Positive Results from First Randomized Study Assessing T-VEC/Ipilimumab Combo in Advanced Melanoma

Claus Garbe, MD

The addition of T-VEC (T-VEC; Imlygic), a herpes simplex virus 1-based oncolytic virus, to CTLA-4 inhibitor ipilimumab (Yervoy) improves the objective response rate (ORR) in patients with unresected stage IIIb to IV melanoma, according to findings presented at the 7th European Post-Chicago Melanoma/Skin Cancer Meeting.

T-VEC was the first approved oncolytic virus therapy in Europe, the United States, and Australia, and its efficacy was previously demonstrated in a phase III trial comprising patients with advanced unresectable melanoma.

In a phase II open-label study, 198 patients with unresected stage IIIb to IV melanoma and measurable/injectable tumor(s) were randomized in a 1:1 ratio to T-VEC plus ipilimumab (n = 98) or ipilimumab alone (n = 100). T-VEC was administered from week 1 and ipilimumab was administered at 3 mg/kg intravenously every 3 weeks for 4 cycles starting from week 6 in the combination arm and from week 1 in the monotherapy arm.

Prior treatment was allowed but was not a prerequisite for study entry. The primary endpoint was ORR, according to immune-related response criteria. At the start of the study, 54% of patients had stage IIIb to IVM1a disease, 46% had stage IVM1b/c disease and baseline characteristics were similar between treatment arms.

After a median follow-up period of 68 and 58 weeks in the combination and monotherapy arms, respectively, T-VEC plus ipilimumab resulted in a doubling of the ORR, compared with ipilimumab alone (38.7% vs 18.0; odds ratio [OR], 2.9; 95% CI, 1.5-5.5; P = .002).

More patients experienced a complete or partial response in the combination arm (13.3% and 25.5%, respectively) than patients who were receiving ipilimumab alone (7.0% and 11.0%, respectively). Significantly more patients had disease control (complete or partial response plus stable disease) in the T-VEC plus ipilimumab arm versus the ipilimumab-alone arm (58.2% vs 42.0%; OR, 1.9; 95% CI, 1.1-3.4; P = .033).

Improvement in ORR in the combination arm was observed across all subgroups analyzed, aside from patients with elevated lactate dehydrogenase, as well as for all disease substages. In patients with stage IIIb/c-IVM1a disease, ORR was 44.0% in the T-VEC plus ipilimumab arm and 19.3% in the ipilimumab-alone arm (OR, 3.3; 95% CI, 1.4-7.8; P = .007). The difference in ORR was no longer significant in patients with more advanced disease, with ORRs of 33.3% and 16.3% being reported, respectively (OR, 2.6; 0.9-7.0; P = .09).

In addition, over a third of patients (35.5%) in the combination arm experienced a reduction from baseline of at least 50% in total visceral tumor area versus 13.6% of patients in the ipilimumab-alone arm, supporting the improved systemic effect of the combination therapy. “Hopefully, this will translate into improved overall survival, which we will see in a future evaluation,” said presenter Claus Garbe, MD, of the University of Tuebingen, Germany. As of the presentation, 89% and 83% of responding patients in the T-VEC plus ipilimumab and ipilimumab-alone arms, respectively, remained in response.

Median progression-free survival was nonsignificantly longer in the T-VEC plus ipilimumab arm, compared with ipilimumab alone (8.2 vs 6.4 months; hazard ratio [HR], 0.83; 95% CI, 0.56-1.23; P = .35).

Ninety-five patients were evaluable for safety in each arm. The combination of T-VEC plus ipilimumab was tolerable and no unexpected adverse events (AEs) occurred. The most frequently reported AEs were fatigue (59% vs 42% of patients in the T-VEC plus ipilimumab and ipilimumab-alone arms, respectively), chills (53% vs 3%), and diarrhea (42% vs 35%). Grade 3 or higher AEs considered related to treatment occurred in 28% of T-VEC plus ipilimumab recipients and 18% of patients receiving ipilimumab alone. Three deaths occurred in the combination therapy arm, none of which were considered related to treatment (progressive disease and myocardial infarction; n = 2 and n = 1, respectively).

“What will be very important is to see the results of the MASTERKEY-265 study, which is a combination of pembrolizumab [Keytruda] plus T-VEC because we have to try to get immune responses in first-line treatment by combining as many treatment approaches as possible,” said Garbe. “So, I am still hoping that T-VEC will add something to that. We will probably not bring ipilimumab plus T-VEC into clinical practice but the main question will be whether we can combine it with PD-1 inhibitors or with both—with PD-1 plus CTLA-4 inhibitors in a triplet combination. And, if T-VEC can improve the outcome in our metastasized patients we will undoubtedly use it.”

Chesney J, Puzanov, Ross M, et al. Combination of talimogene laherparepvec and ipilimumab versus ipilimumab alone in unresected stage IIIB-IV melanoma: primary results from a randomized (1:1), open-label phase 2 study. Presented at: 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017; Munich, Germany.