Two Studies Herald New Era in Melanoma Therapy

New treatment approaches that improve overall survival for patients with late-stage melanoma were spotlighted at the ASCO annual meeting Sunday, with the presentation of dramatic data from separate clinical trials involving the BRAF inhibitor vemurafenib (PLX4032) and first-line use of ipilimumab (Yervoy) immunotherapy.

The studies were presented at a plenary session amid news that the 2 pharmaceutical rivals developing the drugs will work together on a combination trial.

“This is really an unprecedented time for celebration for our patients…it brings unprecedented hope and a pace of discovery that leads to effective therapies,” declared Lynn M. Schuchter, MD, division chief of hematology-oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, as she co-moderated a press briefing where trial results were discussed.

Like other clinicians, Schuchter recalled the paucity of therapies available for patients with melanoma when she started practicing 25 years ago.

The prognosis for advanced melanoma, the most deadly form of skin cancer, remains grim. In late-stage disease, the average survival rate is 6 months, with a 1-year mortality rate of 75%, according to Bristol-Myers Squibb, which is developing ipilimumab.

The 2 studies involve different types of therapy. Vemurafenib targets mutations in the BRAF gene, while ipilimumab, a human monoclonal antibody, releases a braking mechanism on tumor-fighting T cells.

On Thursday, Bristol-Myers Squibb and Roche, which is investigating vemurafenib, announced they have agreed to jointly conduct a phase I/II study to evaluate the 2 agents in combination.

The companies drew praise from oncologists for the cooperative effort.

“These two medicines have very different mechanisms of action that complement each other quite nicely,” Jedd D. Wolchok, MD, director of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center in New York, said at a press briefing.

“It’s very inspiring to us as investigators and patient advocates that these two companies chose a time when both medicines were actually still investigational to collaborate for the best interest of patients,” he said.

Front-Line Use of Ipilimumab Supported

Just 10 weeks ago, ipilimumab became the first drug the FDA ever approved that demonstrated the ability to prolong the lives of patients with unresectable or metastatic melanoma.

Now, the results of a randomized, phase III study of ipilimumab in combination with the standard chemotherapy drug dacarbazine (DTIC) in patients with previously untreated late-stage melanoma support its use as first-line therapy.

Called study 024, the trial involved 502 patients who were randomized to receive ipilimumab plus DTIC or placebo plus DTIC. The 10 mg/kg-dose of ipilimumab was higher than that used in the trial that led to the drug’s March 25 approval, said Wolchok, lead author of the study.

In the ipilimumab arm, overall survival rates were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years. By contrast, overall survival rates in the DTIC-alone arm were 36.3%, 17.9% at 2 years, and 12.2% at 3 years.

The median overall survival for those treated with ipilimumab was 11.2 months versus 9.1 months in the DTIC-alone arm.

Ipilimumab, which was approved with the requirement that a risk evaluation and mitigation strategy be implemented, continued to be associated with adverse events (AEs). Bristol-Myers Squibb reported that 56% of patients in the ipilimumab arm experienced grades 3/4 AEs, as opposed to 28% in the DTIC-alone arm.

The most commonly reported AEs included alanine transaminase elevation, aspartate transaminase elevation, diarrhea, pruritis, and rash.

Wolchok said the latest results suggest future paths of inquiry.

“These results form the foundation for the development of combination regimens in the future and we really look forward to pursuing those studies,” he said.

BRAF Inhibitor Nears FDA Approval

BRAF mutations are present in 40%-60% of melanomas. The mutations typically involve the substitution of glutamic acid for valine at position 600 and are known as “V600E” mutations.

Vemurafenib prevents BRAF mutations from activating the MAP kinase signaling pathway, leading to decreased cell growth and the death of melanoma cells.

A phase I trial of vemurafenib presented at ASCO in 2009 demonstrated significant responses in patients with metastatic melanoma. Vemurafenib had a 53% response rate in patients with metastatic melanoma in a phase II study of vemurafenib, which was presented at this year’s ASCO meeting on Saturday.

On Sunday, lead author Paul B. Chapman, MD, Memorial Sloan-Kettering Cancer Center, presented the phase III vemurafenib results. The non-blinded trial randomized 675 patients with previously untreated, metastatic melanoma and a V600E BRAF mutation to either oral vemurafenib or intravenous DTIC.

At a planned interim analysis at median 3 months, the hazard ratio (HR) for overall survival favored vemurafenib at 0.37, (95% confidence interval [CI], 0.26-0.55; P <.0001), meaning patients receiving the treatment had a 63% lower risk of death than the DTIC arm.

The vemurafenib cohort was also 74% (HR, 0.26; 95% CI, 0.20-0.33; P <.0001) less likely to experience disease progression than patients receiving DTIC. The estimated median progression-free survival was 5.3 months with vemurafenib versus 1.6 months for the DTIC group.

The response rates were 48.4% and 5.5% for the vemurafenib and DTIC arms, respectively.

Based on the positive data, an independent panel recommended that patients receiving DTIC cross over to vemurafenib.

Toxicity levels higher than grade 3 were experienced in less than 10% of patients in the vemurafenib cohort. Approximately 18% of patients developed non-melanoma skin tumors, including skin papilloma, keratoacanthoma, and cutaneous squamous cell cancers. A dermatologist can excise these tumors when they are detected early.

“Discontinuation due to adverse events was uncommon, occurring in only 6% of vemurafenib patients and 4% of DTIC patients,” said Chapman.

Chapman predicted that the phase III results will convince the FDA to approve vemurafenib because “the magnitude of difference in survival that we have seen is unprecedented in oncology trials.”

Chapman PB, Hauschild A, Robert C. Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma. J Clin Oncol. 2011. (suppl; abstr LBA4).

Wolchok JD, Thomas L, Bondarenko N, et al. Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) vs DTIC alone as first line treatment in patients with unresectable stage III or IV melanoma. J Clin Oncol. 2011. (suppl; abstr LBA5).