Robert H.I. Andtbacka, MD, CM
The number of treatment options for advanced melanoma continues to increase steadily. Since March 2011, when ipilimumab (Yervoy) was the first new drug approved by the FDA for melanoma in 13 years, many agents and combination therapies have come to market or received expanded indications or other label changes (Table
Many other treatments continue to show promise in clinical trials. Yet despite significant developments on the advanced melanoma treatment front, “many clinical scenarios remain where there is no clear-cut course of action,” said Robert H.I. Andtbacka, MD, CM, during a recent OncLive
During the Peer Exchange, Andtbacka used 3 case scenarios to lead a panel of melanoma experts in a discussion of some of the key challenges impacting clinical practice today. The cases consisted of an elderly adult with newly diagnosed BRAF
wild-type stage IV melanoma, a patient with BRAF
-mutant stage IV melanoma, and a patient with recurrent disease after resection.
A key area of discussion for this case scenario focused on molecular testing. In addition to testing for BRAF
, the mutational status of 2 other genes were noted to be of potential interest: NRAS
and the c-Kit
is the second most common oncogenic mutation we see in cutaneous melanoma patients, and, in part, it’s because the NRAS
V600 mutations are mutually exclusive. Seeing an NRAS
mutation increases our confidence in the specificity and accuracy of a wild-type BRAF
test,” said Michael A. Davies, MD, PhD. Although these mutations are “quite rare,” he explained that his interest in testing for these mutations stems from an availability of clinical trials for patients with NRAS
mutations and clinical evidence that patients with KIT
mutations, which occur more commonly with mucosal melanomas, can benefit from treatment with KIT inhibitors.
More evidence and standardization are needed, however, before NRAS
mutations become routine testing targets in clinical practice. The panelists noted the same to be true for PD-L1 expression testing. “In melanoma, nivolumab and pembrolizumab do not require testing for PD-L1 expression,” said Antoni Ribas, MD, PhD, whereas initiation of BRAF/MEK inhibitor therapy requires BRAF
V600E or V600K testing, he explained. Furthermore, although PD-L1 expression has been associated with treatment response, it is not a definitive test.
“When you look at the receiver operating characteristic curve, there is no optimal cutoff; the test is not sensitive and it is not specific to predict response and progression-free survival [PFS]... so we [only] use it in research to look at the full tumor in the microenvironment,” said Georgina Long, MD, BSc, PhD, MBBS. Nevertheless, as testing evolves and more data become available, mutation testing is expected to become more comprehensive. “In the future, we’re going to be testing for as many mutations as possible. The techniques are already there, but their standardization and who pays for them is limiting our routine use of them,” said Ribas.
In terms of treatment options, the panelists agreed that PD-1 inhibition would be an optimal approach for this patient, whether as single-agent therapy or as a combination therapy with ipilimumab. “For this patient with very low-volume metastatic disease involving the subcutaneous tissues and lung, I’d feel very comfortable starting her on a single-agent PD-1 inhibitor, such as nivolumab or pembrolizumab, as a first-line treatment approach,” said Michael A. Postow, MD. “We’ve known that patients with small lung metastases can do very well with single-agent PD-1, and we don’t yet have a perfect predictive set of clinical variables or any kind of correlative variables that tell us who exactly can benefit from PD-1 monotherapy versus who may need the combination,” he said.
Although nivolumab/ipilimumab combination therapy has shown a higher response rate than nivolumab monotherapy, it has a much higher toxicity rate, which can be a limiting factor, particularly in more vulnerable or frail patients. Thus, the panelists largely agreed that more aggressive combination immunotherapy might be better reserved for patients with signs of more aggressive disease, such as a rapid increase in tumor size or elevated serum lactate dehydrogenase (LDH) levels.