The safety analysis set included all enrolled patients who received ≥1 dose of T-VEC and was used for analyzing safety endpoints other than patient incidence of DLTs. The qPCR analysis set included patients in the safety analysis set with a swab sample obtained for qPCR testing of T-VEC DNA from any lesion suspected to be of herpetic origin

| Patients
In total, 18 patients were enrolled, all of whom received ≥1 dose of T-VEC ( Figure 1). The number of lesions injected, lesion type injected, and the body site location injected for each patient for the first dose are provided in Table S1. Fifteen (83.3%) patients discontinued T-VEC during the study due to disease progression

| Response to therapy
Two (11.1%) patients showed a durable PR ≥6 months (Table 3). Both patients had stage IVM1b-c disease and had received ≥2 prior lines of therapy that included nivolumab and ipilimumab treatment. One patient with a durable response had ALM and the other had NM.

| Unintended exposure to T-VEC
No cases of unintended exposure to T-VEC were reported in patients' close contacts or healthcare providers. The one case of herpetic lesion reported in this study, which was sampled from a close contact, was confirmed to be negative for T-VEC DNA.

| DISCUSS ION
Talimogene laherparepvec was well tolerated and showed clinical activity in Japanese patients with unresectable stage IIIB-IV malignant melanoma; no DLTs were reported and the DRR was 11.1%.
Overall, the safety and efficacy findings in this study are consistent with the results of the OPTiM trial, which compared intralesional T-VEC with subcutaneous GM-CSF in non-Asian patients with unresectable stage IIIB-IV melanoma. 27 OPTiM was the first randomized controlled phase III study to demonstrate a therapeutic benefit of an oncolytic immunotherapy in patients with melanoma; TA B L E 3 Response to therapy (safety analysis set; n = 18) The study was designed under the responsibility of Amgen Inc., in conjunction with the steering committee. The study was funded by Amgen Inc. Talimogene laherparepvec was donated/provided by Amgen Inc. Amgen Inc. collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.