Treatment of Metastatic Melanoma Beyond Progression

Jason Luke, MD, FACP:For a patient who hasBRAF-mutant melanoma, there really is no wrong initial answer in terms of what to try. We have BRAF-directed therapy with immunotherapy, and starting one versus the other is the subject of clinical investigation; we don’t know the right answer. So, in our case, our patient who hadBRAF-mutant melanoma who was started on BRAF inhibitor, if we said, for example, that perhaps they had the median time on drug of approximately 11.5 months and then had progression of disease, we’d consider the next steps. And certainly, in that case, it would be an immunotherapy consideration. And so, in the standard of care setting, we would then be facing the choice of monotherapy: PD-1 antibody with pembrolizumab or nivolumab, or combination immunotherapy with ipilimumab and nivolumab. That consideration will likely be dictated by the circumstances that we’re facing at the time of that progressive disease.

If the patient is still in a low-volume state—feeling generally well and is somewhat risk adverse in terms of toxicity—then it would see to make a lot of sense to transition to a monotherapy PD-1 antibody. If at the time of progression, however, the progression came in the form of brain metastases or rapid progression with sudden rise in LDH, we might want to be more aggressive in that situation and consider the ipilimumab/nivolumab combination at that time. So, really, we have to adapt it to what the clinical scenario would be, and you could imagine that either one could be relevant. Again, a patient would want to have input in terms of risk and benefit considerations about which treatment would be chosen—no right or wrong answer. And that highlights why we probably would not use PD-L1 testing in this situation, but rather we’d probably use the clinical pace of the disease and the patient’s preference regarding toxicity risk in choosing the next treatment for immunotherapy, whether it be a monotherapy or a combination.

Progression on targeted therapy is an evolving field because it doesn’t always mean the same thing. With targeted therapy, we often see that most of the diseases in fact control, and will have, isolated outgrowth of clones that have gained resistance mechanisms. So, in that case, it’s certainly reasonable to apply local therapy to those progressing lesions while continuing the general systemic approach of BRAF and MEK inhibition. This has been demonstrated in multiple retrospective analyses in clinical trials showing that, for example, a patient who develops a new brain metastasis while on BRAF and MEK inhibitors, you can do isolated stereotactic radiation, get that lesion under control, and yet still maintain disease control, systemically, with the BRAF and MEK over a long period of time. And similarly, you can do such things with, say, isolated pulmonary metastases.

Usually in those situations, we apply stereotactic radiotherapy approaches. We’re usually less amendable to considering surgery for isolated lesions, except for in certain scenarios. If you do surgery and the patient has a complication, etc, they’ll end up being off therapy for quite a while. And if the patient goes through surgery and then they end up with the same problem anyway with progressing lesions, one wonders how much you really helped them. But certainly, it should be considered a standard of care in the context of isolated progression on targeted therapy to treat locally and then consider continuing that targeted therapy out over time. And multiple clinical trial retrospective analyses have shown that the patients, where that strategy is employed, do quite well over a long period of time.

So, our case was a 46-year-old woman diagnosed with stage 3 high-risk melanoma who, unfortunately, had progression to metastatic disease relatively quickly, and she had aBRAFmutation in the context of a good performance status, low LDH, and 3 sites of disease. In that case then, this would be the kind of patient, based on retrospective analysis, who’s most likely to have long-term benefit from BRAF and MEK inhibition. On our case, we chose to give her dabrafenib and trametinib based on all those factors, and we see that she then does quite well out over a long period of time. We would expect her, in fact, to be one of those patients that perhaps could even get 2, 3, and longer number of years of benefit on the therapy.

We then, for the hypothesis of what to do next, considered progression of that patient. We said that if that was isolated progression, say with a brain metastasis or a lung metastasis, we might think about using radiation to zap that and continue BRAF and MEK inhibition. But if we were to say that that was multifocal progression of disease—liver and lung—we then would have to progress to a second-line option. In those situations, we’d consider immunotherapy, and really the consideration would be monotherapy PD-1 antibody, nivolumab or pembrolizumab, or a combination immunotherapy with ipilimumab and nivolumab. That decision-making process would likely be driven by factors at that time such as the pace of progression, the number of lesions progressing, the LDH rising, and the patient’s general aversion to toxicity and how aggressive they would want to be. So, no right or wrong answer per se, but rather framing it in the context of the individual patient that we would be treating, and what would be going in that clinical scenario at that time.

Transcript edited for clarity.

• A 46-year-old Caucasian female presented one year ago with deep ulcerated primary tumor and multiple involved lymph nodes.
• She was diagnosed with stage IIIC melanoma.
• Patient underwent wide local incision and compete lymph node dissection and appeared to be clear of disease.
• Patient decided not to pursue adjuvant therapy after surgery.
• Six months after surgery, she developed abdominal pain.
• Imaging showed multiple masses in the liver, > 1 cm, scattered pulmonary nodules and some enlarged lymph nodes.
• Tumor biopsy confirmed melanoma and mutational analysis showed BRAF V600E mutation.
• The patient is started on dabrafenib 150 mg bid and trametinib 2 mg qd.