Jedd D. Wolchok, MD, PhD


June 13, 2011

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Hello, I'm Jedd Wolchok, Associate Attending Physician and Director of Immunotherapy Clinical Trials at Memorial Sloan-Kettering Cancer Center in New York. Welcome to this edition of Medscape Oncology Insights on Melanoma.

Today I would like to share with you some of the important results in melanoma presented at ASCO® 2011. This year, ASCO® featured several very insightful studies surrounding the treatment of patients with melanoma. In fact, 2 of the 5 plenary talks involved melanoma, and this was certainly a first-time occurrence for this relatively small field, melanoma oncology. It provides a very important source of inspiration to both investigators and physicians and also, importantly, a source of hope to patients and their families that new therapies for melanoma are becoming available.

Vemurafenib for BRAF-Mutated Melanoma

I'd first like to highlight the development of a drug called vemurafenib which is a selective inhibitor of the BRAF kinase molecule, which is mutated in about half of patients with melanoma.

BRIM-1. At ASCO® several years ago, we heard from my colleague, Dr. Keith Flaherty,[1] the early results of a phase 1 study showing that treatment with vemurafenib caused a striking response in patients whose melanoma tumors had the BRAF mutation. This was a very important validation of the field that we now term "personalized medicine" -- that when patients are prospectively studied for whether a genetic aberration is present or not, and then given a medicine that specifically addresses that genetic aberration, we are more likely to see a high response rate if that medicine in fact hits its target than if we treat the general population of melanoma patients at large. Vemurafenib quickly proceeded to a phase 2 study, which is called the BRIM-2 [BRAF Inhibitor in Melanoma] study, which was presented by Dr. Tony Ribas[2] [at this year's ASCO®].

BRIM-2. The BRIM-2 study really confirmed the results seen in BRIM-1 -- that there is a high response rate in approximately 50% of patients with a BRAF mutation, who will have either a partial or complete response, but the durability of these responses is quite heterogeneous from patient to patient. Some patients will have rapid recurrence of the disease due to various highlighted mechanisms of resistance, whereas other patients continue to have response after many months or even years. Some of the patients from the phase 1 trial still have disease control.

BRIM-3. After it became clear from preliminary reports of the BRIM-2 trial that vemurafenib was confirmed to be highly active, a phase 3 trial began in approximately 600 patients, called the BRIM-3 trial. This was an open-label, randomized, international trial that compared treatment with the oral BRAF inhibitor vemurafenib (which, I should say, was previously known as PLX4032), with a standard chemotherapy called dacarbazine given at a standard dose and schedule. The results of BRIM-3 were presented by my colleague from Memorial Sloan-Kettering, Dr. Paul Chapman,[3] and they showed that treatment with vemurafenib resulted in a very impressive improvement in overall survival, as well as progression-free survival, and that the response rates to vemurafenib were shown to be excellent in patients who had the BRAF mutation. It's important to again stress that all of the patients in the BRIM-3 trial were prospectively studied to ensure that their tumors had a BRAF mutation before they enrolled in the treatment aspect of the protocol.

Hoping for approval. Because of the very striking results in BRIM-3, there was a Data Safety Monitoring Board meeting to look at an interim analysis about 1 month after the study began. After it became clear that assignment to the vemurafenib group was resulting in an improvement not only in progression-free survival but in overall survival, the study was unblinded and patients who were on the dacarbazine arm were allowed to cross over and receive vemurafenib. So right now, vemurafenib remains an experimental drug. I think all of us in the community hope that it will be approved for use in the community as soon as possible, but it really does validate the idea that BRAF inhibitor is an important part of a treatment program for patients with BRAF-mutated melanoma.

Ipilimumab: Immunotherapy for Melanoma

The other drug that was highlighted at this year's ASCO® melanoma sessions was ipilimumab, which is a human monoclonal antibody that blocks a molecule called cytotoxic T-lymphocyte antigen 4 (CTLA-4). The mechanism of action of ipilimumab is that it allows for a stronger immune response than would otherwise occur in melanoma patients. CTLA-4, the molecule blocked by ipilimumab, can be considered a break or inhibitor of T cells, and ipilimumab interferes with that breaking mechanism, allowing T cells to become more activated and proliferate more than they otherwise would.

There were certainly previous presentations at ASCO® meetings that revealed that ipilimumab had activity in patients with melanoma. Last year at ASCO® in the plenary session, Dr. Steve O'Day from the Angeles Clinic presented a phase 3 trial of ipilimumab[4]or a peptide vaccine or a combination of the 2 for patients with refractory melanoma (patients who had received at least 1 previous line of therapy for melanoma and then went on this study). These results, which were quite important, demonstrated for the first time that a new drug could improve overall survival in patients with metastatic melanoma. Ipilimumab became the first drug to demonstrate an overall survival advantage. Earlier this year, vemurafenib also showed a survival advantage. This is an immense source of hope to our patients.

The Data That Clinched Ipilimumab's Approval

In March 2011, ipilimumab was approved by the US Food and Drug Administration for treatment of patients with refractory melanoma and patients in the first-line setting. The results of the phase 3 trial that I presented[5]at this year's ASCO® demonstrated that in patients in the first-line setting, ipilimumab also confers an improvement in overall survival. I presented the results of protocol CA184-024, which was a randomized international phase 3 study of ipilimumab in patients with first-line therapy of melanoma. In this study, similar to the vemurafenib study, dacarbazine was used at a standard dose and schedule. In the ipilimumab phase 3 trial, 502 patients were randomized in a 1:1 fashion to dacarbazine with either ipilimumab given at 10 mg/kg kg (which is a higher dose than was used in last year's phase 3 trial and is higher than the currently approved dose) or placebo. The ipilimumab or placebo was given on the same day as dacarbazine. In this trial, it was shown that patients who received ipilimumab plus dacarbazine had a statistically significant improvement in overall survival compared with dacarbazine alone, making this the second trial to show that ipilimumab can extend survival in patients with melanoma, this time in the first-line setting.

Toxicity and Adverse-Events Profile

This study also showed some differences in the toxicity profile of ipilimumab and, previously, we became aware that ipilimumab can cause inflammation in various tissues in the body: the skin, the gastrointestinal tract, and the endocrine organs. This can sometimes be severe but is generally responsive to stopping the treatment or using corticosteroids or other immunosuppressant medications. The side effects that caused the most concern previously were high-grade diarrhea and colitis, which, in a few patients, caused perforation in the gastrointestinal tract, and there were treatment-related deaths in the phase 3 trial that was presented last year.

In this year's phase 3 analysis, there were no treatment-related deaths in the ipilimumab-plus-dacarbazine group compared with 1 death in the dacarbazine-alone group, and there were no gastrointestinal perforations. What we think is that perhaps the dacarbazine could have shifted the toxicity profile away from the gastrointestinal tract, because we actually saw more elevations of AST and ALT transaminases in this study than were seen before. Or it's simply that investigators may have become more familiar with the treatment guidelines for these immune-related adverse events and were able to intervene quicker and, therefore, avoid more serious gastrointestinal toxicity.

Where Do We Go From Here?

When we take a step back and look at the results using ipilimumab as a prototypical immune-modulator, and vemurafenib as a prototypical BRAF inhibitor or a targeted pathway inhibitor, we naturally ask the question of where the field is going next. There was a lot of discussion at the ASCO® meeting this year about how these 2 types of medicines can be combined, and there are plans to do a clinical trial with these 2 specific medicines -- ipilimumab and vemurafenib -- later this year. In fact, in the run-up to the ASCO® meeting, there was a press release by Roche and Bristol-Myers Squibb, the manufacturers of both of these medicines, announcing their partnership in this clinical trial. I think this is a very important step forward to show that our industry colleagues are really behind the development of combination regimens that have the potential to provide the highest possible benefit for our patients. The fact that this is happening in real time, right after the survival advantage was confirmed for both of these drugs, is very emblematic of the attention and hard work that is being done in our field to deliver even more potent therapies for melanoma.

Closing Remarks

I'd like to thank you for joining me today. This is Jedd Wolchok for Medscape Oncology Insights, coming to you from ASCO® 2011.


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