Factors to Consider in Treating Metastatic Melanoma

Jason Luke, MD, FACP:Patients who have recurrent metastatic disease, stage 4 disease, the median life expectancy is now actually an unknown. So, before 2011, it was commonly quoted that the median life expectancy was on the order of about 9 months for metastatic melanoma due to the dearth of the effect of systemic therapies. That’s all now radically changed with 11 FDA approvals of the new approaches for metastatic melanoma in the last 6 years.

To the point that for patients withBRAF-mutant melanoma, you really can’t quote them on median life expectancy anymore. If you look at the different registrational phase III trials of BRAF and MEK inhibitors or PD-1 antibodies, the median life expectancy in those trials was 2 years each, and many of those patients never had the opportunity to actually cross over and get other therapies. So, at a minimum, it has to be 2 years, but likely, it’s much longer. And we know that based on the trials of BRAF inhibitors and MEK inhibitors now, maybe 20% to 30% appear to have long term survival. Similarly, with anti-PD-1 monotherapy, we now know that about 34% could be alive even at 5 years. We’re hopeful that with the ipilimumab/nivolumab combination, maybe that number is even higher.

For a patient withBRAF-mutant melanoma, quoting a median life expectancy is not an easy thing to do. That being said, I approach this as still talking about the therapy as palliative and intent; meaning that I tell the patient that, God forbid, if everything goes wrong, the median life expectancy for a patient with melanoma is on the order of 9 to 12 months. We have many effective therapies and we’re going to try them all to our utmost ability, but you should be aware of that idea because that can inform patients’ considerations of risks and benefits, and getting their life in order and doing the things that they find to value the most.

Patients who develop melanoma both locally in the stage 1 through 3 setting, as well as in the metastatic setting, I think they should always be considered in a multidisciplinary setting. The patient in our case has multifocal metastatic disease involving multiple organs—liver, lung, and lymph nodes. So, in this case, almost certainly the choice would be to administer systemic therapy in some form. But that being said, getting the input from our colleagues in pathology, even surgery in such as case, they are informative about where we might go otherwise.

In a different patient who perhaps has had an isolated recurrence in the lung, that would be a clear indication where a multidisciplinary approach, where you involve the surgeon perhaps to do a metastasectomy of the lesion only, would be reasonable. So, I would suggest that multidisciplinary consideration of treatment options is always a good idea as it can help us to broaden our perspective, and maybe think about multiple lines of therapy and how we’re going to integrate all of our options.

In terms of choosing frontline therapy for a patient with metastatic melanoma, really the obvious question comes to using BRAF-directed therapy in aBRAF-mutant patient versus starting with immunotherapy. And unfortunately, at this time, we really don’t know the correct answer. We don’t have randomized data to tell us. There are clinical trials ongoing to assess that sort of question, but for an oncologist trying to make a treatment choice, right now it’s somewhat difficult.

Now that being said, we do have some factors that we can use clinically to help guide whether one treatment might be more or less efficacious. In the context of targeted therapies against BRAF, we have learned now in retrospective analyses that certain clinical factors really do associate with those patients who are most likely to benefit. So, particularly, we look at the presence of a normal LDH level, the ECOG performance status, and the number of sites of disease to really help us identify which patients are likely to derive the greatest benefit from BRAF inhibition.

When we think about our case, our patient actually fits those criteria pretty well. She had normal LDH, she’s in good health, ECOG’s 0, and she had 3 sites of disease. So, she would then fit that paradigm of the patient most likely to derive long-term benefit. And this is an important point to make because, historically, we thought about using targeted therapy when we had bulky tumors that seemed to be more aggressive, so targeted therapy would work quickly. And while that’s certainly true, that’s likely not a population of patients who are going to derive the longest-term benefit.

There has been a longstanding assumption that, “Oh, you should use immunotherapy in those patients with low volume of disease,” and that is probably true as well, but that’s probably the same population where you get the most benefit from targeted therapy. So, considering these clinical factors can really inform the use of targeted therapy in terms of maximizing long-term benefit.  

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.