September 25, 2009 (Berlin, Germany) — Effective treatment for metastatic malignant melanoma remains elusive, and it is almost invariably a fatal disease. However, 2 early studies, presented here at the 15th Congress of the European CanCer Organization (ECCO) and the 34th European Society for Medical Oncology Multidisciplinary Congress, show promise in improving survival.

Even though the data are preliminary, they are very encouraging, according to Alexander Eggermont, MD, PhD, president of ECCO. "It is safe to say that the last 30 randomized phase 3 trials have failed to have an impact on overall survival," he said during a press briefing that highlighted the studies.

There were a few trials that showed an impact on progression-free survival, but further study showed no impact on overall survival, he explained. "Therefore, progression-free survival in melanoma has not panned out to be a reliable target end point."

"What we have succeeded in doing in those 30 trials is to significantly increase toxicity," Dr. Eggermont added.

Bevacizumab Added to Combination Therapy

One of the new studies evaluated the efficacy and safety of adding bevacizumab (Avastin) to a combination regimen of carboplatin plus paclitaxel in treatment-naïve patients with stage IV melanoma. In this phase 2 trial, 214 patients were randomized in a 2:1 fashion (143 to the bevacizumab group, 71 to the control group) and stratified according to Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) (0 or 1) and disease stage (M1a/b or M1c).

This was a relatively small phase 2 study and the primary end point was progression-free survival, explained lead author Steven J. O'Day, MD, chief of research and director of the melanoma program at the Angeles Clinic and Research Institute in Los Angeles, California. "Even though there was a trend toward improvement in progression-free survival, the P value was not significant, and this has been consistent all along in our original analysis," he said. "There was no reason to update it because it was a mature end point."

Overall Survival Not Reached

An initial analysis of the overall survival data showed a significant benefit, but a follow-up analysis when more data were available failed to reach significance.

The initial analysis suggested that there was a survival benefit of more than 3 months, with a P value that was significant (P = .04). "It was very encouraging data and was a secondary end point of the study," said Dr. O'Day, adding that "the study was not powered to look at survival overall, as it was a relatively immature end point."

The researchers had planned to conduct a follow-up analysis on survival and that was completed immediately prior to the conference. The updated analysis did change the outcome in terms of the P value, Dr. O'Day explained. Although there continued to be a 3 month survival advantage for the group that received bevacizumab, the P value was still trending but was no longer significant (P = .19)

"These are still very encouraging data," Dr. O'Day emphasized, "because all of the efficacy parameters — progression-free survival, overall survival, response rate, stable disease at 6 months — are consistent in this trial and there's about a 20% improvement in all of them for patients who used bevacizumab."

"There are strong data that [show that] angiogenesis is a pivotal part of melanoma and there is already evidence that bevacizumab has improved survival in other diseases and in combination with other chemotherapeutic agents," he added. "I think that melanoma is an excellent prototype disease that's very vascular, and that these data will prompt a larger phase 3 study to prove its ability to improve survival."

Chris Twelves, MD, clinical director and professor of clinical cancer pharmacology and oncology at the Institute of Cancer Therapeutics in West Yorkshire, United Kingdom, pointed out that it is "worth remembering that the first study of bevacizumab in breast cancer showed encouraging trends but failed to meet a statistical threshold.

It took additional studies for the drug's value to be discovered. "The benefits were later confirmed in larger studies in slightly different settings," said Dr. Twelves, who moderated the press briefing.

Another issue is the high price of bevacizumab, and whether the cost is worth the modest benefits that are seen with the drug. This issue was highlighted in a recent study conducted by National Institutes of Health staff, as reported by Medscape Oncology.

Details of Bevacizumab Study

All patients received carboplatin (area under the curve = 5, maximum of 10 cycles) and paclitaxel (175 mg/m2), and those in the bevacizumab group received 15 mg/kg of the agent, administered intravenously on day 1, every 3 weeks. Evaluations for Response Evaluation Criteria in Solid Tumours (RECIST) were performed every 2 cycles, and progression-free survival was the primary end point. Secondary end points included overall survival, response rates, and safety.

The majority of patients within the cohort (73%) had M1c disease, and 54% of these had abnormal lactic acid dehydrogenase levels.

The researchers observed a trend toward benefit for progression-free survival among patients randomized to bevacizumab plus carboplatin/paclitaxel (5.6 vs 4.2 months; hazard ratio [HR], 0.78; = .14). The updated analysis for overall survival was no longer significant, but still showed a trend toward a benefit for bevacizumab (12.3 vs 9.2 months; HR, 0.79; P = .19).

The response rate was also higher among patients in the bevacizumab group (25.5% vs 16.4%; P = .16). Therapy was generally well tolerated, although there was a 2% or greater incidence of grade 3 to 5 adverse events observed among patients receiving bevacizumab. These included febrile neutropenia, neutropenia, peripheral neuropathy, pulmonary embolism, hypertension, anorexia, and musculoskeletal pain.

Novel Targeted Compound Shows High Response Rate

The other new study was a phase 1 extension trial of a novel oral selective inhibitor of the V600E mutant BRAF kinase, which is implicated in 60% of melanomas and 10% of colorectal cancers.

We also saw responses in bone and liver metastases, which almost never respond to chemotherapy.

"We have seen a response rate in 70% of the patients who have been evaluated to date," said study author Paul Chapman, MD, an attending physician on the melanoma/sarcoma service at Memorial Sloan-Kettering Cancer Center in New York City. "We also saw responses in bone and liver metastases, which almost never respond to chemotherapy."

In 1 case, he added, recalcification was observed in the affected bone, which is something that is not ordinarily seen.

PLX4032 is being codeveloped by Roche and Plexxikon, and the results of an initial dose-escalation study, which comprised 55 patients, were presented earlier this year at the meeting of the American Society of Clinical Oncology, and were reported by Medscape Oncology at that time.

The extension trial included 31 heavily pretreated melanoma patients with BRAF mutations (45% ECOG PS 0; 55% ECOG PS 1) who were treated with 960 mg of PLX4032 twice daily. To date, evaluable data are available for 27 patients.

Of this group, explained Dr. Chapman, 25 patients experienced some degree of tumor shrinkage. There have been 2 complete responses and 17 partial responses, but progression-free survival has not yet been reached. Responses to the agent have also been associated with resolution of symptoms.

Overall, PLX4032 was well tolerated, with adverse events including fatigue, arthralgias, photosensitivity, and rash. In addition, squamous cell carcinoma was seen in 23% of the patients. However, Dr. Twelves emphasized, this was not "swapping one cancer for another."

"Melanoma can be lethal, whereas squamous cell carcinomas are easily treated," he said. "They are generally a dermatologic event that can be easily excised."

A phase 2 trial of PLX4032 is scheduled to get underway soon in the United States and Australia, and a phase 3 trial is slated to start in December 2009 or in early 2010.

"Simply Spectacular"

Dr. Eggermont described the results of this early trial as "simply spectacular" and compared them with "imatinib with [gastrointestinal stromal tumors]."

"What's very encouraging is that the response rate in nonmutated melanoma is 0%, so we know exactly what we're doing," he said. "It's so specifically inhibiting that the side effect data are also very encouraging."

Dr. Eggermont added that "if I had a young talented medical oncologist in a cancer center, now I would have no reservations recommending that he [or she] become a melanoma specialist, because now it's an exciting field instead of a graveyard."

The studies were supported by Genentech (O'Day) and Roche (Chapman).

15th Congress of the European CanCer Organization (ECCO 15) and the 34th European Society for Medical Oncology (34th ESMO) Multidisciplinary Congress: Abstract 6BA, presented September 24, 2009; Abstract 23 LBA, presented September 23, 2009.


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