Dramatic Progress in Fight against Advanced Melanoma

June 2011, Vol 2, No 3 - ASCO Annual Meeting

Chicago, IL—Oncologists do not engage in hyperbole. It is not in their nature. If the word “unprecedented” is used to describe a clinical outcome, it’s because something truly remarkable has occurred; such is the case in the reporting of 2 investigations of advanced melanoma at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) for the drugs vemurafenib (PLX4032) and ipilimumab (Yervoy).

“You have to understand the landscape of what our patients with advanced melanoma has looked like,” said melanoma expert Lynn M. Schuchter, MD, Professor of Medicine and Chief, Hematology Oncology, Department of Medicine, Abramson Cancer Center, Philadelphia. “Over the years we’ve had only 2 drugs approved for this, and both have pretty limited activity in advanced patients.” Yet, in the course of 20 minutes, the results reported for 2 clinical trials with 2 new drugs with entirely different mechanisms of action strongly suggest that the lives of thousands of patients are about to change.

“With ipilimumab approved just weeks ago [on March 25, 2011] and vemurafenib very likely to be approved soon on the basis of the randomized phase 3 trial presented here today, it is really unprecedented to have 2 new types of therapeutic approaches with such high level of activity become available at the same time,” Dr Schuchter said. And that activity can be profound.

“When patients with the BRAF mutation are treated with vemurafenib [the mutation required for the activity of the drug], within 72 hours their symptoms can improve—this level of activity in patients who are seriously ill is remarkable.” Further, the drug is very well tolerated, incurring few of the side effects expected with the use of chemotherapy. “This is truly a time for celebration for our patients,” she pointed out.

The successful results for both new drugs were published in the New England Journal of Medicine (Chapman PB, et al. 2011 Jun 5 [Epub ahead of print]) on the day of the ASCO presentations.

Vemurafenib, an oral drug, is a targeted therapy that inhibits the activity of the BRAF genetic mutation, an aberration that exists in up to 60% of patients with melanoma. “This pathway is one of the primary ways a cell begins to proliferate when it receives an appropriate signal,” explained study investigator Paul B. Chapman, MD, of Memorial Sloan-Kettering Cancer Center, New York. Normally the pathway is inactive, but with the BRAF mutation the pathway is constitutively active. “It’s like having a switch broken in the on position.” Vemurafenib was designed to bypass that switch, thereby interrupting the signaling pathway and resulting in melanoma (and only melanoma) cell death.

In this phase 3, randomized, openlabel trial, vemurafenib was compared with dacarbazine (administered by injection) in 675 previously untreated patients with late-stage melanoma identified as having the BRAF mutation. After beginning treatment, patients’ responses to therapy were assessed at 6 and 12 weeks and then every 9 weeks thereafter.

Positive results for the vemurafenibreceiving cohort were seen almost immediately. “It is unprecedented to report a trial this early,” said Dr Chapman. “Yes, our median follow-up time is still only 3 months, yet, the survival curves separated very early.” Although not enough time had passed to calculate a median overall survival (OS), the estimated 6-month survival rate for patients taking vemurafenib was 84% versus only 64% in those treated with dacarbazine. “That’s a 63% decrease in risk of death, a huge difference,” he said.

Large differences in progression-free survival (PFS) were also seen (median of 5.3 months for vemurafenib vs 1.6 months for dacarbazine), with a 74% decrease in disease progression risk for the former. The general response rate was 48.4% for vemurafenib and 5.5% for dacarbazine. All treatment benefits were gained with only minimal side effects.

“This is the first single agent that as a monotherapy improves the proportion of therapeutic response, progression- free survival, and overall survival as compared with a chemotherapy treatment,” concluded Dr Chapman. “This is a foundation that our field can build on to develop even more effective treatment by using melanoma drug combinations.”

The second study in advanced melanoma reported at the meeting included a new combination of dacarbazine and ipilimumab. Ipilimumab is a human monoclonal antibody that interacts with the activated T-cells of the immune system, causing the T-cells to persist in their attack on diseased tissue rather than have that activity be naturally attenuated over time. “This allows for a much more robust T-cell activation and proliferation,” said lead investigator Jedd D. Wolchok, MD, Medical Oncologist at Memorial Sloan-Kettering Cancer Center.

Ipilimumab had previously demonstrated activity in melanoma in a study presented at last year’s ASCO meeting; however, patients in that trial had already received standard treatment before administration of ipilimumab. “This was the first drug ever to improve overall survival in previously treated patients,” said Dr Wolchok, who reported that based on those results, the current study was initiated to give ipilimumab to patients as front-line therapy, just after their late-stage melanoma diagnosis. In this randomized, blinded investigation, 502 patients with late-stage melanoma were randomized in a 1:1 fashion to a combination of ipilimumab/dacarbazine or to dacarbazine/placebo, administered every 3 weeks. After 4 treatment cycles, all patients who were showing response to either treatment were allowed to continue in the study for the maintenance phase, where they received either ipilimumab or placebo.

At a median follow-up of 3 years, the OS results showed superiority for the active-drug combination: 47.3% of patients were alive at 1 year with the ipilimumab/dacarbazine combination versus 36.3% of patients with dacarbazine alone; median times of survival were 11.2 months versus 9.1 months, respectively.

“This equated to a 28% reduction in the risk of death for the combination,” said Dr Wolchok. An improvement in PFS was also observed; the median duration of response was 19.3 months with ipilimumab versus 8.1 months with dacarbazine alone. “This sustained response is very characteristic of ipilimumab as an immunotherapy.”

Of note, serious side effects were more frequent with ipilimumab and were related to the immune response (ie, inflammatory in nature). However, these effects were typically resolved with dose de-escalation or with the use of corticosteroids.

“This is the second randomized study to show a survival advantage for the use of ipilimumab,” concluded Dr Wolchok. “We look forward to combining ipilimumab with other active agents, perhaps vemurafenib, in the near future.”