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ASCO: Ipilimumab Plus Dacarbazine Prolongs Metastatic Melanoma Survival

Publish date: June 5, 2011
By
Mary Jo M. Dales

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Toxicity Raises Concern

The high rates of hepatoxicity seen with ipilimumab and dacarbazine, with no evident therapeutic advantage, indicate that chemotherapy should not be used in combination with ipilimumab at any dose or schedule, said Dr. Kim Allyson Margolin.

Given ipilimumab's black box warning regarding the potential risks of immune-related adverse events, the drug should only be used at the approved duration of therapy.

One intriguing finding is that the ipilimumab results challenge our presumptions about the blood-brain barrier in melanoma patients with brain metastasis. Ipilimumab at the approved dose and schedule has the same magnitude of benefit for those with and without brain metastases, with these subsets of patients showing similar 26% rates of 2-year overall survival.

How will ipilimumab and vemurafenib fit into the new approaches to melanoma therapy? To move our knowledge of how best to use new therapies, biomarkers of response and toxicity are needed.

Given early findings on vemurafenib-treated patients, it appears this drug offers immediate cyto-reduction and symptom relief and may be a bridge to other therapies including surgery, radiotherapy, or immunotherapy.

Vemurafenib may work best at achieving rapid tumor response and lowering tumor burden, at which time patients might switch to ipilimumab therapy. Alternatively, initial ipilimumab therapy may be more appropriate for patients with a low tumor burden and minimal symptoms if the goal is durable benefit. Definitive progression should trigger the switch from ipilimumab to vemurafenib.

Effective use of both agents will require experience and commitment to managing patient toxicities. We need a better handle on patient subsets, than has been reported to date, so we can identify which subsets will benefit from which therapies. We also need more information on optimal dosing and durations of therapy. Further, we need to evaluate the activity of these drugs against uveal and mucosal melanomas.

Some of this information may emerge from the EORTC trial of ipilimumab versus placebo and the ECOG trial of ipilimumab versus interferon, which is just starting.

Melanoma is a very smart cancer that, until recently, has eluded nearly all therapeutic efforts. Fortunately for oncology and our patients, in the words of Yogi Berra, "the future is not what it used to be" for treating melanoma.

Dr. Margolin is with the Fred Hutchinson Cancer Research Center at the University of Washington, Seattle. She reported no financial disclosures.


 

FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY

CHICAGO –More good news on ipilimumab for metastatic melanoma emerged from the results of a trial reported at the annual meeting of the American Society of Clinical Oncology.

In a double-blind, randomized, phase III study, nearly 21% of 250 metastatic melanoma patients who underwent first-line treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) in combination with dacarbazine were alive after 3 years, compared with 12% of 252 patients given placebo and dacarbazine, Dr. Jedd Wolchok reported during a plenary session at the meeting.

Overall survival was 11.2 months in the ipilimumab plus dacarbazine group and 9.1 months in the placebo plus dacarbazine group. The study was simultaneously published in the New England Journal of Medicine (2011 June 5;doi:10.1056/NEJMoa1104621).

A divergence in the survival curve was evident at 1 year, with 47% survival in the ipilimumab plus dacarbazine group, compared with 36% in the placebo plus dacarbazine group; at 2 years, the survival rates were 28% and 18%, respectively. The hazard ratio was 0.72, or 28% reduction in death.

At last year’s ASCO meeting, ipilimumab monotherapy was shown to prolong survival in previously treated metastatic melanoma patients. The drug was approved earlier this year as a first-line monotherapy treatment at a dosage of 3 mg/kg.

This is the first trial to show efficacy and safety of combining immunotherapy and chemotherapy in metastatic melanoma, said Dr. Wolchok of Memorial Sloan-Kettering Cancer Center, New York. The next step for ipilimumab combination therapy is to look to other combination therapies, such as the investigational agent vemurafenib (PLX4032), as well as other targeted agents and immune-modifying agents.

Dr. Wolchok cautioned that ipilimumab is approved only as a monotherapy and should only be used at the approved dose. Any use in combination therapy should be conducted as part of a clinical trial, several of which are ongoing or about to get underway.

In another plenary presentation at ASCO, Dr. Paul Chapman, also of Memorial Sloan-Kettering, reported a 63% reduction in risk of death with vemurafenib, compared with dacarbazine alone, in metastatic melanoma patients with BRAF mutations. Vemurafenib is an investigational oral drug that inhibits BRAF kinase.

In Dr. Wolchok’s study, progression-free survival was not significantly different between the two treatment groups. Ipilimumab, a monoclonal antibody that blocks CTLA-4 and augments T-cell activation, may improve survival by re-establishing an immuno-equilibrium that allows patients to survive despite the presence of tumors, he said. "The immune system is a ‘living drug,’ able to adapt itself to changes in the tumor ... overall survival is a more accurate way to gauge treatment effectiveness than progression-free survival."

In the trial, patients received either ipilimumab (10 mg/kg, three times per week for 4 weeks) plus dacarbazine (850 mg/m2, three times per week for 8 weeks) or placebo plus dacarbazine at the same dose and schedule. More than half of the patients in the study had MC1 disease.

Tumors were assessed at weeks 1, 12, and 24 in the protocol. For the maintenance therapy section of the trial, placebo or ipilimumab at 10 mg/kg once every 12 weeks was given until the disease progressed or patients had toxic effects.

Treatment discontinuations due to disease progression and adverse events were higher in the ipilimumab plus dacarbazine group; 92 patients received all four doses, compared with 165 patients in the placebo plus dacarbazine group.

Most discontinuations were due to disease progression, which occurred in 46% of the ipilimumab plus dacarbazine group and in 77% of the placebo plus dacarbazine group.

Of those who received at least one dose of therapy, 89 of 247 patients in the ipilimumab plus dacarbazine group and 10 of 251 patients given dacarbazine plus placebo discontinued. In the ipilimumab plus dacarbazine group, 85 of 247 discontinued after the induction phase because of a drug-related adverse event as did 10 of 251 in the placebo plus dacarbazine group.

After the maintenance dose, 4 of 43 in the dacarbazine plus ipilimumab group and none of the 53 in the placebo plus dacarbazine group discontinued therapy after receiving the maintenance dose.

The only treatment-related death occurred in the placebo plus dacarbazine group. Immune-related adverse events were seen in 78% of the ipilimumab plus dacarbazine group and in 38% of the placebo plus dacarbazine group. Grade 3 and 4 adverse events occurred in 38% of the ipilimumab plus dacarbazine group and in 4.4% of the placebo plus dacarbazine group. Liver function abnormalities were the most common immune-mediated adverse event. Most of the patients received steroids and their liver function normalized.

The study was funded by Bristol-Myers Squibb, the maker of ipilimumab. Dr. Wolchok is a consultant/advisor to Bristol-Myers Squibb.

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