Almost two-thirds of patients with advanced melanoma responded to combination therapy with pembrolizumab and talimogene laherparepvec (T-vec) in a small phase 1b trial, investigators reported.
A third of patients achieved a complete response and median progression-free and overall survival were not reached after typically 18.6 (range, 17.7 to 20.8) months of follow-up, said Antoni Ribas, MD, of the University of California, Los Angeles, and his coinvestigators. In contrast to single-agent pembrolizumab therapy, responders to the combination regimen included patients with very low levels of CD8+ T cell infiltrates or negative interferon-gamma (IFN-gamma) gene signatures in baseline tumor biopsies, suggesting that oncolytic virotherapy might make anti-PD-1 therapy more effective by altering the tumor microenvironment, the researchers concluded. Serious adverse events were uncommon in this study, and there were no dose-limiting toxicities, they wrote (Cell. 2017 Sept. 7 doi: 10.1016/j.cell.2017.08.027 ).
Anti-programmed death-1 (PD-1) antibodies are becoming standard for treating various cancers, including metastatic melanoma. But regardless of cancer type, checkpoint blockade only helps some patients because most are resistant to PD-1 blockade, the researchers said. Tumor specimens from nonresponders have been found to lack CD8+ T cells, leaving anti-PD-1 antibodies without an effective target.
To see if attracting CD8+ T cells into tumors helped surmount this obstacle, the researchers treated 21 patients with advanced melanoma with pembrolizumab and T-vec, an intratumorally administered, genetically modified clinical herpes simplex virus-1 strain approved for treating melanoma. Patients first received up to 4 mL T-vec (106 plaque-forming units [pfu] per mL) to induce a protective immune response. Three weeks later, they started receiving to 4 mL (108 pfu/mL) T-vec plus 200 mg intravenous pembrolizumab every 2 weeks.
Thirteen patients (62%) showed at least a partial response, and seven (33%) had a complete response based on immune criteria. Notably, 9 of 13 (69%) patients with baseline tumor CD8+ densities below 1,000 cells/mm2 responded to combination treatment, as did three of five patients with low baseline IFN-gamma signatures.
“There was only one baseline biopsy that was scored as PD-L1 negative, but that patient went on to have a complete response to the combined therapy,” the researchers wrote. “Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, [and] IFN-gamma gene expression on several cell subsets in tumors after [T-vec] treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-gamma signature.” Increased levels of circulating immune cells and shrinkage of untreated tumors both suggested that intratumoral T-vec injections led to systemic effects, they added.
The most common treatment-related adverse events were fatigue (62%), chills (48%), and fever (43%), which occur with intratumoral T-vec therapy, said the investigators. Serious adverse events included grade 1 cytokine-release syndrome deemed possibly related to combination therapy, and one case each of aseptic meningitis, autoimmune hepatitis, and pneumonitis attributed to pembrolizumab. Ongoing studies include a phase 3 trial (NCT02263508) of the combination regimen and a study of immune biomarkers of the inflammatory effects of T-vec on tumors (NCT02366195).
Amgen and Merck provided funding. Dr. Ribas disclosed consulting fees from both companies.