Promising New Agents and Treatment Failures in Melanoma

Zosia Chustecka

June 19, 2008

June 19, 2008 (Chicago, Illinois) — Therapy for melanoma is a "work in progress," but there is now a "significant glimmer of hope" for new drugs that are being investigated, commented Jeffrey Weber, MD, from the H. Lee Moffitt Cancer Center, in Tampa, Florida.

At a "highlights of the day" session here at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting, Dr. Weber reviewed positive new data from 3 phase 2 trials (with axitinib, OncoVEX, and ipilimumab), and highlighted negative results, including the failure of tremelimumab in a phase 3 study and the failure of a ganglioside GM2-KLH21 vaccine. All of the studies of drugs under development were sponsored by the manufacturers.

Very Impressive Results With Axitinib

Axitinib is an investigational agent under development by Pfizer, and phase 2 trials are currently underway for a number of cancer indications. Monotherapy with this compound, an oral potent and selective inhibitor of vascular endothelial growth-factor receptors 1, 2, and 3, has already shown preliminary evidence of activity in aggressive proangiogenic malignancies, such as metastatic renal cell carcinoma, the meeting heard. Axitinib has also shown activity in pancreatic and thyroid cancer, as previously reported by Medscape Oncology.

The data for melanoma come from a phase 2 trial of 32 patients presented by J.P. Fruehauf, from the University of California, Irvine, in Orange (abstract 9006). These patients, who had metastatic disease and had received only 1 or no previous therapy, were treated with single-agent axitinib starting at 5 mg twice daily. The most common adverse events were fatigue (in 62.5% of patients), hypertension (43.8%), hoarseness (34.4%), and diarrhea (31.3%); 1 patient had a grade 5 bowel perforation.

The objective response rate was 15.6% per investigator assessment, with a response duration ranging from 2.3 months to more than 10.2 months. Blood pressure was monitored regularly, and a preliminary analysis suggested that patients who had elevated blood pressure (diastolic blood pressure ≥90 mm Hg) while taking axitinib had a longer survival, Dr. Fruehauf commented. Median overall survival for the 13 patients who had elevated blood pressure was 13 months, compared with 6.2 months for the 9 patients who did not.

Although the sample was small, these results are "very impressive," Dr. Webber commented. "There were 6 bona fide responses, which is not bad for metastatic melanoma, and the product was well tolerated." Axitinib should be tested further in melanoma, he said.

Further Evaluation of OncoVEX Warranted

The responses to another investigation product, OncoVEX, are "worth a second look," Dr. Weber commented. It had an effect on distant lesions, both those that had been injected and those that had not. This product, under development by Biovex, is a second-generation oncolytic herpes-simplex-virus-encoding granulocyte macrophage colony-stimulating factor (GM-CSF). In addition to melanoma, it is also being investigated in head and neck, pancreatic, and colorectal cancer.

New results, presented by Neil Senzer, MD, from the Mary Crowley Medical Research Center, in Dallas, Texas (abstract 9008), come from a phase 2 trial of patients with unresectable stage 3c/4 melanoma who had 10 or fewer lesions that could be injected.

Of 42 evaluable patients, complete responses were seen in 6 patients (with 5 still ongoing) and partial responses were seen in 5 patients (with 4 still ongoing). "The rate and durability of response is impressive compared with other treatment options available to patients with advanced melanoma, particularly in the second-line/salvage therapy setting," Dr. Senzer and colleagues concluded. "Further evaluation is therefore warranted."

Biovex is planning a phase 3 trial of 306 melanoma patients. It is slated to begin in early 2009.

Enthusiasm for Immunotherapy with Ipilimumab

Dr. Weber was enthusiastic about the results seen so far with ipilimumab, under development by Bristol-Myers Squibb and Medarex. He pointed out that he presented 1 set of results himself (abstract 9010) and also disclosed that he shares ownership of a patent related to this drug with the manufacturers.

Ipilimumab is a monoclonal antibody directed against cytotoxic T–lymphocyte-associated antigen 4 (CTLA-4), which is found on T cells and is thought to play a critical role in regulating natural immune responses. It has been evaluated in 3 company-sponsored phase 2 studies, and initial results were announced by the manufacturers late last year. One of the studies (abstract 9021) did not meet its primary end point, which was to rule out a best objective response rate of less than 10%. Nevertheless, other data from the 3 studies suggested a clear dose-response effect and a unique pattern of responses, the companies said. After a meeting with the US Food and Drug Administration, at which the agency requested overall survival data, the companies announced that they will delay submission for approval; it will likely not happen before 2009.

Details from these 3 phase 2 studies, conducted in patients with unresectable stage 3 or 4 melanoma, were reported in a series of presentations:

  • Clinical activity (either objective response or stable disease) was seen in 27% of 155 patients; for these patients, the 1-year projected overall survival rate was 46.7 % (abstract 9021).

  • A statistically significant trend in 217 patients indicated an increase in best overall response rate with increasing dose (11% with the highest dose of 10 mg/kg; 4.2% with 3 mg/kg, and 0% with 0.3 mg/kg; P = .0015); the 1-year projected survival rate was 53.4% (abstract 9025).

  • The best overall response rate in 115 patients was 15% with ipilimumab alone and 12.1% with ipilimumab plus budesonide (added as a prophylactic to reduce the incidence of diarrhea); the 1-year projected survival rate was 59.1% (abstract 9010).

These data are "particularly important when you consider that the recent medical literature reports a median overall survival of 6 to 9 months, and a 1-year survival rate of 25% to 35% for patients with stage 3 or 4 metastatic melanoma," commented Steven O'Day, MD, from the Angeles Clinic and Research Institute, in Santa Monica, California, and presenter of abstract 9021.

"These data are pretty impressive," Dr. Weber commented, and the 1-year survival is "as good as it gets in melanoma." Dr. Weber also noted that patients showed a pattern of responses that has never been seen before: some patients have slow regression of old lesions and then develop new lesions, which then shrink; some patients show a slow regression over a long period, with a partial response at 6 months; and some patients show progression of disease followed by regression.

"Ipilimumab involves immune activation that begins early and builds an immune response over time," commented Steven Hodi, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts. He presented the results of a study that proposed novel efficacy criteria for antitumor activity with immunotherapy (abstract 3008). "The ipilimumab data show patterns of response that are different from conventional chemotherapy and underscore the need for criteria that more accurately describe clinical activity and long-term benefit," he said in a statement.

A phase 3 trial of melanoma comparing dacarbazine alone with combination ipilimumab and dacarbazine is currently in progress, and trials of several other cancers are also being conducted.

Similar Product Failed in Phase 3 Trial

However, a phase 3 trial of advanced melanoma with tremelimumab, a product similar to ipilimumab, under development by Pfizer, failed (abstract LBA9011). "Sad to say, this was a negative trial," Dr. Weber commented.

There is a very small difference between the 2 products — both are fully human monoclonal antibodies directed against CTLA-4, but ipilimumab is an immunoglobulin (Ig)G1 isotype and tremelimumab is an IgG2 isotype. Some commentators have said that the failure of tremelimumab in this phase 3 trial does not bode well for the future of ipilimumab. However, Dr. Weber told Medscape Oncology that the tremelimumab findings might have been the result of the dosing, scheduling, and trial design, and alternative dosing, scheduling, and trial designs might have led to a successful trial. "Thus, I do not feel that the tremelimumab results spell trouble for ipilimumab," he said.

The failed phase 3 study involved 655 patients with unresectable stage 3 or 4 melanoma who were treated with either tremelimumab or chemotherapy (either temozolomide or dacarbazine). It was stopped early, after a second interim analysis. The median overall survival was 11.8 months with tremelimumab and 10.7 months with chemotherapy (hazard ratio, 1.05; P = .679).

"Tremelimumab as a single agent failed to demonstrate an improvement in overall survival as a first-line treatment in patients with metastatic melanoma when compared with standard therapy," the researchers concluded.

In April 2008, Pfizer announced the top-line result from this trial; at that time, the outcome was disappointing. "We will continue to assess the study data to understand the clinical benefit seen in some patients who received tremelimumab," the company said. Studies of the product, alone and in combination with other therapies, are continuing in several other cancers.

Vaccination Approach Has Failed

A vaccination approach to melanoma also failed. A second interim analysis from the EORTC 18961 trial "emphasizes the negative results," Dr. Weber commented, and "raises significant concerns about vaccination for melanoma and for cancer in general."

EORTC 18961 is the largest adjuvant phase 3 trial to date conducted in stage 2 melanoma (1314 patients), and had no commercial sponsor. The product, a ganglioside GM2-KLH21 vaccine, is directed against cell-surface gangliosides that are often overexpressed in malignant melanoma.

The latest results from EORTC 18961 were presented by Alexander Eggermont, MD, PhD, from the Erasmus University Medical Center, in Rotterdam, the Netherlands (abstract 9004). All patients underwent surgery, and those randomized to treatment received the vaccine subcutaneously once weekly for the first 4 weeks, then every 3 months for the first 2 years (starting at week 12), and then every 6 months during the third year (for a total of 14 vaccinations).

The primary end point was relapse-free survival, and the second interim analysis was performed after 267 events were reported (67% of events required for final analysis). The median follow-up was 1.8 years. There was no difference in relapse-free survival between the 2 groups (135 events with vaccination vs 132 events with observation), although distant-metastasis-free survival was worse in the treated group (86 events with vaccination vs 65 events with observation; stratified hazard ratio, 1.32; P = .10).

However, the results for overall survival showed that "patients on the vaccine clearly did worse than those followed with observation," Dr. Webber commented. The stratified hazard ratio was 1.66 (P = .02), with 56 deaths in the vaccination group and 35 deaths in the observation group.

The results for distant-metastasis-free survival and overall survival point in the direction of a detrimental effect of the vaccine, Dr. Eggermont and colleagues commented. "Adjuvant GM2-KLH21 vaccination is ineffective and could even be detrimental in stage 2 melanoma patients," they concluded. The trial has been stopped, with no more vaccinations administered; all patients will continue to be followed.

Thalidomide Plus Temozolomide Should Not be Used as Standard

Another negative result highlighted by Dr. Weber comes from the Southwest Oncology Group SO508 trial, reported by John Clark, MD, from Loyola University, in Chicago, Illinois (abstract 9007). This phase 2 study of 64 patients with metastatic malignant melanoma (MMM) found that the addition of thalidomide to temozolomide results in "little clinically meaningful activity" over temozolomide alone.

Dr. Clark explained that this large multicenter study aimed to better define the clinical efficacy of the combination. Previous single-institution phase 2 studies have yielded response rates of up to 32% with the combination, and have led some physicians to start using this combination as standard therapy. However, the SO508 trial yielded a response rate of 14%, and all the responses were partial, he pointed out. When the results are compared with a recent meta-analysis of temozolomide alone in MMN, the combination fares poorly, he concluded; hence, the combination should not be considered a standard treatment for MMN.

Dr. Weber echoed these conclusions.Although the combination of thalidomide and temozolomide is being used in the community, these results suggest that it should not be considered standard therapy and that it is not worth studying further, he said.

American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstracts 9006, 9008, 9010, 9021, 9025, LBA9011, 9004, and 9007. Presented June 1, 2008. Abstract 3008. Presented May 31, 2008.

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