Expert Discusses Immunotherapy Advancements on the Horizon for Melanoma

Jedd D. Wolchok, MD, PhD

Jedd D. Wolchok, MD, PhD

Melanoma research is rapidly advancing, explains Jedd D. Wolchok, MD, PhD, particularly with immunotherapy.

“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 talimogene laherparepvec (T-VEC; Imlygic) and ipilimumab (Yervoy) in patients with advanced melanoma demonstrated an objective response rate of 50% in a single-arm phase Ib trial after a median follow-up time of 20 months. Forty-four percent of patients had a durable response lasting more than 6 months; after 18 months, progression-free survival (PFS) was 50% and overall survival was 67%.¹

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 unrespectable metastatic melanoma using multiparameter-flow cytometry demonstrated that response to pembrolizumab (Keytruda) strongly correlated to the percentage of CD8-positive tumor-infiltrating lymphocytes (TILs) that expressed high levels of both PD-1 and CTLA-4.²

In an interview withTargeted Oncology, Wolchok, who is also a 2014 Giant of Cancer Care winner in Melanoma, discusses these 2 studies, their impacts, and how far the field of immunotherapy has come in melanoma.

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

Wolchok:

T-VEC 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 ipilimumab.

The use of oncolytic viruses, such as T-VEC, 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.

TARGETED ONCOLOGY:What biomarkers are being investigated for immunotherapy in melanoma?

Wolchok:

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% 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.

TARGETED ONCOLOGY:How far have we come with immunotherapy in melanoma in the past 5 years and what still needs to be done?

Wolchok:

If you look back before 2011 when ipilimumab was approved, the median life expectancy for a patient with metastatic melanoma was 6 or 7 months. The best immunotherapy for patients with metastatic melanoma was high-dose interleukin-2, which benefited somewhere between 3% and 5% of patients.

Now, we have the combination of ipilimumab and nivolumab (Opdivo), which provides a major objective clinical response in about 60% of patients. We are routinely seeing cohorts from clinical trials where patients are living, on average, 2 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% durable response or disease control at the very least, but we have made a major impact in a relatively brief period of time.

References:

1. Puzanov I, Milhem M, Minor D, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma [published online June 13, 2016].J Clin Oncol.doi:10.1200/JCO.2016.67.1529.
2. Daud A, Loo K, Pauli M, et al. Tumor immune profiling predicts response to anti—PD-1 therapy in human melanoma [published online August 15, 2016].J Clin Invest. doi:10.1172/JCI87324.