ECCO2017 NEWS: The Immunotherapy, Pembrolizumab, Is Active Against Mucosal Melanoma Tumours and Prolongs Survival for Patients with Bladder Cancer

Excerpt:

“Clinical trials of a new immunotherapy, pembrolizumab, have shown that it prolongs life significantly for patients with bladder cancer and is active against a rare sub-type of melanoma, called mucosal melanoma. The findings were presented in two presentations at the European Cancer Congress 2017 today.”

“Until now, mucosal melanoma has often been excluded from immunotherapy treatments for the disease. Melanoma usually occurs in the skin and is caused by exposure to ultraviolet radiation (such as sunlight). Mucosal melanoma occurs in the moist surfaces that line the body’s cavities, such as the airways, digestive tract and genitourinary tracts, and is not caused by UV radiation; there is no known cause. It makes up about one per cent of all melanomas and has a poor prognosis, usually because of late diagnosis – the majority of patients with metastatic disease (cancer that has spread to other parts of the body) survive for less than a year if they have received conventional treatments.”

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Immunotherapies Could Open the Door for Additional Treatments in Mucosal Melanoma

“Despite limited information on treatment options for mucosal melanoma, Richard Joseph, MD, says immunotherapies could be a rewarding challenge for oncologists to undertake in the field.

“Joseph, a medical oncologist at Mayo Clinic, says one recent study investigating the immunotherapy nivolumab in the treatment of mucosal melanoma resulted in response rates that could possibly warrant further investigation.

” ‘What they found was that the response rates tended to be slightly lower than what we typically see in cutaneous melanoma, but still a relatively good response rate,’ he said.

” ‘This gives us, for the time being, some quality data for when we are treating patients with mucosal melanoma. We can now give our patients some good numbers regarding if we should treat them with immunotherapy. Before, we were treating them with immunotherapy without really knowing the efficacy.’ “


Immunotherapy Shows Potential in Rare Melanoma Subtype

“Few studies have investigated mucosal melanoma, a rare and aggressive subtype of melanoma. As a result, oncologists often base treatment choices on cutaneous melanoma data.

“The use of nivolumab (Opdivo) was recently investigated in patients with mucosal melanoma based on a pooled analysis of 889 patients, 10% (86) of whom had mucosal melanoma.

“At a median follow-up of 9.2 months (0.3-62.5), median progression-free survival (PFS) was 3.0 months (95% CI, 2.2-5.4) for patients with mucosal melanoma and 5.1 months (95% CI, 3.9-6.1) for all treated patients. The objective response rate (ORR) was 23.3% (95% CI, 14.8-33.6) for patients with mucosal melanoma and 35.9% (95% CI, 32.7-39.1) for all treated patients, with complete responses in 6% of patients in both cohorts.”


New Antibody-drug Conjugate Shows Early Promise Against All Forms of Melanoma

“The investigational drug DEDN6526A, which is a new member of a class of drugs called antibody-drug conjugates, was safe, tolerable, and showed hints of activity against different forms of melanoma—cutaneous, mucosal, and ocular—according to results of a first-in-human phase I clinical trial presented here at the AACR Annual Meeting 2014, April 5-9.

“Antibody-drug conjugates consist of an antibody attached to a toxic chemotherapy by a special linker that keeps the chemotherapy inactive. In the case of DEDN6526A, the antibody recognizes the protein endothelin B receptor (ETBR) and the toxic chemotherapy is monomethyl auristatin (MMAE). Infante explained that when administered to the patient, the antibody portion of DEDN6526A recognizes and attaches to ETBR, which is often present at elevated levels on the surface of tumor cells in patients with melanoma. The whole antibody-drug conjugate is then taken up by the cells and MMAE is released from the linker to become active, killing the melanoma cells.”


Checkpoint Modulation in Melanoma: An Update on Ipilimumab and Future Directions

“Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first therapy demonstrated to improve overall survival in melanoma. Since ipilimumab’s approval by the FDA in 2011, a wealth of data has amassed, helping clinicians to optimize its use. We have learned how to mitigate the adverse effects of ipilimumab, identified its effects in melanoma subpopulations such as those with brain metastases, uveal melanoma, and mucosal melanoma, discovered potential biomarkers of activity, and investigated its use in combination with other therapeutic modalities. These discoveries have paved the way for rapid development of second-generation immunomodulatory antibodies such as inhibitors of the programmed cell death 1 receptor axis. These new agents hold promise as monotherapy, but perhaps the greatest allure lies in the possibility of combining these agents in synergistic multidrug regimens.”


Another Option in Our KIT of Effective Therapies for Advanced Melanoma

“Hodi et al reported the final results of a multicenter phase II trial of imatinib in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene. KIT is a transmembrane receptor tyrosine kinase, normally expressed on melanocytes, that plays a critical role in melanocyte migration, survival, proliferation, and differentiation. Mutations and amplification of KIT have been identified in melanomas arising from mucosal, acral or chronically sun-damaged surfaces, and they characterize a distinct genetic subset of disease. The alterations identified are, in most instances, mutually exclusive of BRAF and NRAS mutations and lead to constitutive activation of downstream signaling pathways including the MAPK, PI3K/AKT, and JAK/STAT pathways.”


Phase II Randomized Trial Comparing High-dose Interferon Alfa-2b with Temozolomide plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma

“Mucosal melanoma is rare and associated with extremely poor prognosis. However, standard adjuvant therapy for mucosal melanoma has not been established. We conducted a randomized phase II clinical trial in resected mucosal melanoma (MM) patients to compare the efficacy and safety of high-dose IFN-α2b (HDI) and temozolomide-based chemotherapy as adjuvant therapy.”


KIT-Mutated Melanomas Respond to Imatinib

“Imatinib has activity in KIT-mutated mucosal, acral, or chronically sun-damaged melanoma.”


Imatinib for Melanomas Harboring Mutationally Activated or Amplified KIT Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin

“Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities…We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations…Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.