Targeted therapy for skin malignancies

The past decade has seen significant advances in the understanding of molecular pathogenesis of skin cancer leading to the development of targeted treatments and immunotherapies that have dramatically improved progression free survival and even overall survival in melanoma, basal cell carcinoma (BCC) and even some rarer cutaneous carcinomas.

Until 2011, the standard of care for metastatic melanoma was chemotherapy with dacarbazine (DTIC) as monotherapy or part of a combination regimen which was associated with response rates of only 5–28% and no significant increase in survival duration. At that time median survival of patients with non-resectable metastatic melanoma was 6–10 months, with only 4–6% of patients surviving to 5 years.

Since 2011 targeted therapy with BRAF (BRaf proto-oncogene serine/threonine kinase) inhibitors and MEK (mitogen-activated protein kinase) inhibitors, and immunotherapy with checkpoint inhibitors against CTLA-4 (cytotoxic T-lymphocyte- associated protein 4) inhibitors and PD-1 (programmed cell death protein 1) and its ligand L1 (PD-L1) has become available. All are associated with increased response rates and extended progression-free survival and overall survival compared with dacarbazine.

Melanomas can be classified into four large genomic subtypes: mutant BRAF, mutant NRAS, mutant NF1 and triple wild-type (i.e., without mutations in these 3 genes),ⁱ and types of mutation vary according to sun damage and tumour type, says Eggert Stockfleth, Klinik für Dermatologie, Venerologie und Allergologie, St. Josef-Hospital, Ruhr-Universität Bochum, Bochum, Germany.  For example, melanomas from chronically sun-exposed skin have most often NF1, NRAS mutations and occasionally BRAF mutations, whereas melanomas from intermittently sun-exposed skin tend to have BRAF mutations (50%) or NRAS mutations (15–20%). Significantly mutated genes in cutaneous melanoma include BRAF, NRAS, CDKN2A and TP53 and although the specific mutation will not influence outcome it will determine which is the most appropriate therapy.

Oncogenic mutations in BRAF and NRAS induce overstimulation of the RAS/RAF/MEK/ERK signalling pathway (also known as the MAPK [mitogen-activated protein kinase] pathway), which is central to the pathogenesis of cutaneous melanoma. Most BRAF mutations (89%) involve the kinase activation loop at the p.V600 position (BRAF V600), and the most common BRAF V600 mutation (80%) is a valine to glutamic acid mutation at codon 600 (V600E), which is associated with a 500-fold increase in the kinase activity of BRAF. This leads to cascade activation of MEK and ERK.

Mutations of BRAF V600 are an important target in recently developed molecular targeted therapy for melanoma and three BRAF inhibitors are available for treatment of BRAF V600-mutated advanced melanoma: vemurafenib, dabrafenib and encorafenib. The current first-line treatment is a combination of a BRAF inhibitor and MEK inhibitor. “BRAF/MEK combined therapy which produces response rates around 20% higher than BRAF inhibitor monotherapy, median progression free survival exceeds one year and overall survival reaches approximately 2 years,” says Stockfleth

A combination of targeted therapy and immunotherapy may be a future potential therapeutic option for BRAF V600 mutant advanced melanoma, as BRAF V600 mutation in melanoma increases production of immunosuppressive factors, leading to an immune-suppressive phenotype, he adds. “Mutated BRAF may induce T-cell suppression via secretion of inhibitory cytokines or by membrane suppression of co-inhibitory molecules such as PD-1 and PD-L1, suggesting that a combination strategy targeting BRAF, MEK and PD-1 signalling could be effective.” Clinical trials are producing promising results with these triplet combinations.

Basal cell carcinoma (BCC) is the most common type of skin cancer and most cases result from mutations in key receptors in the Hedgehog (HH) signalling pathway, which controls cell proliferation, cell fate specification, tissue patterning and tissue homeostasis. In 85–90% of cases of BCC this involves inactivation mutations in the PTCH1 (Patched 1) transmembrane receptor and in 10% of cases activating mutations in SMO (smoothened) transmembrane receptor, a cell-associated signal transmitting component.  Two agents that inhibit SMO in the HH pathway – vismodegib and sonidegib - showed efficacy in clinical trials and have received regulatory for treatment of locally advanced BCC and, for vismodegib only, metastatic BCC.  Other HH pathway inhibitors are in development.

Over the last ten years the incidence of the Merkel cell carcinoma (MCC), a rare but aggressive neuroendocrine tumour of the skin, has increased worldwide. The Merkel cell polyomavirus (MCPyV) is clonally integrated in approximately 80% of MCC tumours, and the remaining 20% have large numbers of ultraviolet radiation associated mutations.

Merkel cell carcinoma is characterized by high tumour expression of PDL1 in the tumours, which led to recent clinical trials involving PD-1 pathway blockade in advanced MCC and clinical trials have shown a high frequency of durable responses in patients treated with PD-1 inhibitors who had not received prior chemotherapy.ⁱⁱ The PD-1 blocker avelumab has recently become the first agent to be approved for metastatic, relapsed/refractory MCC.

However, approximately 50% of patients with MCC do not benefit long term from PD-1 pathway blockade.

Dermatofibrosarcoma protuberans (DFSP) is a rare intermediate- to low-grade soft tissue neoplasm malignancy that rarely metastasizes. Activating mutations in the genes for PDGF or PDGF receptors have been recorded which led to the approval of molecularly targeted therapy with imatinib, which inhibits tyrosine kinases as well as PDGF receptors, in unresectable cases and as neoadjuvant therapy.ⁱⁱⁱ

Potential new therapies for advanced or metastatic DFSP include multikinase inhibitors pazopanib and regorafenib.

References

ⁱThe Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 2015; 161: 1681–1696.

ⁱⁱTello TL, Coggshall K. Yom SS,Yu SS Merkel cell carcinoma: an update and review: current and future therapy. J Am Acad Dermtaol 2018; 78: 445–454.

ⁱⁱⁱRutkowski P, Van Glabbeke M, Rankin CJ et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol 2010; 28: 1772–1779.