Melanoma: A model for testing new agents in combination therapies
- PDF / 684,132 Bytes
- 7 Pages / 595 x 794 pts Page_size
- 61 Downloads / 207 Views
Open Access
COMMENTARY
Melanoma: A model for testing new agents in combination therapies Commentary
Paolo A Ascierto*1, Howard Z Streicher2 and Mario Sznol3
Abstract Treatment for both early and advanced melanoma has changed little since the introduction of interferon and IL-2 in the early 1990s. Recent data from trials testing targeted agents or immune modulators suggest the promise of new strategies to treat patients with advanced melanoma. These include a new generation of B-RAF inhibitors with greater selectivity for the mutant protein, c-Kit inhibitors, anti-angiogenesis agents, the immune modulators anti-CTLA4, antiPD-1, and anti-CD40, and adoptive cellular therapies. The high success rate of mutant B-RAF and c-Kit inhibitors relies on the selection of patients with corresponding mutations. However, although response rates with small molecule inhibitors are high, most are not durable. Moreover, for a large subset of patients, reliable predictive biomarkers especially for immunologic modulators have not yet been identified. Progress may also depend on identifying additional molecular targets, which in turn depends upon a better understanding of the mechanisms leading to response or resistance. More challenging but equally important will be understanding how to optimize the treatment of individual patients using these active agents sequentially or in combination with each other, with other experimental treatment, or with traditional anticancer modalities such as chemotherapy, radiation, or surgery. Compared to the standard approach of developing new single agents for licensing in advanced disease, the identification and validation of patient specific and multi-modality treatments will require increased involvement by several stakeholders in designing trials aimed at identifying, even in early stages of drug development, the most effective way to use molecularly guided approaches to treat tumors as they evolve over time. Current prospects for melanoma therapy The only approved chemotherapy for metastatic melanoma, DTIC, or its oral equivalent temozolomide, has a response rate of about 10% and a median survival of 8-9 months. The other approved agent for advanced melanoma is high dose interleukin-2, which can induce dramatic complete and durable responses. However, only one patient in twenty derives lasting benefit. Multi-agent combinations [1-7] and bio-chemotherapy regimens [815] were reported to produce much higher objective response rates in phase 2 trials, but did not improve overall survival. A series of scientific and clinical advances in the past decade has led to a rapid evolution of new treatment strategies. Mutations in B-RAF and c-Kit, have recently been proven to be therapeutic targets in phase 1 clinical trials [16]. Of great potential, a small molecule inhibitor * Correspondence: [email protected] 1 Unit of Medical Oncology and Innovative Therapy, National Tumor Institute, Naples, Italy
Full list of author information is available at the end of the article
of B-RAF, PLX 4032, induced t
Data Loading...
