September 2015, Vol. 2, No. 5
Encouraging Treatments Are Plentiful in BCC, CTCL, and MCC
Several therapies for advanced nonmelanoma malignancies have recently taken hold or have shown encouraging potential, said presenters at the 2015 World Cutaneous Malignancies Congress.
Basal Cell Carcinoma
Basal cell carcinoma (BCC) represents a spectrum of disease, from curable with surgery to locally advanced or metastatic disease, for which surgery is inappropriate. Systemic therapies are needed in the latter segment, said Aleksandar Sekulic, MD, PhD.
The Hedgehog signaling pathway is activated in BCC and, therefore, represents a target for therapy. The 2 agents approved for the treatment of BCC that act on the Hedgehog pathway are the Smoothened inhibitors vismodegib and sonidegib, which was approved on July 24, 2015. A number of other drugs targeting Smoothened are in the clinical phase of study.
“Vismodegib works in metastatic and locally advanced disease, and the recently approved sonidegib is similar,” said Sekulic, Vice Chair, Department of Dermatology, Mayo Clinic, Scottsdale, AZ. “Inhibition of this pathway also works in Gorlin syndrome patients, or basal nevus syndrome.”
Toxicities (ie, muscle spasms, alopecia, dysgeusia, weight loss) are a major barrier to treatment with Smoothened inhibitors and are a class effect. “These are on-target effects in small tissue compartments,” he said.
Muscle cramps seem to be the most devastating toxicity, but they can be managed with hydration with water and electrolyte-supplemented beverages, muscle relaxants, and drug holidays. Weight loss is more problematic in older patients who may already be thin or frail, so ensuring adequate caloric intake in this population is important.
Candidates for treatment with Smoothened inhibitors are a “moving target,” said Sekulic, and their use depends partly on available treatment options, potentially histologic subtype (nodular vs infiltrative vs superficial), and clinical characteristics.
The appropriate duration of treatment with a Smoothened inhibitor is unknown. “We typically treat until we get to a plateau where there’s no clinical or imaging evidence of disease, and then follow, initially frequently and then less often,” he said. For patients with Gorlin syndrome, intermittent treatment would be advantageous, and such an approach is being explored in a phase 2 study of vismodegib in patients with multiple BCCs.
Therapeutic resistance to Smoothened inhibitors occurs. The mode of resistance identified in medulloblastoma is a mutation in Smoothened that prevents binding of the drug to the target. “This may also be happening in BCC,” he said. Preexisting mutations present at very low frequency may also confer resistance.
A neoadjuvant approach to the use of Smoothened inhibitors in BCC has potential utility if it turns inoperable into operable tumors or reduces the extent of surgery. A phase 1 trial of neoadjuvant vismodegib for 2 to 4 months in 15 patients with large BCC found a reduction in the estimated surgical defect of 31% (J Am Acad Dermatol. 2014;71:904-911).
Cutaneous T-Cell Lymphoma
Research in cutaneous T-cell lymphoma (CTCL) has exploded over the past 2 decades, resulting in 4 novel agents over the past 5 years, whereas in the previous 15 years, only 2 agents (bexarotene and denileukin diftitox) received approval for this indication, said Larisa J. Geskin, MD, Director, Comprehensive Cutaneous Oncology Center at Columbia University, New York City.
With the lack of a diagnostic marker, the diagnosis of CTCL is currently based on clinical-pathological correlations. TOX and PLS3 are potential diagnostic markers that are being investigated to differentiate CTCL from other dermatologic conditions.
In the treatment realm, antibiotic therapy is “a hot area of investigation,” said Geskin, as Staphylococcus aureus has been found to play a role in the etiology of CTCL.
A new gel formulation of mechlorethamine that does not require compounding by a pharmacy is now approved for the treatment of mycosis fungoides CTCL.
A number of sensitizers for use with photodynamic therapy (PDT) are being studied as topical treatment for patients with thick plaques. Hypericin is a photodynamic agent shown to induce apoptosis in normal and malignant B and T lymphocytes; it requires no special light source. Reductions of 50% in target lesions have been obtained with PDT using hypericin.
Of the systemic therapies, denileukin diftitox is the established agent for CTCL, notable for the durable responses it produces. “We think that not only does it kill the CTCL cells directly, but it may influence CD25+ cells such as T regulatory cells and the tumor microenvironment,” said Geskin.
Histone deacetylase (HDAC) inhibitors have multiple mechanisms of antitumor activity, including influence on the expression of genes that control the cell cycle and differentiation, disruption of mitotic progression, and inducement of cell cycle arrest.
In addition to their direct cytotoxic effects, HDAC inhibitors may also modulate antitumor immunity. Vorinostat and romidepsin are the 2 HDAC inhibitors approved in the United States.
Vorinostat approval was granted based on responses in the skin only. Romidepsin is the more powerful agent, and when used in combination with radiation, a significant clinical response was noticed within 1 month with nearly complete resolution of tumor lesions. Vorinostat is also a good candidate for combination therapy, she indicated.
Pralatrexate is associated with impressive responses, but in clinical trials of patients with mycosis fungoides, mucositis occurred in 25% of patients. Leucovorin rescue results in good clinical response and no dose-limiting toxicities. Thus, leucovorin rescue will be tested in prospective clinical trials to allow patients with CTCL to receive the full benefit of pralatrexate therapy without intolerable toxicity.
Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. KIR proteins are thought to play an important role in regulation of the immune response. Anti-KIR antibodies have been tested in acute myeloid leukemia and in combination with nivolumab in solid tumors. IPH4102 is a first-in-class anti-KIR3DL2 antibody that has received orphan drug designation in the European Union for the treatment of CTCL, with phase 1 trials expected to start this year.
Brentuximab vedotin is an anti-CD30 monoclonal antibody that is involved in 83 active clinical trials, including several in CTCL, one of which is a phase 3 study. It is currently approved for the treatment of relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.
Merkel Cell Carcinoma
The need for rational biology-driven drug development in Merkel cell carcinoma (MCC) is strong, said Shailender Bhatia, MD, Assistant Professor, University of Washington/Fred Hutchinson Cancer Research Center, Seattle.
A case can be made for immunotherapy in MCC, said Bhatia. With the discovery of the Merkel cell polyomavirus (MCPyV), “there is a very strong rationale for immunotherapy in this cancer,” he said. “We know that the viral oncoproteins are expressed in most MCC tumors and should be recognized as ‘non-self’ antigens by the immune system.”
He said, “When the immune system is able to recognize the presence of fallen antigens into the tumor and mount an immune response, the outcomes are fairly good.” As evidence, MCC patients who have a strong CD8+ infiltrate have improved survival compared with those with poor infiltration.
MCC can evade immunotherapy by several mechanisms. One is by downregulation of major histocompatibility complex (MHC) class I molecules on tumor cells, rendering them invisible to the immune system. In addition, intratumoral CD8+ infiltration is lacking in about 80% of MCC tumors, and, when detected, immune exhaustion of tumor-infiltrating lymphocytes is evident.
Several immunotherapy trials in MCC are ongoing in an attempt to overcome host immunity evasion mechanisms employed by MCC tumors, including intratumoral interleukin-12 electroporation, intratumoral glucopyranosyl lipid A (GLA), pembrolizumab and avelumab, virus-specific T cells, and Neukoplast.
Immune exhaustion in MCC tumors may be reversed by immune checkpoint drugs, he said. Durable complete response has been obtained in an MCC patient treated with pembrolizumab 2 mg/kg in a phase 1 study (Clin Cancer Res. 2015;pii:clincanres.2607.2014). At the last follow-up, the patient is continuing on treatment at >100 weeks, and the duration of complete response is now at 90+ weeks. This observation is promising for programmed death-1 inhibitor treatment of MCC.
MCPyV viral oncoprotein–targeted autologous T cells are being infused in an ongoing study to increase MHC class I expression, allowing the T cells to identify tumor cells, followed by immune checkpoint blockade.
Intratumoral GLA is a toll-like receptor 4 agonist that is showing potential in a pilot study of MCC (J Clin Oncol. 2015;33[suppl]. Abstract 3083). One patient had a pathologic complete response after 2 injections and is recurrence-free at 11 months. Another patient with near-complete response for >8 months had increased intratumoral CD8+ T-cell infiltration that correlated with clinical regression of the disease.
For patients in whom the disease is too aggressive for immunotherapy, targeted therapies such as cabozantinib, lanreotide, pazopanib, and F16IL2/paclitaxel are being studied as debulking agents and bridges to immunotherapy.
Single-fraction high-dose (8 Gy) radiation therapy has been effective with minimal toxicity in a palliative setting and is potentially immunogenic, said Bhatia.
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Emerging concepts in the treatment of melanoma include new definitions for stage I/II and stage III disease, new surgical paradigms that incorporate systemic neoadjuvant therapy for advanced disease, and locoregional treatment with intralesional therapies that have both local and distant effects, said presenters at the 2015 World Cutaneous Malignancies Congress. [ Read More ]