While both agents activate anti-tumor immunity, T-VEC (Imlygic, Amgen) and pembrolizumab (Keytruda, MSD) have very different and potentially complementary modes of action. T-VEC is a genetically modified herpes simplex virus-1, which selectively replicates in tumor cells. It induces tumor cell lysis, antigen release and production of granulocyte-macrophage colony-stimulating factor, thereby enhancing antigen presentation to effector T cell. Meanwhile pembrolizumab blocks the immune checkpoint inhibitor known as programmed cell death receptor-1 (PD-1), leading to T cell activation against tumor. Both agents are recently FDA approved for the treatment of advanced melanoma while neither is current first line treatment regimen for this disease.
The combination of the two agents showed improved clinical benefits in the phase 1b part of the MASTERKEY-265 (NCT02263508) trial, consisting of 21 patients (median age, 58 years) with stage IIIB-IVM1a melanoma (48%) or stage IVM1b/c melanoma (52%).1
Efficacy data were analyzed from 16 evaluable patients. Results showed that the combination of pembrolizumab (200 mg every two weeks) with T-VEC (up to 4 mL of 106 PFU/mL for first dose followed by 108 PFU/mL every two weeks) resulted in a confirmed objective response rate (ORR) of 48%, with 14% confirmed complete responses (CR),1 in contrast to ORR of 33%2/26.4%3 (pembrolizumab/T-VEC) when used as monotherapy in previous studies. The disease control rate (DCR) was 71.4% and the median time to response was 17 weeks. With a median follow-up of 33 weeks, median progression free survival was not reached.1
The combo was generally well tolerated, and no dose-limiting toxicities were reported. Treatment-related adverse events were consistent with previously reported safety data for pembrolizumab. All 21 patients enrolled had at least one adverse events, but most were Grade 1/2. Grade 3 adverse events included headache (5%) and diarrhea (5%).1
“This is a phase Ib trial, and it’s only in 21 patients”, said lead study investigator Georgina V. Long, PhD, MBBS, Melanoma Institute Australia and The University of Sydney. “Like all phase I trials, it’s interesting—but it’s not going to change practice. We need to wait for randomized results…that will tell us whether there is truly an additive effect with T-VEC and pembrolizumab.”4
A 2-year randomized, double-blind, placebo-controlled phase III trial involving approximately 660 patient with unresectable state IIIb/IV melanoma is currently under way.5
In light of the promising initial result, Merck and Amgen, decided to expand their collaboration to initiate a trial for recurrent or metastatic squamous cell carcinoma of the head and neck (HNSSC) last year.6
Although the incidence of skin cancer in HK is relatively low compared with many Western countries, the prevalence of head and neck cancer, especially nasopharyngeal carcinoma, is high in Southern China.7 The new trial may provide new opportunities to improve disease control.
In summary, these new findings highlight the potential of using combination immunotherapy for the treatment of advanced melanoma and other cancers, but more data will be needed to truly tell its efficacy.