Based on the rationale for combining talimogene laherparepvec with agents that can promote T-cell responses, talimogene laherparepvec has been evaluated in clinical trials for melanoma in combination with ipilimumab or pembrolizumab. Data on combination therapy with intralesional therapies have, until recently, been lacking; therefore, these studies provide a benchmark for future research.
Ipilimumab combined with talimogene laherparepvec
Ipilimumab is indicated in both Europe and the US for the treatment of advanced (unresectable or metastatic) melanoma in adults [
32,
38] (see Camacho LH [
39] for a recent review). It is a IgG1 monoclonal antibody directed against CTLA4, which blocks immunosuppression mediated by the interaction of B7 ligands (B7.1 and B7.2) on antigen-presenting cells and CTLA4 on CD8+ and CD4+ T cells and might deplete immunosuppressive regulatory T cells [
36,
40,
41]. This disinhibits the expansion of T-cell responses, promoting the production of autoreactive T cells [
36]. When administered as a monotherapy, ipilimumab demonstrated significant efficacy in patients with unresectable and metastatic melanoma, although immune-related AEs were common [
42]. In a Phase III trial, ipilimumab was associated with a response rate of 10.9% and a median OS of 10.1 months [
42]. OS data from a pooled analysis of ten prospective and two retrospective observational studies of ipilimumab, including two Phase III trials, indicate a 3-year survival rate of 22% with ipilimumab [
43]. The survival rate plateaus around year 3 and is maintained up to 10 years in some patients [
43]. Consequently, while efficacious, the low response rate and the frequency of severe AEs limit its use as a monotherapy.
The addition of ipilimumab to talimogene laherparepvec has the potential to enhance the priming and activation of T cells: dendritic cells present tumor antigens that are released following the oncolytic replication of talimogene laherparepvec (Fig.
2) [
8,
36]. Talimogene laherparepvec was evaluated in combination with ipilimumab in the Phase Ib portion of an ongoing Phase Ib/II clinical trial (Study 20110264; clinicaltrials.gov identifier: NCT01740297). For this portion of the study, 21 patients were screened and 19 patients were enrolled across five US sites from February 2013 to July 2013 [
44]. Patients with unresectable, injectable stage IIIB–IVM1c melanoma, who had received no prior systemic therapy (except prior adjuvant therapy ≥ 6 months from last therapy) were included in the study [
44]. Talimogene laherparepvec was administered intralesionally as monotherapy at an initial dose of 10
6 PFU/ml and then at 10
8 PFU/ml every 2 weeks from week 4 [
44]. Intravenous ipilimumab, administered at a dose of 3 mg/kg every 3 weeks for four infusions, began at the time of the third dose of talimogene laherparepvec [
44]. Talimogene laherparepvec was continued until CR, all injectable tumors disappeared, progressive disease (PD) per modified immune-related response criteria (irRC), or drug intolerance [
44]. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), defined as any treatment-related non-laboratory grade ≥4 AE, grade ≥4 immune-mediated dermatitis or endocrinopathy, and grade ≥3 immune-mediated AE of any other type (e.g., pneumonitis, pancreatitis, nephritis, uveitis, and vasculitis).
No DLTs were observed during the DLT evaluation period or throughout the Phase Ib portion of the study [
44]. Grade 3/4 treatment-related AEs were seen in 26% of patients (16% were attributed to talimogene laherparepvec and 21% were attributed to ipilimumab) (Table
2) [
44]. ORR was 50% (95% CI, 26.0 to 74:0), which was almost double that observed in OPTiM (Table
2) [
6,
42,
44]. This ORR was also higher than that observed in a Phase III trial with ipilimumab alone (data not shown), although it should be noted that patients were not required to have injectable disease in that Phase III study, so it is likely to have included a somewhat different patient population. Four patients (22%) had a confirmed CR [
44], relative to 1.5% of patients treated with ipilimumab monotherapy in a Phase III trial [
42]. All four patients were still in CR after a year [
44]. Overall, 44% of patients in Study 20110264 had a DRR (defined as duration of response [DOR] lasting ≥6 months, where DOR is the interval from a first confirmed objective response to confirmed PD), compared with 16% of patients experiencing a DRR (defined as objective response lasting continuously ≥6 months) in OPTiM [
6,
44]. Following the combination treatment, probabilities of 18-month PFS and OS were 50 and 67%, respectively [
44].
Table 2
Key safety and efficacy data from the Phase 1b arm of clinical trial NCT01740297 (investigating ipilimumab in combination with talimogene laherparepvec in melanoma), the Phase 1b arm of clinical trial NCT02263508 (investigating pembrolizumab in combination with talimogene laherparepvec in melanoma), and historical data for talimogene laherparepvec monotherapy from the Phase III OPTiM clinical trial in melanoma*
Baseline characteristics
| | | |
Disease stage | | | |
IIIB | 1 (5) | 1 (5) | 22 (8) |
IIIC | 3 (16) | 7 (33) | 66 (22) |
IVM1a | 4 (21) | 2 (10) | 75 (25) |
IVM1b | 5 (26) | 3 (14) | 64 (22) |
IVM1c | 6 (32) | 8 (38) | 67 (23) |
Unknown | 0 (0) | 0 (0) | 1 (<1) |
ECOG performance status | | | |
0 | 14 (74) | 19 (91) | 209 (71) |
1 | 5 (26) | 2 (10) | 82 (28) |
Unknown | 0 (0) | 0 (0) | 4 (1) |
LDH | | | |
≤ULN | 15 (79) | 16 (76) | 266 (90) |
>ULN | 1 (5) | 5 (24) | 15 (5) |
Unknown | 3 (16) | 0 (0) | 14 (5) |
Safety findings
| | | |
Grade 3/4 TRAE, N (%) | | | |
Any event | 5 (26) | 7 (33)† | 33 (11) |
Any attributed to talimogene laherparepvec | 3 (16) | 4 (19) | 33 (11) |
Any attributed to checkpoint inhibitor | 4 (21) | 6 (29)† | NA |
Efficacy findings
| | | |
ORR, n (%) | 9 (50) | 12 (57) | 78 (26) |
CR, n (%) | 4 (22) | 5 (24) | 32 (11) |
PR, n (%) | 5 (28) | 7 (33) | 46 (16) |
SD, n (%) | 4 (22) | 3 (14) | 134 (45) |
PD, n (%) | 5 (28) | 6 (29) | 62 (21) |
DRR, n (%)‡
| 8 (44) | NR | 48 (16) |
DCR, N (%) | NR | 15 (71) | 225 (76) |
12-month PFS, % | 50 | 71 | NR |
12-month OS, % | 72 | NR | 74 |
Tumor response at the lesion level, %#
| | | |
Injected lesions | 74 | 80 | 64 |
Non-injected lesions | 52 | 35 | NR |
Non-visceral | 54 | 45 | 34 |
Visceral | 50 | 28 | 15 |
There was evidence of immune modulation during the study and total CD8 + T cells and activated CD8 + T cells were significantly increased from baseline following treatment with talimogene laherparepvec [
44]. The increase in activated CD8+ T cells seemed to be greater in those patients experiencing disease control rather than progressive disease [
44]. However, this differentiation was lost after ipilimumab administration [
44]. CD4 + T cells expressing ICOS (inducible T-cell costimulator), an activation marker upregulated by CTLA-4 blockade, significantly increased from baseline at weeks 9 and 15 after ipilimumab was given, but not during the talimogene laherparepvec monotherapy period [
44]. These immune findings indicate that T-cell responses with talimogene laherparepvec and ipilimumab may be complementary.
There are inherent limitations with comparing data across trials. For example, the distribution of patients across the disease stages differs between Study 20110264 and OPTiM and different assessment criteria were used. Nonetheless, these early phase findings suggest that the efficacy of combined ipilimumab and talimogene laherparepvec may be greater than that seen historically with ipilimumab or talimogene laherparepvec monotherapy [
6,
42,
44].
Pembrolizumab combined with talimogene laherparepvec
Pembrolizumab, recently reviewed by Khoja et al. [
47], is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults (Europe and US) and for disease progression following ipilimumab and, if BRAF V600 mutant, a BRAF inhibitor (US) [
33,
48]. Pembrolizumab is a monoclonal IgG4 antibody directed against PD-1, which blocks the immunosuppression mediated by the interaction of PD-L1 on tumor cells and PD-1 on CD8+ and CD4+ T cells, therefore, improving tumor cell recognition by T cells [
36,
40,
49]. In the randomized Phase III KEYNOTE-006 trial (clinicaltrials.gov identifier: NCT01866319) that assessed the efficacy of pembrolizumab vs ipilimumab in advanced melanoma, pembrolizumab improved PFS, OS, and ORR and was associated with fewer grade ≥3 AEs [
50].
The addition of pembrolizumab to talimogene laherparepvec has the potential to enhance the systemic antitumor response by enhancing the recognition and killing of tumor cells by T cells that have been primed as a result of talimogene laherparepvec injection (Fig.
2) [
8,
36]. Talimogene laherparepvec was evaluated in combination with pembrolizumab in the Phase Ib portion of the Phase Ib/III clinical trial, called MASTERKEY-265 (clinicaltrials.gov identifier: NCT02263508) [
45,
51]. For this portion of the study, 21 patients with stage IIIB–IVM1c melanoma with injectable lesions and no prior systemic therapy were enrolled from December 2014 to March 2015 at 11 institutions in Europe and the US [
45,
51]. Talimogene laherparepvec was administered as monotherapy at an initial dose of 10
6 PFU/ml and then at 10
8 PFU/ml every 2 weeks from week 3 [
45]. Pembrolizumab was administered intravenously at a dose of 200 mg every 2 weeks, commencing at the time of the third dose of talimogene laherparepvec [
45]. Treatment with both therapies was continued for up to 2 years or until (whichever occurred first) CR or PD per modified irRC, intolerance, or, for talimogene laherparepvec only, when there are no longer any remaining injectable lesions [
51]. The primary endpoint for the Phase Ib portion of the trial was the incidence of DLTs, with the evaluation period defined as 6 weeks from the initial administration of pembrolizumab [
45,
51]. Data cutoff for the Phase Ib safety and efficacy results was January 4, 2016 [
45]. The study met its primary endpoint with no DLTs observed during the monitoring period [
45]. There was no additional toxicity with the combination treatment compared with that expected for the monotherapies (Table
2).
The combination therapy was associated with clinical benefit with a confirmed ORR of 57% and confirmed CR rate of 24% (Table
2) [
45]. This ORR was greater than previously seen with pembrolizumab in a Phase III trial (34%) and with talimogene laherparepvec seen in OPTiM (26%)—although it should be recognized that cross-trial comparisons are associated with limitations, particularly as these studies had different designs and patient populations [
6, 439]. Unconfirmed ORR was 67%, and unconfirmed CR rate was 29% [
45]. Median PFS was not reached during the study, with 71% of patients being progression free at 6 months; disease control rate (DCR) was 71% [
45]. As seen previously, an increase in circulating cytotoxic T cells (CD3+/CD8+) was observed after the start of talimogene laherparepvec monotherapy, as well as an upregulation of PD-1 and TIM-3 on these cells [
45]. These results need careful interpretation, since melanoma patients with skin metastases often present with a less aggressive clinical course. However, the data still indicate that talimogene laherparepvec primes the immune response to enable an optimum response to pembrolizumab. Overall, these early findings suggest increased efficacy with combined pembrolizumab and talimogene laherparepvec treatment compared with pembrolizumab or talimogene laherparepvec monotherapy [
6,
45,
50].