Understanding the molecular biology of melanoma and unraveling of several signaling pathways over the last few years, as well as advances in immunology have led to the development of a number of novel therapeutic targets in melanoma. Nevertheless, therapy for advanced melanoma remains an enormous challenge. None of the aforementioned novel and promising strategies have yet shown an OS benefit compared with standard therapy in a randomized Phase III setting. Some of the novel therapeutics are simply not yet developed sufficiently to have reached this stage of clinical testing, but others have failed (i.e., sorafenib in combination with chemotherapy in first and second line, oblimersen combined with dacarbazine in unselected stage IV melanoma patients and tremelimumab as a single agent in the first-line setting). For some of the new immune-regulatory antibodies described above, standard RECIST criteria might not be adequate for the assessment of clinical response. It has been suggested that potential clinical activity of immunological checkpoint blockade with tremelimumab might have been missed in Phase III testing owing to the failure to recognize the fact that immune-related response criteria are needed for response assessment. Clinical trials combining agents with different targets and requiring tissue biopsies to assess the impact of these agents on pathways and biomarkers are vital for the advancement of the treatment of this disease. Identifying genetic signatures of tumors in responding patients will assist in the future selection of therapeutic options for patients once these unique features are characterized.
Und unter "Other Targeted Drugs Currently in Clinical Development" ist Genasense erwähnt:
One of the mechanisms for chemotherapy resistance in melanoma is thought to be the overexpression of Bcl-2, an anti-apoptotic protein that blocks the release of cytochrome C, a key player in the apoptotic cascade. Oblimersen sodium (Genasense®, Genta International Inc.) is an 18-base phosphorothioate antisense oligonucleotide that binds the first six codons of the Bcl-2 mRNA open-reading frame and mediates RNA cleavage by RNase, thereby downregulating Bcl-2. Based on the results of a Phase I/II study suggesting that the addition of oblimersen to dacarbazine might improve RRs and OS in patients with advanced melanoma without increasing toxicity, a large Phase III trial of oblimersen in combination with dacarbazine compared with dacarbazine alone was conducted. Among 771 patients randomly assigned, the combination yielded a significant increase in RR (13.5 vs 7.5%) and a small improvement in PFS (2.6 vs 1.6 months), but only a trend toward improved survival at 24-month minimum follow-up (median: 9.0 vs 7.8 months). Interaction between baseline serum lactate dehydrogenase and treatment was observed: In patients with normal serum lactate dehydrogenase, survival was significantly increased with the addition of oblimersen (median OS: 11.4 versus 9.7; p = 0.02). This observation is now being tested prospectively in a Phase III trial. At our institution, the combination of Nab-paclitaxel (paclitaxel protein-bound particles for injectable suspension), temozolomide and oblimersen is currently being investigated in a Phase I/II trial and has shown encouraging clinical activity in an initial cohort of 14 patients.