Wolchok on Research, Perfecting Immunotherapy in Melanoma

The world of immunotherapy in melanoma is changing quickly, according to Jedd D. Wolchok, M.D., Ph.D.

“With immunotherapy, we have come an extremely long way in the treatment of melanoma,” says Wolchok, the Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation, chief, Melanoma and Immunotherapeutics Service, associate director, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center.

Combination trials with immunotherapies offer great promise, he says. Recently, the combination of Imlygic (T-VEC; talimogene laherparepvec) and Yervoy (ipilimumab) in patients with advanced melanoma demonstrated an objective response rate of 50 percent in a single-arm phase 1b trial after a median follow-up time of 20 months. Forty-four percent of patients had a durable response lasting more than six months; after 18 months, progression-free survival (PFS) was 50 percent and overall survival was 67 percent.

Biomarker research is also moving forward, although Wolchok says there is still much to be determined.

Results of a recent study examining 20 patients with unresectable metastatic melanoma using multiparameter-flow cytometry demonstrated that response to Keytruda (pembrolizumab) strongly correlated to the percentage of CD8-positive tumor-infiltrating lymphocytes (TILs) that expressed high levels of both PD-1 and CTLA-4.

In an interview with CURE, Wolchok discusses these two studies, their impacts and how far the field of immunotherapy has come in melanoma. Wolchok shared this insight during an interview at the Society for Immunotherapy of Cancer 101 Session, where he also served as a faculty member.

The following has been edited for brevity and clarity.

What research is underway to explore the optimal role of T-VEC in melanoma?

[Imlygic] is an altered herpes simplex virus that can be used for intralesional injection in melanoma. It can lead to regression of injected lesions; it can also lead to regressions, which is a very powerful immunologic observation. By itself, it clearly has activity; it is FDA approved. We and others are exploring it in combination with other immune modulators. There are ongoing clinical trials looking at it with PD-1 blockade. There are some very recently published data showing promising results in a single-arm study looking at it with CTLA-4 blockade using [Yervoy].

The use of oncolytic viruses, such as [Imlygic], can provide one avenue for augmenting activity of checkpoint blockade; however, we still have much more to learn about that. It does address one challenge that we see in immunotherapy, which is that there are some tumors that do not attract a baseline immune infiltrate. Injecting a tumor with an oncolytic virus would be one way to address that.

What biomarkers are being investigated for immunotherapy in melanoma?

The area for biomarker research for immunotherapy is a very active one; there are many new studies published weekly. Recent findings regarding the value of flow cytometry analysis of TIL specimens from the University of California, San Francisco showed that T cells with both CTLA-4 and PD-1 markers on their surface. The presence of those cells at a given frequency could identify patients who have a higher likelihood of benefit with PD-1 blockade.

We don’t yet have a perfect biomarker; that quest must continue. We should not settle for any biomarker that has less than 100 percent negative predictive value. The importance of this point is quite high, because these immunotherapies can convey long-term disease control.

We do not want to necessarily exclude any patient from receiving these medicines because of an imperfect biomarker. We have many things to consider, including intertumor and intratumor heterogeneity, timing of biopsies, and sensitivity of the given assay. It is a very exciting time in biomarker development, but we still have a lot of work to do.

How far have we come with immunotherapy in melanoma in the past five years and what still needs to be done?

If you look back before 2011 when [Yervoy] was approved, the median life expectancy for a patient with metastatic melanoma was six or seven months. The best immunotherapy for patients with metastatic melanoma was high-dose interleukin-2, which benefited somewhere between 3 percent and 5 percent of patients.

Now, we have the combination of [Yervoy] and [Opdivo (nivolumab)], which provides a major objective clinical response in about 60 percent of patients. We are routinely seeing cohorts from clinical trials where patients are living, on average, two years or longer.

We have come a very long way. We are not done. We are not going to be satisfied until we see 100 percent durable response or disease control at the very least, but we have made a major impact in a relatively brief period of time.