Is There a Role for Intralesional Therapy in Melanoma?

On Monday during ASCO, Dr. Axel Hauschild reviewed the role of intralesional therapy in melanoma in a sub-session of the melanoma abstract review talk entitled, “Evolving Utility of Intralesional Therapy for Melanoma.”  Dr. Hauschild presented recent data from current abstracts being presented at ASCO and discussed looming questions surrounding the utility and effectiveness of intralesional therapy in clinical practice in melanoma, which I review and summarize here.

One study looked at IL-12 given intralesionally by electroporation, which involves injection of the plasmid into tumors.  Electrodes are then inserted and create a more porous environment to allow for distribution of the drug.  IL-12 is thought to upregulate interferon gamma.  Nine out of 28 patients were found to have objective responses and three patients had a complete response in the lesion.  Additionally, 13 out of 22 patients demonstrated regression of non-injected lesions. 

One limitation seen in this intralesional therapy was that the standard RECIST criteria were difficult to use for measuring response.  For example, very small lesions may be difficult to assess using RECIST criteria, despite the fact that a clinical response might be noted.  It was proposed that another way to characterize response in these lesions other than using RECIST criteria would be to use soft tissue sonography or MR sonography.  The strength of IL-12 intralesional therapy was the very low toxicity reported-mainly consisting of injection site pain and inflammation. This was a very small study with a highly selected group of patients and without a control arm, which makes it difficult to draw conclusions from it.  However, the reported overall response rates were reasonable; several patients had a complete response; and some of the untreated lesions demonstrated regression. 

Another intralesional therapy known as PV-10 was looked at in a phase II study of 80 patients with cutaneous melanoma who had a mean age of 70 years old and who were refractory to a median of six prior therapeutic interventions.  PV-10 is an intralesional injection that accumulates in tumor lysosomes and results in lysosome rupture.  In 57 evaluable patients, there was a 71% overall response rate with a time to response of 1.8 months.  It was also noted that melanin A expression decreased after treatment with intralesional PV-10.  The therapy was non-toxic.

Finally, in the phase III OPTiM trial, patients were randomized in a 2:1 fashion for intralesional T-VEC, which is an HSV-1 derived oncolytic immunotherapy, versus subcutaneous GM-CSF.  A current abstract looks at disease progression prior to response.  Durable responses (defined as lasting for at least six months) were seen in 48 out of 295 patients.  Of those 48 patients, 25 had no progression prior to response and 23 had progression prior to response.  Of those 23 patients, 14 had new lesions only and nine had existing lesions but may have developed new lesions.  Of 48 T-VEC-treated patients with a durable response, it is now reported that currently, 40 (83%) still have durable responses in the lesions.

Dr. Hauschild raised several interesting conclusions from the current debate regarding the utility of intralesional therapy in melanoma.  Because intralesional therapy appears to have virtually no significant systemic toxicities and has been shown to have complete responses in some patients, this type of therapy may be considered in combination with other standard therapies, but its role as a single agent is not clear. For example, in a current abstract, the combination of T-VEC plus Ipilimumab shows an overall response rate of 56% in 18 patients evaluated by RECIST criteria. The responses were broken down as complete response (33%), partial response (22%), stable disease (17%), and progressive disease (28%).  It is still unclear how to measure any type of potential systemic response from intralesional treatment, and additionally, this therapy has a very limited patient population in which to apply it since it requires patients to have injectable skin or lymph node lesions. 

Furthermore, the goals of treatment need to be clarified. Would improved quality of life from resolution of a skin lesion be enough to provoke clinicians to use intralesional therapy?  His definition of response rates, and how to measure and assess responses also needs to be addressed, as discussed above. Finally, more randomized studies, with active control arms, are needed.  It would be difficult to show that single-agent intralesional therapy would demonstrate a progression-free survival or overall survival advantage over BRAF inhibitors or anti-PD-1 immunotherapy, but combination therapy should be further studied.