Intralesional Combinations Are Promising in Melanoma

Intralesional therapies — those delivered directly to the tumor site – used in conjunction with checkpoint inhibitors have shown improvements to the treatment of people with melanoma, says Robert Andtbacka, M.D., in a presentation at the 2017 World Congress of Melanoma.

Traditionally, when considering a combination therapy for patients with melanoma, the combination of two checkpoint inhibitors, the PD-1 antibody Opdivo (nivolumab) and the CTLA-4 inhibitor Yervoy (ipilimumab), come to mind. However, this is associated with more than 50 percent 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 percent to 45 percent with response rates between 39 percent and 62 percent.

This combination approach saw an increase in response compared with monotherapy. For example, in a phase 2 study investigating Imlygic (T-VEC; talimogene laherparepvec) plus Yervoy in the first-line setting, the responses were double compared with what was seen with Yervoy alone. The overall response rate (ORR) was 39 percent versus 18 percent, with a complete response (CR) rate of 13 percent to 7 percent 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 Keytruda (pembrolizumab), another PD-1 inhibitor, in the phase 1b MASTERKEY-265 study, published in Cell. This study, investigating 660 patients confirmed a response rate of 62 percent. Patients were randomized to either T-VEC plus Keytruda or placebo plus Keytruda in patients with stage 3/4 melanoma.

An area that requires further data is the durability of response with the combination regimens. In the study investigating Yervoy plus Imlygic versus Yervoy alone, the median progression-free survival (PFS) was 8.2 months compared with 6.4 months with Yervoy 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 Yervoy, there was a median PFS of 22 months, which is more than the 8.2 months seen with T-VEC plus Yervoy. 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 Yervoy, response rates were seen between 23 percent and 33 percent, according to findings of the phase 2 VLA-013 study. Compared with single-agent Yervoy, patients who failed PD-1 therapy and Yervoy experienced response rates of 10 percent and 13 percent when treated with coxsackievirus.

Research is ongoing investigating intralesional combinations in the neoadjuvant setting, meaning that it is offered before the main line of treatment. 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.