LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life. But historically, it has not been a major focus in oncology, in part because of its propensity to metastasize early and the very limited treatment options when it does.
This is changing – and not just because of the landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients, Dr. Steven O’Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference
Ipilimumab targets the immune system so that it can contain the cancer, rather than targeting the tumor to eradicate the disease, explains Dr. Steven O'Day.
Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O’Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.
Targeted Chemotherapy: nab-Paclitaxel
Targeted chemotherapy with nab-paclitaxel (Abraxane)has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.
"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O’Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer,
Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.
These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.
"I predict this drug will get on the market" for melanoma, Dr. O’Day said, "because I think it’s so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."
Antiangiogenesis Therapy: Bevacizumab
Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O‘Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).
Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.
"Many in the melanoma community are really pushing [the drugs’ manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."
Targeted Immunotherapy: Ipilimumab
The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells’ antitumor activity.
"What’s important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient’s immune system," Dr. O’Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."
The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.
There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.
The other trial, conducted in the second-line setting and presented by Dr. O’Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).