Metastatic Melanoma: Encouraging Data Keep Coming 

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Grant McArthur, MD

James Larkin, MD, PhD

Mario Sznol, MD

F. Stephen Hodi, MD

Howard Kaufman, MD

Excitement continues to build in the metastatic melanoma arena, as novel agents keep upping the ante for efficacy. The following news from the 2013 European Cancer Congress has added to the buzz.

New MEK Inhibitor

In the phase IB BRIM7 study, cobimetinib, a novel MEK inhibitor, when combined with vemurafenib (Zelboraf), showed strong antitumor activity in melanoma patients not previously treated with a BRAF inhibitor, reported Grant McArthur, MD, of the Peter MacCallum Cancer Centre in Victoria, Australia.1

Acquired resistance to vemurafenib frequently results in MAPK reactivation through MEK. Combined MEK and BRAF inhibition can overcome or delay acquired resistance, and for this reason, combinations of BRAF and MEK inhibitors are of interest.

BRIM7 evaluated the safety, tolerability, dose-limiting toxicities, and maximum tolerated dose of cobimetinib, and its efficacy in 65 patients who had disease progression on vemurafenib and 63 patients not previously treated with a BRAF inhibitor. Patients in the dose-escalation portion received vemurafenib at 720 mg or 960 mg twice daily, continuously, and cobimetinib at 60, 80, or 100 mg daily for 14 days on, 14 days off (14/14); 21 days on and 7 days off (21/7), or continuously. Two dose levels were expanded: vemurafenib at 720 mg and 960 mg twice daily plus cobimetinib at 60 mg/d (21/7).

Overall, 53 of 63 BRAF inhibitor–naive patients responded to this combination, with an objective response rate of 85%, including 6 (10%) complete responses. Another 8 (13%) had stable disease. Only 2 patients (3%) had disease progression while on the combination.

“Most responses occurred by the first tumor assessment,” he said, “and median progression-free survival was not reached, despite a median follow-up time of 10 months.”

Of 61 patients whose disease had progressed on vemurafenib, 9 (15%) responded and 26 (43%) had stable disease on the combination. After 3 months’ follow-up, median progression-free survival was 2.8 months. “Antitumor activity of the combination in ‘vemurafenib progressors’ is modest, and investigations are ongoing to identify a subpopulation that may benefit from cobimetinib plus vemurafenib after progression on vemurafenib monotherapy,” he said.

Four patients experienced dose-limiting toxicities, including grade 3 fatigue, QT prolongation, mucositis, and arthralgia. The most common treatment-related adverse events of grade ≥ 3, regardless of treatment assignment, were non-acneiform rash, diarrhea, photosensitivity, and liver abnormalities (7%–19%). Grade ≥ 3 squamous cell carcinoma/keratoacanthoma was observed in four patients (6%). Diarrhea was common, affecting 81% of the BRAF inhibitor–naive patients, with grade ≥ 3 noted in 8%.

Toxicity Differences vs Other Regimens

Commenting on the cobimetinib/vemurafenib combination, James
Larkin, MD, PhD
, of the Royal Marsden Hospital in London, said, “There is encouraging efficacy in the BRAF inhibitor–naive population and limited efficacy in BRAF inhibitor–pretreated population,” but beyond this observation, “further comments on efficacy are not possible,” he said.

He did note that there appear to be some differences between the cobimetinib/vemurafenib regimen and the regimen of dabrafenib (Tafinlar)/trametinib (Mekinist) in terms of toxicity, “though the data are very early, so caution is necessary.”

Dr. Larkin added, “I would distinguish toxicity that is generally easier to manage, such as diarrhea, from that which is more difficult to manage, such as fever/chills and skin toxicity,” he said. “The main differences appear to be the incidence of fever/chills with dabrafenib/trametinib and skin toxicity with vemurafenib/cobimetinib.”

With vemurafenib/cobimetinib, acneiform rash (all grades) was observed in 33%, non-acneiform rash in 89%, and photosensitivity and sunburn in 70%; grade ≥ 3 side effects were seen in 3%, 13%, and 0%, respectively. The vemurafenib/cobimetinib combination is currently being evaluated in a phase III trial.

Nivolumab Plus Ipilimumab

Mario Sznol, MD, of Yale University School of Medicine, New Haven, presented early results for combined immunotherapy with the anti–PD-1 agent nivolumab and ipilimumab (Yervoy), reporting the combination to have “a manageable safety profile and clinical activity that appears distinct from published monotherapy data.”2

In the phase I study of 86 stage III and IV melanoma patients, 53 received concurrent treatment and 33 received sequential treatment, first with nivolumab and then with ipilimumab. In the concurrent cohorts, 38% had received prior treatment, whereas 100 % of the sequential cohort was previously treated.

The overall response rate for the concurrent cohort was 40%, and 31% of patients had ≥ 80% tumor reduction at 12 weeks. Overall survival at 1 year was 82%.

“In the concurrent cohort, for the 21 patients with confirmed objective responses, responses ranged from 6-plus to 72-plus weeks at the time of data analyses. A total of 19 of the 21 responding patients had ongoing responses,” Dr. Sznol noted. “Objective responses were observed in patients irrespective of absolute lymphocyte count or baseline tumor PD-L1 expression.”

Clinical activity of nivolumab/ipilimumab was much less pronounced in the sequential cohort, of whom 20% responded, and 13% had ≥ 80% tumor reduction at 12 weeks.

“Based on these results, a phase III trial is open to investigate the efficacy of concurrent nivolumab plus ipilimumab vs nivolumab and vs ipilimumab in patients with advanced melanoma.

Long-Term Survival With Ipilimumab

In the largest survival analysis of the CTLA-4 monoclonal antibody to date, melanoma patients receiving ipilimumab in phase II and III clinical trials had a median overall survival of 11.4 months, and 22% of patients were alive at 3 years, reported F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston.3

The pooled analysis included 1,861 patients from 12 prospective and retrospective trials, and an additional 2,985 patients who were treated with ipilimumab outside of a clinical trial in the expanded access program. The findings are the most precise estimate yet of the benefit of ipilimumab, Dr. Hodi said.

T-VEC Oncolytic Virus

A phase III trial of talimogene laherparepvec (T-VEC) met its primary and secondary endpoints, producing durable responses in 16% of melanoma patients who received the injections, reported Howard Kaufman, MD, of Rush University Medical Center, Chicago.4 “T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III trial,” he said.

T-VEC is a novel oncolytic immunotherapy derived from the herpes simplex virus type-1, designed to selectively replicate within tumors and produce endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance locoregional and systemic antitumor immune responses.

The phase III OPTiM study included 436 patients with stage III/IV melanoma randomly assigned 2:1 to T-VEC or recombinant GM-CSF (Leukine), which was injected into cutaneous, subcutaneous, or nodal lesions every 2 weeks for 24 weeks. There were no limits on number of lesions injected per visit; precedence was given to new lesions, then larger lesions.

The primary endpoint, durable response rate per endpoint assessment committee, was met, as were secondary endpoints. Durable responses (≥ 6 months) were observed in 16.3% of the T-VEC group vs 2.1% of the GM-CSF group, for an unadjusted odds ratio of 8.9 (P < .0001). Objective response rates were 26.4% and 5.7%, respectively. About half the responders exhibited interval progression before achieving a response.

The interim analysis found median overall survival to be 23.3 months with T-VEC and 19.0 months with GM-CSF—a nonsignificant trend favoring the vaccine (hazard ratio [HR] = 0.79; P = .07). At 3 years, overall survival rates were 40.6% and 27.8%, respectively.

“T-VEC significantly improved both durable response rates and objective response rates vs GM-CSF in patients with unresected stage IIIB/IV melanoma with limited visceral disease, both by investigator and independent central review, Dr. Kaufman reported. “Responses occurred as early as 1.2 months and as late as 16.9 months, with a median of 4.1 months after the first dose. Median duration of response was not reached in the T-VEC arm, with the majority of responders still in response as of the last tumor assessment.” ■

Disclosure: Drs. McArthur, Larkin, Sznol, Hodi, and Kaufman reported no potential conflicts of interest.


1. McArthur G, Gonzalez R, Paulick A, et al: Vemurafenib and MEK inhibitor, cobimetinib (GDC-0973) in advanced BRAF V600-mutated melanoma (BRIM7): Dose-escalation and expansion results of a phase IB study. 2013 European Cancer Congress. Abstract 3703. Presented September 28, 2013.

2. Sznol M, Callahan MK, Kluger H, et al: Combined nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab in the treatment of advanced melanoma patients: Safety and clinical activity. 2013 European Cancer Congress. Abstract 3734. Presented September 30, 2013.

3. Schadendorf D, Hodi FS, Robert C, et al: Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. 2013 European Cancer Congress. Abstract LBA24. Presented September 28, 2013.

4. Kaufman H, Andtbacka RHIU, Harrington K, et al: Secondary endpoints from OPTiM: A multicenter, randomized phase 3 trial of talimogene laherparepvec vs GM-CSF for the treatment of unresected stage IIIB/C and IV melanoma. 2013 European Cancer Congress. Abstract 3733. Presented September 30, 2013.