T-VEC has been evaluated in early-phase studies, which demonstrated intratumoral replication and expression of GM-CSF and an acceptable safety profile (low-grade fever, chills, myalgias, and injection site reactions) after intralesional administration. 4 , 12 In a single-arm phase II study, an overall response rate (ORR) of 26% was reported in patients with stage IIIC to IV melanoma, with responses observed in both injected and uninjected lesions, including visceral lesions. 12 Biopsy of regressing lesions suggested an association between response and presence of interferon γ–producing MART-1–specific CD8 + T cells and reduction in CD4 + FoxP3 + regulatory T cells, consistent with induction of host antitumor immunity. 13 Here we report the primary analysis results from the phase III OPTiM study designed to evaluate whether treatment with T-VEC resulted in an improved durable response rate (DRR) compared with GM-CSF in patients with unresected stage IIIB to IV melanoma. ORR and OS are also reported.

Oncolytic viruses are novel cancer treatments that include wild-type and modified live viruses. Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus based on a modified herpes simplex virus (HSV) type 1 designed to selectively replicate in and lyse tumor cells while promoting regional and systemic antitumor immunity. T-VEC is modified through deletion of two nonessential viral genes. 4 Functional deletion of the herpes virus neurovirulence factor gene ( ICP34.5 ) attenuates viral pathogenicity and enhances tumor-selective replication. 5 – 8 T-VEC is further modified by deletion of the ICP47 gene to reduce virally mediated suppression of antigen presentation and increase the expression of the HSV US11 gene. 9 , 10 Insertion and expression of the gene encoding human granulocyte macrophage colony-stimulating factor (GM-CSF) results in local GM-CSF production to recruit and activate antigen-presenting cells with subsequent induction of tumor-specific T-cell responses. 11

Development of targeted therapy and immunotherapy has resulted in important advances in melanoma treatment. Improvement in overall survival (OS) has been reported with T-cell checkpoint inhibitors and BRAF inhibitors, with objective response rates ranging from 11% with single-agent ipilimumab to 76% with the combination of BRAF and MEK inhibitors, although drug resistance and recurrence are still challenges. 1 – 3 New strategies promoting tumor cell death and/or inducing protective host antitumor immunity are of high priority.

The planned population size was 430 patients (randomly assigned at a two-to-one ratio). This provided 95% and 90% power for a two-sided α of 0.05 using Fisher's exact test in the intent-to-treat and per-protocol populations, respectively, to detect an estimated DRR difference of 13% versus 3%. Primary efficacy analyses were based on the intent-to-treat population. Safety analyses included patients who received at least one dose of T-VEC or GM-CSF. Interim analysis of DRR was planned after 75 patients were enrolled (one-sided α = 0.0001) and after all patients were randomly assigned (one-sided α = 0.0005). Primary analysis of DRR (with one-sided type I error rate of 0.0244) was planned when no additional patients had the possibility of meeting the criteria for durable response, at which time, on a positive result, an interim analysis of OS was planned after 250 events and tested (one-sided α = 0.0001). OS was tested with an unadjusted log-rank test conditional on a statistically significant difference in DRR. Primary analysis of OS required at least 290 events with 90% power to detect a hazard ratio (HR) of 0.67 with two-sided α of 0.05, without adjustment for interim analysis. 15 Difference in DRR per EAC between treatment arms was evaluated using an unadjusted Fisher's exact test. OS, TTF, time to response, and duration of response were evaluated using unadjusted log-rank tests and Cox proportional hazards models. Difference in incidence of grade ≥ 3 AEs between arms was evaluated using χ 2 test (analysis was not prespecified). Analyses were performed using SAS software (version 9.2; SAS Institute, Cary, NC).

Visible or palpable lesions were evaluated by clinical evaluation (caliper or ruler). Deeper palpable lesions and nonpalpable subcutaneous and distant metastatic lesions were assessed by whole-body computed tomography (CT), positron emission tomography (PET) or PET-CT, and ultrasonography if appropriate. Baseline and new tumors were observed, and response was assessed per modified WHO criteria. 14 If a response was suspected to have occurred, confirmatory assessments were to be performed within 1 week. Patients with a best response per investigator of CR or PR or receiving treatment for ≥ 9 months were evaluated by a blinded end point–assessment committee (EAC). Digital photography encompassing all visible disease was required for response assessment by EAC. Clinical evaluation was performed at baseline and day 1 of each cycle; other assessments were performed at baseline and every 12 weeks. Adverse events (AEs) occurring from day 1 to 30 days after last treatment were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

The primary end point was DRR, defined as the rate of complete response (CR) plus partial response (PR) lasting ≥ 6 months continuously and beginning within the first 12 months. Key secondary end points included OS (time from random assignment to death), best overall response and tumor burden, onset and duration of response, and time to treatment failure (TTF; time from baseline to first clinically relevant disease progression for which no objective response was subsequently achieved or until death).

Discontinuation of treatment because of progressive disease per response assessment criteria was not required before 24 weeks unless alternate therapy was clinically indicated. After 24 weeks, treatment continued until clinically relevant disease progression (progressive disease associated with reduced performance status), intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or (T-VEC only) disappearance of all injectable lesions. After 12 months, patients with stable or responding disease could continue treatment for 6 additional months.

This open-label study was conducted at 64 centers in the United States, the United Kingdom, Canada, and South Africa and overseen by an independent data monitoring committee. Patients were assigned at a two-to-one ratio using central random assignment to receive intralesional T-VEC or subcutaneous recombinant GM-CSF. Random assignment was stratified by site of first recurrence, presence of liver metastases, disease stage, and prior nonadjuvant systemic treatment. The first dose of T-VEC was administered at 10 6 pfu/mL (to seroconvert HSV-seronegative patients). Subsequent T-VEC doses of 10 8 pfu/mL were administered 3 weeks after the first dose and then once every 2 weeks. Total T-VEC volume was up to 4.0 mL per treatment session. Injected volume per lesion ranged from 0.1 mL for lesions < 0.5 cm to 4.0 mL for lesions > 5 cm in longest diameter. Injection of all lesions was not required, and different lesions could be injected at different visits based on prioritization of injection to any new or largest lesions. Injection into visceral lesions was not allowed. GM-CSF 125 μg/m 2 was administered subcutaneously once daily for 14 days in 28-day cycles. Dose modifications for T-VEC were not permitted. GM-CSF doses could be reduced by 50% for absolute neutrophil count > 20,000/μL or platelets > 500,000/μL. If absolute neutrophil count or platelets decreased below these thresholds, GM-CSF dose could be increased 25%; if they persisted, GM-CSF was permanently discontinued.

Eligible patients were age ≥ 18 years with histologically confirmed, not surgically resectable, stage IIIB to IV melanoma suitable for direct or ultrasound-guided injection (at least one cutaneous, subcutaneous, or nodal lesion or aggregation of lesions ≥ 10 mm in diameter). Bidimensionally measurable disease, serum lactate dehydrogenase ≤ 1.5× upper limit of normal, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, and adequate organ function were also required. Patients requiring intermittent or chronic treatment with an antiviral agent (eg, acyclovir) or high-dose steroids were excluded, as were those with primary ocular or mucosal melanoma, bone metastases, active cerebral metastases, more than three visceral metastases (except lung or nodal metastases associated with visceral organs), or any visceral metastasis > 3 cm; liver metastases had to be stable for ≥ 1 month before random assignment. Patients with history of autoimmune disease, but not use of high-dose steroids, were eligible. Patients provided written informed consent; study procedures received institutional approval.

Grade ≥ 3 AEs occurred in 36% of patients receiving T-VEC and 21% of patients receiving GM-CSF ( P = .003). The only grade 3 or 4 AE occurring in ≥ 2% of patients was cellulitis (T-VEC, n = 6 [2.1%]; GM-CSF, n = 1 [< 1%]). Of 10 fatal events in the T-VEC arm, none were considered treatment related per investigator, and most (80%) were associated with disease progression, with the exception of sepsis in the setting of Salmonella infection and myocardial infarction. Two fatal non–treatment-related AEs occurred in the GM-CSF arm, both associated with disease progression.

AEs occurring more frequently among patients receiving T-VEC included chills (T-VEC, 49% v GM-CSF, 9%), pyrexia (43% v 9%), injection-site pain (28% v 6%), nausea (36% v 20%), influenza-like illness (30% v 15%), and fatigue (50% v 36%; Table 3 ). Vitiligo was reported in 15 T-VEC patients (5%) and one GM-CSF patient (< 1%; all grade ≤ 2). Injection-site erythema occurred more frequently among GM-CSF patients (T-VEC, 5% v GM-CSF, 26%). For T-VEC and GM-CSF, respectively, incidence of AEs of any grade was 99% and 95%, and incidence of treatment-related grade 3 or 4 AEs was 11% and 5%. The rate of discontinuation as a result of AEs was 4% and 2% with T-VEC and GM-CSF, respectively; disease progression was the most common reason for treatment discontinuation in both arms ( Fig 1 ).

The proportion of patients receiving subsequent selected effective antimelanoma therapy was similar between arms, although T-VEC patients received treatment approximately 2 months later than GM-CSF patients (Appendix Table A2 , online only). Because between-arm imbalances in nonrandomization prognostic factors of disease stage (IIIB, IIIC, or IVM1a v IVM1b or IVM1c) and ECOG performance status were identified, a sensitivity analysis (stratified Cox proportional hazards model) was used to adjust for these factors; the HR for OS with T-VEC versus GM-CSF was 0.76 (95% CI, 0.59 to 0.98; adjusted log-rank P = .03; Appendix Table A3 , online only).

Subgroup analyses were performed to investigate the relative effects of treatment across a number of key covariates for DRR, ORR, and OS. Differences in DRR between the T-VEC and GM-CSF arms were more pronounced in patients with stage IIIB or IIIC (33% v 0%) and IVM1a disease (16% v 2%) than in patients with stage IVM1b (3% v 4%) and IVM1c disease (7% v 3%; Fig 4 A). Differences in DRR were also more pronounced in patients with treatment-naive metastatic melanoma (24% v 0%) than in those receiving treatment as second-line or greater therapy (10% v 4%). Similar patterns were seen for ORR in these subgroups (Appendix Fig A1 , online only). Effects of T-VEC on OS were also pronounced among patients with stage IIIB, IIIC, or IVM1a disease (HR, 0.57; 95% CI, 0.40 to 0.80) and previously untreated patients (HR, 0.50; 95% CI, 0.35 to 0.73; Figs 4 B to 4 F).

At the primary analysis of OS, 290 deaths had occurred (T-VEC, n = 189; GM-CSF, n = 101). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) in the T-VEC arm and 18.9 months (95% CI, 16.0 to 23.7 months) in the GM-CSF arm (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051; Fig 3 ). Estimated 1-, 2-, 3-, and 4-year survival rates are listed in Table 2 .

Median time to response among the 78 responding patients in the T-VEC arm was 4.1 months (range, 1.2 to 16.7 months), whereas among the eight patients in the GM-CSF arm with a response, it was 3.7 months (range, 1.9 to 9.1 months). Of the 78 responding T-VEC patients, 42 (54%) met criteria for disease progression before ultimately achieving a response. Among patients with a response, median duration of response in the GM-CSF arm was 2.8 months (95% CI, 1.2 to not estimable), whereas median duration of response was not estimable for the T-VEC arm. The estimated probability of being in response at 12 months from response onset was 65% (95% CI, 51% to 76%) among T-VEC responders ( Table 2 ). At the time of the final tumor assessment included in the primary analysis of DRR (minimum follow-up for responding patients, 5.0 months), a majority (56 of 78) of T-VEC responses were ongoing ( Fig 2 B). Responses were observed in both injected and uninjected lesions, including a ≥ 50% decrease in size in 15% of evaluable, uninjected, measurable visceral lesions. 16 , 17

DRR per EAC assessment (primary end point) was significantly higher in the T-VEC arm (16.3%; 95% CI, 12.1% to 20.5%) compared with the GM-CSF arm (2.1%; 95% CI, 0% to 4.5%; unadjusted odds ratio, 8.9; 95% CI, 2.7 to 29.2; P < .001; Table 2 ; Fig 2 A). ORR was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%; P < .001 [not prespecified]); 32 patients (10.8%) in the T-VEC arm and one patient (< 1%) in the GM-CSF arm had a CR ( Table 2 ).

Between May 2009 and July 2011, 436 patients were assigned to treatment and included in intent-to-treat analyses (T-VEC, n = 295; GM-CSF, n = 141; Fig 1 ). Four patients in the T-VEC arm and 14 in the GM-CSF arm did not receive T-VEC or GM-CSF. Overall, 57% had stage IIIB, IIIC, or IVM1a disease, and 47% had not received prior systemic therapy for metastatic disease ( Table 1 ). At time of analysis, all patients had discontinued study treatment in the main protocol but could have enrolled onto a treatment extension study if appropriate. Median duration of treatment in the T-VEC and GM-CSF arms was 23.0 weeks (range, 0.1 to 78.9 weeks) and 10.0 weeks (range, 0.6 to 72.0 weeks), respectively. Median potential follow-up (time from random assignment to analysis) was 44.4 months (range, 32.4 to 58.7 months) at the primary analysis of OS.

DISCUSSION Section: Choose Top of page Abstract INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION << REFERENCES

To our knowledge, OPTiM is the first randomized controlled phase III study evaluating an oncolytic immunotherapy to demonstrate a therapeutic benefit in melanoma. The study met its primary end point: T-VEC significantly improved the rate of responses lasting continuously for ≥ 6 months in patients with unresected stage IIIB to IV melanoma compared with subcutaneous GM-CSF. ORR was also higher.

Among responding patients in the T-VEC arm, median time to response was 4.1 months, and more than half experienced ≥ 25% increase in the size of lesions or appearance of new lesions before achieving a response. This pattern of pseudoprogression is consistent with that seen with other immunotherapies19–23 and illustrates the importance of continuing treatment in clinically stable patients even if individual lesions increase in size or new lesions develop. In the context of the low historical CR rate reported for other single-agent immunotherapies, the 10.8% CR rate with T-VEC is high.1,20 The duration of T-VEC responses is also notable, with two thirds of responses expected to last ≥ 1 year.

Durable responses to T-VEC were seen across all disease stages tested, including in patients within each subset of stage IV disease. More than half of the patients had skin, subcutaneous, or nodal disease only (stage IIIB, IIIC, or IVM1a disease), and DRR and ORR with T-VEC were greater among these patients than among those with lung or other visceral organ metastases (stage IVM1b or IVM1c disease). In addition, the difference in OS favoring T-VEC compared with GM-CSF in patients with stage IIIB, IIIC, or IVM1a disease (HR, 0.57; 95% CI, 0.40 to 0.80) is of particular note. Although the reasons for the apparent differences in activity by disease stage are not known, it is possible that some patients with visceral disease may have had insufficient survival time to derive benefit from T-VEC–initiated systemic antitumor immunity. Alternatively, injection of T-VEC into dermal, subcutaneous, and nodal metastases may activate T cells that preferentially traffic to metastases in similar anatomic sites.24 Disease control in patients with stage IIIB, IIIC, or IVM1a disease can be achieved as a result of locoregional lytic effects of the virus as well as through immune effects, whereas responses in visceral lesions can only occur through systemic immune effects. Systemic immune effects of T-VEC were demonstrated, with the finding that 15% of measurable visceral (all uninjected) metastases reduced in size by ≥ 50% among T-VEC–treated patients. Development of vitiligo in T-VEC–treated patients indicates that an immune response to melanocyte antigens was induced, at least in some patients.25 Increased numbers of MART-1–specific T cells have been observed in metastases undergoing regression after T-VEC therapy compared with untreated lesions, and T-VEC has also been shown to decrease CD4+FoxP3+ regulatory T cells and CD8+FoxP3+ suppressor T cells in injected lesions, consistent with systemic antitumor immunity.13

DRR and ORR were greater in patients receiving T-VEC as first-line therapy than in those receiving T-VEC after prior treatment. Similarly, the difference in OS favoring T-VEC versus GM-CSF was also notable in previously untreated patients (HR, 0.50; 95% CI, 0.35 to 0.73). This outcome might be influenced by the increased time and selective pressure under which previously treated tumors have had to develop mechanisms of immunologic escape, such as reduced antigenicity or increased immunosuppressive state.26 Other factors to consider include prior exposure to immunosuppressive chemotherapy, higher baseline tumor burden, and potentially more indolent disease among patients receiving second-line or greater treatment in this study, because a lower tumor growth rate might affect the replicative efficiency of the virus.27

OS was a secondary end point; in the intent-to-treat analysis (based on 290 events), patients in the T-VEC arm had a 21% reduced risk of death (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051) and 4.4-month longer median OS compared with patients treated with GM-CSF. Median TTF was 5.3 months longer with T-VEC. Combined with the limited toxicity observed, these are clinically important results.

Several factors might have influenced the efficacy outcomes. GM-CSF was selected as a comparator based on its immune-mediated mechanism of action, established safety profile, and preliminary evidence of clinical benefit as adjuvant therapy in resectable stage III to IV melanoma.11,28,29 Although the duration of treatment was shorter in the GM-CSF arm, the reported activity of single-agent GM-CSF in advanced melanoma has been modest11; it is unlikely that shorter exposure contributed meaningfully to the reduced treatment effect. Effective subsequent antimelanoma therapies were received earlier by GM-CSF patients and could have overcome some of the OS benefit achieved with T-VEC. Furthermore, it is plausible that prior GM-CSF treatment may have had a beneficial impact on subsequent therapies, because concomitant administration of GM-CSF and ipilimumab has been shown to increase OS over ipilimumab alone.30 There were also small but meaningful imbalances in prognostic factors (disease stage and ECOG performance status) favoring the GM-CSF arm that may have affected the overall result, as suggested by a sensitivity analysis adjusting for these imbalances. In addition, the open-label study design may have influenced assessment of some end points (particularly TTF).

Both treatments administered in this study had tolerable safety profiles, and few patients discontinued because of toxicity in either arm. Frequently occurring AEs with T-VEC were flu-like symptoms (including fatigue, chills, and pyrexia). The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC–treated patients was cellulitis; there were no treatment-related deaths. In the context of toxicity reported for some other melanoma therapies,1,20,31 the low rate of grade 3 or 4 AEs with T-VEC is notable, particularly when considering combined immunotherapy approaches. The evidence of local and systemic immune responses with T-VEC supports combination with other immunotherapies as a rational approach. A phase 1b/2 study of T-VEC and ipilimumab is evaluating the safety and efficacy of this combination.32

In conclusion, this randomized phase III study demonstrated that treatment with T-VEC, an oncolytic virus immunotherapy, improved DRR compared with GM-CSF in patients with unresected stage IIIB, IIIC, or IV melanoma. T-VEC treatment resulted in long-lasting CRs, suggesting T-VEC could delay or prevent relapses or preclude progression to later stages of disease. T-VEC represents a novel potential new treatment option for patients with injectable metastatic melanoma and limited visceral disease.