How Do Melanoma Experts Use the New Agents?

Caroline Helwick

Immunotherapy

Melanoma experts gathered at the second annual World Cutaneous Malignancies Congress to debate the optimal means of treating melanoma using the new agents and to share predictions about the future treatment landscape in metastatic melanoma. Their insights are shared in this report.

Metastatic Melanoma: Which Drug First?

Despite excitement over the robust responses observed with the BRAF inhibitors, the lack of durability of response (ie, the development of resistance) has dampened enthusiasm for them, according to speakers at this meeting. For this reason, immunotherapy is becoming the clinicians’ first choice for initiating treatment in many cases, but treatment should always be personalized, they said.

Mario Sznol, MD, professor of medicine at Yale University School of Medicine, indicated that he often starts patients on the anti–CTLA-4 antibody ipilimumab, to which patients slowly build an immune response over 3 to 6 months but, once responding, often maintain this response long-term. The overall survival rate is approximately 50% after treatment with ipilimumab.

“With ipilimumab you get durable remissions, but you need time to get there. For patients progressing or declining rapidly, and for those with poor performance status, it’s not the drug to use first,” he said.

These patients, if they have BRAF-mutated tumors, will typically receive a BRAF inhibitor, but even in this case, “we have taken the strategy that once we get them to their best response, we stop the targeted therapy and start ipilimumab,” he added.

Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles, took a more flexible position. “I agree that the majority of patients pro­gress on BRAF inhibitors, but not all. If a patient comes in even with a small-volume indolent tumor, I may start with a BRAF inhibitor because the patient may want quick response for personal reasons. If we only use BRAF inhibitors in the worst cases and assume we are only getting temporary benefit, then we are failing to get the full spectrum of benefit of these drugs,” he offered.

Steven O’Day, MD, director of the Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center, emphasized that with so much speculation, long-term follow-up is greatly needed. “The follow-up on the BRAF inhibitors is much shorter than for immunotherapy, where the data are more mature. But at the same time, there is a tremendous impression that immunotherapy only works in small-volume, indolent disease. What really matters is the kinetics of response to ipilimumab: if the patient has 2 to 3 months to live, he or she cannot possibly benefit from a drug that takes 3 to 6 months to work.”

While an ASCO 2013 study showed that the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to ipilimumab improved overall survival and reduced toxicity, the panelists were not ready to act on these findings. “I am not quite ready to give GM-CSF. It’s expensive, and it’s a tedious injection process. Although this is a strong signal we need to follow up on, I would like to see more data,” O’Day commented.

Combination Therapy

Sznol said he is increasingly using a BRAF inhibitor combined with a MEK inhibitor (trametinib), which greatly reduces the toxicity of vemurafenib and da­brafenib. “With vemurafenib alone, lots of patients feel bad. I would much rather give both drugs. We have been doing that successfully, just based on toxicity issues and the reduced risk of secondary skin cancers,” he said.

O’Day agreed on the value of combining the 2 targeted agents. “The last thing you want is for your patient to progress on monotherapy. You can’t predict that,” he said.

Jeffrey Sossman, MD, professor of medicine and director of the Melanoma and Tumor Immunotherapy Program at Vanderbilt-Ingram Cancer Center, weighed in. “Right now, there is no indication for combination therapy. The combination does have some efficacy with regard to side effects, but there is just a few months’ benefit in PFS [progression-free survival], not an overall survival benefit,” he said.
He added that for the patient progressing after a long response on a BRAF inhibitor, the addition of a MEK inhibitor could be advantageous.

Sossman further pointed out that while the combination of a BRAF and MEK inhibitor can reduce the side effects associated with vemurafenib, the combination of trametinib plus dabrafenib can actually increase fever and chills versus dabrafenib alone.

“Dabrafenib does not cause the photosensitivity we see with vemurafenib, and this is important, but it does cause fever and chills, and if you add trametinib these go up dramatically. About 60% to 70% of patients have significant fever and chills [with the combination],” he said. He predicted that while the combination may become the standard, “it is not clear that all patients or even any patient should get this up front.”

According to Ribas, one advantage of the combination is durability of response. “There is no doubt that with the combination there are patients with durable responses. The question is whether the targeted therapies can be discontinued and have patients remain in remission,” he said. “That may be the difference between this approach and immunotherapy. With immune treatment, I think we can discontinue the drugs. I would like to see a trial in which patients are taken off these drugs and have complete responses maintained. That would be important information.”

The Anti–PD-1/PD-L1 Drugs Will Change the Landscape

The speakers agreed that the landscape is about to change, thanks to antibody-mediated blockade of the programmed death 1 protein (PD-1) and its ligand (PD-L1). The anti–PD-1/PD-L1 monoclonal antibodies elicited excitement at the 2013 ASCO Annual Meeting, and speakers at this meeting said clinical trials of these compounds were a high priority.

In phase 1 studies reported at ASCO, nivolumab paired with ipilimumab produced responses in 40% of heavily pretreated patients and led to durable responses in the vast majority, while responses to MPDL3280A were observed in 21% of refractory patients (36% of those staining positive for PD-1).
The possibility of using these agents in combination with other melanoma drugs holds great promise, according to the specialists, though the trade-off may be an increase in toxicity. “With the combination of nivolu­mab and ipilimumab, without question we have seen a higher incidence of toxicity, but it was qualitatively similar to ipilimumab alone,” said Sznol, who led the phase 1 trial of nivolumab presented at ASCO 2013. “I think if the combination is a better regimen, then the toxicity is worth it to obtain a better outcome.”

He emphasized that randomized trials must be done to evaluate such combinations. “I still don’t know if nivolumab/ipilimumab is better than nivolumab alone, or better than lambrolizumab alone,” Sznol continued. “However, the impression is that with large-bulk, rapidly progressive disease, with the combination we are seeing responses within a period of weeks.”

Ribas commented, “The data on nivolumab/ipilimumab are so impressive, it’s hard to believe either drug alone is as good. But I agree that we must be careful about comparing small studies.”

Sznol further noted that one particular anti–PD-1/PD-L1 agent has not been shown to be superior to another, and that the study populations have not been completely comparable. “At the end of the day,” he said, “we always need randomized trials.”

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