Addressing the Key Clinical Questions in Advanced Melanoma 

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This is a brave new world of immunotherapy. Using anti-PD-1/PD-L1 with ipilimumab in combination will improve this even further.

—Steven J. O’Day, MD

At the 3rd Annual World Cutaneous Malignancies Congress, in La Jolla, California, Steven J. O’Day, MD, Director of Clinical Research at the Beverly Hills Cancer Center and Adjunct Member of the John Wayne Cancer Institute, Los Angeles, addressed what he labeled the “key clinical questions” about metastatic melanoma in 2013.

More Complex Decisions

“In the treatment of advanced melanoma, decision-making in the community is becoming more complex,” Dr. O’Day noted. “Conventional therapies have largely been ineffective. However, surgery remains an option for a subgroup of stage IV patients, high-dose interleukin (IL)-2 [Proleukin] can still cure select patients, and there is still a limited role for chemotherapy and biochemotherapy, primarily as a bridge to more effective treatments in patients with fast-growing disease.”

But now, with the availability of immunotherapy and targeted agents, the focus has shifted to the optimal use of these compounds in the clinic. These drugs currently include (1) targeted T-cell immunotherapy with the anti-CTLA4 agent ipilimumab (Yervoy) and the anti-PD-1 and anti-PD-L1 agents in clinical trials (nivolumab, lambrolizumab, MPDL3280A), and (2) targeted cancer cell pathway inhibitors, including BRAF inhibitors (vemurafenib [Zelboraf], dabrafenib [Tafinlar]), MEK inhibitors (trametinib [Mekinist]), and their combination.

In the application of these effective agents, Dr. O’Day said he considers the patient’s disease biology and metastatic presentation, molecular profile, involvement of the central nervous system, age, comorbidities, personal preferences, and goals of care, in an effort to truly personalize treatment.

Ipilimumab vs Vemurafenib

Ipilimumab exerts a large benefit in a small subset of patients and often achieves durable disease control, but kinetically is associated with a slow response (3–6 months) and carries autoimmune toxicity (though side effects are responsive to steroids). Approximately half of treated patients are alive at 1 year, and about one-third are alive at 2 years.

“It is remarkable that blocking one important brake to the immune system gives long-term survival to one in four patients with widespread metastases,” he noted. He said the investigational anti-PD-1/PD-L1 agents will produce a more rapid response and will also be a less toxic form of immunotherapy.

Vemurafenib and dabrafenib, on the other hand, exert a large benefit in almost 90% of BRAF-mutated patients and response occurs within days or weeks, but relapse is nearly uniform about 6 months after treatment initiation. Toxicity involves the skin and joints, and constitutional symptoms are not uncommon.

The mechanism of resistance to BRAF inhibitors seems to be predominantly through MAP kinase reactivation. Therefore, the goal of blocking MEK with an oral agent “was an obvious choice,” he said. The MEK inhibitor trametinib has single-agent activity, though it is less than is seen with the BRAF inhibitors; its toxicity profile is probably less favorable, he added.

BRAF-Mutated vs Wild-Type

In patients with BRAF-mutated disease, the questions to be answered include whether to start with an immunotherapeutic or targeted agent, how long to use targeted therapy once initiated, and whether to sequence or combine targeted agents and immunotherapy. In BRAF wild-type patients, the oncologist needs to determine if a rapid response is needed; if not, the question is whether to incorporate high-dose IL-2/adoptive cell therapy or move directly to ipilimumab therapy, he said.

Dr. O’Day emphasized that while the BRAF inhibitors elicit a rapid response, the response is less durable than can be achieved with the anti-CTLA4 agents, eg, ipilimumab, though response to ipilimumab can be slow. Due to the possibility of gaining a durable remission, bridging patients to immunotherapy is an important goal, he said.

“I tend to reserve targeted treatment for patients who need a rapid response, with the goal of transitioning them to ipilimumab. And when I choose a targeted treatment, I am also now shifting to a BRAF/MEK inhibitor combination,” he said.

Regardless of BRAF mutation status, there remains a need to identify the best way of targeting brain lesions and incorporating this treatment into the protocol, he said.

‘Triple-Negative’ Melanoma

For the patient whose tumor does not have mutations in BRAF, or even c-KIT (for which a drug such as imatinib [Gleevec] might be effective) or NRAS (for which a clinical trial might be appropriate), he decides between immunotherapy (ipilimumab or high-dose IL-2, possibly with adoptive cell therapy) or enrollment in a clinical trial of a front-line anti-PD-1/PDL-1 agent.

“The challenge in this group is the patient who presents very aggressively and may not be eligible for a trial,” he said. “It’s about how to bridge the patient for whom the kinetics of response to a drug won’t allow 3 to 6 months of waiting.”

Bridging therapies include carboplatin/paclitaxel, paclitaxel/bevacizumab (Avastin)—perhaps with carboplatin—or biochemotherapy. Chemotherapy can work well in the short run, but the patient must ultimately be transitioned to immunotherapy.

Treatment in the Near Future

The approval of the anti-PD-1/PD-L1 agents is highly anticipated, and these clinical trials are a high priority. Studies are evaluating various schedules of PD-1 antibodies compared with or in combination with ipilimumab. In a phase I trial, patients receiving the anti-PD-1 agent nivolumab had a median overall survival of almost 17 months, 1-year survival rate of 63%, and 2-year survival of 43%.1

Similarly, lambrolizumab, which recently received “breakthrough therapy” status from the FDA, had a median progression-free survival exceeding 7 months, and at 11 months, 81% of responders were still on treatment.2 Importantly, efficacy and safety were comparable between patients who had previously received ipilimumab and those naive to immunotherapy.

The tumor control rate exceeds 50%, and the kinetics of response are better (1–3 months) with the anti-PD-1/PD-L1 agents, which makes them similar to the BRAF inhibitors, but with “remarkable” durability of disease control and less immune-related toxicity. Dr. O’Day predicted, therefore, that these drugs will “change the landscape” of advanced melanoma. “This is a brave new world of immunotherapy,” he commented. “Using anti-PD-1/PD-L1 with ipilimumab in combination will improve this even further.” ■

Disclosure: Dr. O’Day reported no potential conflicts of interest.


1. Topalian SL, Sznol M, Brahmer JR, et al: Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial. 2013 ASCO Annual Meeting. Abstract 3002. Presented June 3, 2013.

2. Ribas A, Robert C, Daud A, et al: Clinical efficacy and safety of lambrolizumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9009. Presented June 1, 2013.