Intralesional Combinations Pave the Way for Melanoma Treatment

Robert Andtbacka, MD

The use of intralesional therapies in combination with checkpoint inhibitors has shown to be an improvement to monotherapy and combinations with immunotherapy, according to Robert Andtbacka, MD, in a presentation at the 2017 World Congress of Melanoma.

Traditionally, when considering a combination therapy for patients with melanoma, the combination of 2 checkpoint inhibitors, the PD-1 antibody nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) come to mind. However, this is associated with more than 50% grade 3/4 immune-related adverse events (AEs), Andtbacka explained. Due to these safety concerns, other modalities have been investigated to achieve long-lasting responses in these patients.

“There were no substantially increased toxicity by combining intralesional therapy and checkpoint inhibitors,” explains Andtbacka, an associate professor in the Division of Surgical Oncology, Department of Surgery at the University of Utah School of Medicine and a surgeon and investigator with Intermountain Healthcare and Huntsman Cancer Institute. These combinations demonstrated grade 3 or higher AEs from 37% to 45% with response rates between 39% and 62%.

This combination approach saw an increase in response compared with monotherapy. For example, in a phase II study investigating talimogene laherparepvec (T-VEC; Imlygic) plus ipilimumab in the first-line setting, the responses were double compared with what was seen with ipilimumab alone. The overall response rate (ORR) was 39% versus 18%, with a complete response (CR) rate of 13% to 7% with the combination and monotherapy, respectively.

“These agents can improve the response rate compared with monotherapy intralesional agents or monotherapy checkpoint inhibitors when we use them in combination,” Andtbacka said.

The same was also seen with the combination of T-VEC plus pembrolizumab (Keytruda), another PD-1 inhibitor, in the phase Ib MASTERKEY-265 study, published in Cell. This study, investigating 660 patients confirmed a response rate of 62%. Patients were randomized to either T-VEC plus pembrolizumab or placebo plus pembrolizumab in patients with stage III/IV melanoma.

An area that requires further data is the durability of response with the combination regimens. In the study investigating ipilimumab plus T-VEC versus ipilimumab alone, the median progression-free survival (PFS) was 8.2 months compared with 6.4 months with ipilimumab alone. Although this was not statistically significant, it could be important from a clinical standpoint.

Additional studies are ongoing to determine if all the intralesional agents are the same. In a study of HF10 spinal cord stimulation therapy plus ipilimumab, there was a median PFS of 22 months, which is more than the 8.2 months seen with T-VEC plus ipilimumab. However, select patient populations need to be considered when giving these agents.

“Moving forward, we need to further understand that there are differences between intralesional agents when we combine them with checkpoint inhibitors in regard to response and the durability of those responses,” Andtbacka explained.

In patients who failed prior therapy with PD-1 inhibitors or combinations of PD-1 inhibitors and ipilimumab, response rates were seen between 23% and 33%, according to findings of the phase II VLA-013 study. Compared with single-agent ipilimumab, patients who failed PD-1 therapy and ipilimumab experienced response rates of 10% and 13% when treated with coxsackievirus.

Research is ongoing investigating intralesional combinations in the neoadjuvant setting. In patients at high risk of surgical resection, they are being given intralesional agents to combine with checkpoint inhibitors. Further data are needed to determine the significance of this approach.

“We don't know yet how good these are in neoadjuvant approach, but there are some early data stating that this can be beneficial,” Andtbacka said, noting that combining intralesional agents with checkpoint inhibitors shows an increase in response compared with monotherapy, is not associated with significant toxicity, and provides an alternative for patients who have failed on prior therapy.

Andtbacka R, Ross M, Agarwala SS. et al. Combination of intralesional immunotherapy: the path forward. In: Proceedings from the 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Abstract SY015.

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