The combination of an oncolytic virus plus a checkpoint inhibitor improved survival among patients with advanced melanoma compared with monotherapy, according to data from a phase 2 study published in Journal of Clinical Oncology.
Novel monotherapies, such as ipilimumab (Yervoy, Bristol-Myers Squibb) — a CTLA-4 antibody — have “transformed patient care in advanced melanoma,” the researchers wrote.
“Immunotherapies don’t always shrink tumors, but they are very effective at increasing life span as a result of the durability of their clinical benefits, including objective responses and stabilization of disease without new metastases,” Jason Chesney, MD, PhD, director of the James Graham Brown Cancer Center at the University of Louisville, told HemOnc Today.
In a similar fashion, the combination use of these novel agents, designed to target complementary cancer immunity pathways, may improve antitumor responses with lower toxicity.
“The majority of melanoma patients who receive immune checkpoint inhibitors do not experience durable objective responses,” Chesney said. “We now have multiple approaches to enhance the effectiveness of CTLA4 and PD1 inhibitors and agents that facilitate the priming of antigen-specific T cells are expected to synergize with immune checkpoint inhibitors.”
Talimogene laherparepvec (Imlygic, Amgen) — also known as T-VEC — is a herpes simplex virus-1-based oncolytic immunotherapy, that like ipilimumab, can enhance T-cell activation through different mechanisms.
“I believe that the combination of melanoma cell death and antigen release caused by the oncolytic virus with the secretion of granulocyte-macrophage colony-stimulating factor that has been engineered into its genome enhances dendritic cell differentiation and antigen presentation resulting in expansion of melanoma antigen-specific T cells, which in turn, can be promoted by CTLA4 and PD-1 inhibitors,” Chesney said.
The researchers conducted the open-label, multicenter, randomized trial designed to evaluate the safety and efficacy of T-VEC in combination with ipilimumab in 198 patients with unresectable stages IIIB to IV melanoma.
Patients were randomly assigned 1:1 to receive either T-VEC plus ipilimumab (n = 98; median follow-up, 68 weeks) or ipilimumab alone (n = 100; median follow-up, 58 weeks).
On the first day of week 1, the combination arm received an injection of T-VEC at a dose of 4 mL x 10 plaque-forming units/mL, followed by administration on day 1 of week 4, and every 2 weeks thereafter at a dose of 4 mL x 10 plaque-forming units/mL.
In addition, the arm received 3 mg/kg ipilimumab every 3 weeks beginning on day 1 of week 6 for up to four infusions.
In the control arm, patients received 3 mg/kg every 3 weeks beginning on day 1 of week 1 for up to four infusions.
Investigator-assessed objective response rate served as the primary endpoint. Secondary endpoints included OS, best overall response rate, disease control rate, time to response, duration of response, PFS and safety.
The combination arm demonstrated a superior objective response rate (39% vs. 18%; OR = 2.9; 95% CI, 1.5-5.5; P = .002), including 13% with a complete response and 7% with a partial response, compared with the ipilimumab arm.
The combination arm also showed superior median time to response (5.8 vs. not estimable; HR = 1.41; 95% CI, 0.8 to not estimable), disease control rate (58% vs. 42%; OR = 1.9; 95% CI, 1.1-3.4) and PFS (8.2 vs. 6.4 months; HR = 0.83; 95% CI, 0.56-1.23) compared with those who received ipilimumab alone.
Median duration of response was not reached in either arm.
At data cutoff, 20 patients in the combination arm and 23 patients in the ipilimumab arm had died (HR = 0.80; 95% CI, 0.44-1.46).
At the time of analysis, 89% of the combination arm and 83% of the ipilimumab arm with a response remained in response.
Of note, responses occurred in both injected and uninjected lesions, including visceral lesions decreases observed in 52% of the combination arm and 23% of the ipilimumab arm.
“The observation that noninjected, visceral lesions were significantly more likely to respond to the combination of ipilimumab with talimogene laherparepvec than ipilimumab monotherapy was an encouraging surprise that suggests that the virus is enhancing systemic antimelanoma immunity,” Chesney said.
Common adverse events in the combination and monotherapy arms included fatigue (59% vs. 42%), chills (53% vs. 3%), diarrhea (42% vs. 35%), pruritus (40% vs. 36%), rash (39% vs. 28%) and nausea (38% vs. 24%).
Moving forward, T-VEC is also being investigated in combination with pembrolizumab (Keytruda, Merck) for the treatment of advanced melanoma, and as a monotherapy to treat solid tumor types.
“My personal expectation is that we will observe efficacy of the combination of intrahepatic talimogene laherparepvec with immune checkpoint inhibitors in phase 1/phase 2 trials that focus on cancers like non-small cell lung cancer, breast cancer, colon adenocarcinoma, etc.,” Chesney said. – by Kristie L. Kahl
Disclosures: Chesney is a consultant for Amgen; and receives research funding and travel accommodations from Amgen. from Please see the full study for a list of all other authors’ relevant financial disclosures.