Epigenetic-Active Agents May Improve Sensitivity to Temozolomide in Melanoma

July 16, 2015
Michael R. Page, PharmD, RPh

Using treatments that target epigenetic pathways, including the DNA methyltransferase inhibitor decitabine and the histone deacetylase (HDAC) inhibitor panobinostat, investigators hoped to improve the sensitivity of melanoma cells to the alkylating agent temozolomide.

In a study published by Chang Xia, MD, PhD, and colleagues affiliated with several hospitals and treatment centers in the Midwestern United States, investigators reported results of an early trial using a triple therapy strategy of temozolomide plus panobinostat and decitabine for patients with resistant metastatic melanoma.1Because this was an early trial, investigators focused on safety and tolerability.

For the first week of therapy, patients received subcutaneous injections of decitabine 3 times weekly. During the second week of therapy, patients received 3 weekly injections of decitabine in addition to oral doses of panobinostat (administered every 4 days) and daily oral doses of temozolomide. Although each treatment cycle lasted 6 weeks, patients received treatment on the first 2 weeks of each cycle. In the trial, patients received up to 6 cycles of treatment or up to 36 weeks of therapy.

About 65% of patients enrolled in the trial were male, and the remaining third were female. Patients enrolled in the trial had a median age of 56 years. Of all 17 patients treated, efficacy was not evaluable in nine patients because of disease progression before completion of 2 treatment cycles. Of the remaining eight patients who were considered evaluable, two patients did not respond to therapy, five patients had stable disease, and one patient experienced a complete response. In the patient with a complete response, the patient’s response continued for 8 months before relapse occurred (Figure 1).

Figure 1. Result of combination therapy with panobinostat, decitabine, and temozolomide in patients with metastatic melanoma.

No dose-limiting toxicities or maximum tolerable medication doses were identified in the trial. However, investigators identified several adverse events (AEs) that were considered related to treatment, including grade 3 lymphopenia, anemia, neutropenia, and fatigue, as well as grade 2 leukopenia, neutropenia, nausea, and lymphopenia. Although treatment is associated with several AEs, the five cases of stable disease and one case of a complete response to therapy indicate an early positive result that may lead to further development of targeted therapies to alter epigenetic signaling in melanoma.

Although no indications for epigenetic therapies in melanoma have been secured, therapies that are active on epigenetic targets have recently gained approvals in the treatment of some types of cancers, including multiple myeloma and cutaneous T-cell lymphoma. Among these agents, the HDAC inhibitor panobinostat has been considered a strong candidate for treatment of melanoma because of its direct cytotoxicity against melanoma cells in vitro and its immunostimulant properties of the immune system on tumor cells.

For instance, in early 2013, Woods and colleagues published a study supporting the efficacy of panobinostat in an animal model of melanoma. In mice implanted with melanoma cells, panobinostat significantly improved survival, but only in mice that were not treated with immunosuppressive medications. The fact that survival advantages in mice treated with panobinostat were eliminated in immunocompromised mice further supports the immunomodulatory effects of panobinostat as its anticancer mechanism. Research has confirmed that programmed cell death ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors augment the innate anticancer activity of tumor-infiltrating lymphocytes. Now emerging evidence indicates that panobinostat may be similarly active in enhancing tumor-infiltrating lymphocyte activity against melanoma cells.2

Considering the preclinical evidence of the immunomodulatory effect and potentially synergistic effect of panobinostat with immunotherapies, it is not surprising that researchers at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, are recruiting participants for a clinical trial to test the combination of panobinostat and ipilimumab in patients with melanoma (NCT02032810).

The phase I study3is recruiting adult patients with stage III and stage IV metastatic melanoma who have had up to 3 prior treatments, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and have laboratory values within certain parameters.

Epigenetic-active agents have already been approved for the treatment of certain types of cancer. Although use of these agents as a monotherapy is unlikely, use of treatments such as HDAC inhibitors may enhance the effectiveness of other treatments, such as CTLA-4 inhibitors and PD-L1 inhibitors. By finding more agents to enhance the effectiveness of existing treatments and new combinations of treatments, scientists are making headway in the fight against metastatic melanoma.

References

1. Xia C, Leon-Ferre R, Laux D, et al. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide).Cancer Chemother Pharmacol.2014;74(4):691-697.

2. Woods DM, Woan K, Cheng F, et al. The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity.Melanoma Res.doi:10.1097/CMR.0b013e328364c0ed.

3. National Institutes of Health. Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02032810. Accessed April 2015.