Weber Discusses Treatment Choices for 3 Metastatic Melanoma Patients
Published Online:2:08 PM, Thu December 1, 2016
Jeffrey S. Weber, MD, PhD
In the first case, the patient was a 62-year-old Caucasian male, who presented to his primary care physician with fatigue, dyspnea upon exertion, and a non-productive cough that lasted for 6 to 8 weeks. The patient’s ECOG performance status score was a 1. His lactate dehydrogenase (LDH) levels and liver function test results were normal, and he had no history of cancer.
Following a physical exam, a suspicious mole was biopsied, which resulted in a diagnosis of a deep ulcerated melanoma, 4.5 mm thick, and a chest x-ray showed a suspicious right-sided nodule. A PET/CT scan showed metastases to the lung and a soft tissue nodule in the liver. Genetic testing revealed a BRAF V600K mutation. Treatment was then initiated with a combination of BRAF and MEK inhibitors.
TARGETED ONCOLOGY: What factors do you consider when determining the optimal frontline treatment for this patient with metastatic melanoma?
Weber: The factors are what the disease burden is and what the pace of the disease is. I think those are the 2 most important factors. With a patient with a BRAF mutation, the biggest factor would be how much disease do they have at the baseline—their disease burden and their LDH, which is really one in the same—and also what is the pace of the disease, how fast is it growing.
TARGETED ONCOLOGY: How might this patient’s moderate disease burden impact his potential for a response to targeted therapy?
Weber: It’s well known from a number of studies, including studies recently presented at the European Society for Medical Oncology (ESMO) meeting, that the LDH burden and the number of sites of disease has a clear impact on your ability to have long-term survival with the use of BRAF/MEK inhibition. If you look at the slides from the presentation of Carolyn Robert, MD, PhD, if you have a normal LDH and 3 or fewer sites of disease, the survival at 2 to 3 years is greater than 50%, implying that those patients will do very well long term. It may constitute the tail of the curve that we can see with targeted therapy, so those patients will have a prolonged duration of response, which is excellent.
TARGETED ONCOLOGY: How durable a response to the targeted therapy combination would you anticipate for this patient, based on his LDH level, age, and sites of disease?
Weber: In a normal LDH patient, with a relatively low disease burden—that is modest disease burden, plus a few sites of disease—is a patient who can do very well in the long term. You’re anticipating a response duration of years, with a potential plateau on that survival curve.
TARGETED ONCOLOGY: What impact have BRAF/MEK inhibitors had on the management of metastatic melanoma since their initial approval, and how has this changed practitioner attitudes toward molecular testing of melanoma?
Weber: Clearly it has had a significant impact in prolonging survival where, for all the BRAF-mutated patient population, we’re talking a median survival of over 2 years. That would be compared to a decade ago when your chemotherapeutic survival was probably no more than 10 months, so that’s a significant increase. It’s also a significant increase over ipilimumab (Yervoy) alone, where you’re talking maybe 15 months, and it’s certainly caused us to routinely, in all patients with stage III and IV disease, test for BRAF mutations. In most academic centers, there will be a genomic panel that is obtained.
TARGETED ONCOLOGY: When testing is done, what mutations should be assessed?
Weber: We always look for BRAF V600E and BRAF V600K, and we usually look for NRAS, and often we will look for KIT if it’s mucosal or acral lentiginous melanoma.
TARGETED ONCOLOGY: If required, what would your second-line therapy be in this patient who received frontline BRAF and MEK?
Weber: If this is a patient who went on BRAF/MEK inhibitors, usually in a low-burden patient we would go to a PD-1 drug alone.
In the second case, the patient was a 50-year-old Caucasian female presented to her primary care physician with multiple, raised flesh-colored cutaneous nodules and palpable lymph nodes in the right axilla. The patient’s ECOG performance status score was a 0, and all laboratory values, as well as her LDH values, were found to be normal.
A workup, biopsy of the axillary node, and mutation test were conducted, which revealed BRAF V600E mutation-positive melanoma that had metastasized to the lymph nodes, subcutaneous tissue, and right adrenal gland, in the CT scan.
The patient was started on the combination of dabrafenib (Tafinlar) and trametinib (Mekinst). She experienced a durable complete response and remained on therapy for 36 months.
She has had intermittent fevers and fatigue that require stopping treatment and the use of steroids several times in the last 6 months that is not disabling.
TARGETED ONCOLOGY: What factors do you consider when determining treatments for patients like this who are BRAF-mutated?
Weber: The factors to think about are disease burden, LDH, and the desire of the patient to deal with toxicity, because that is often a big issue. This is a patient who was intermediate, meaning there was an intermediate disease burden, although the LDH was normal and they could have gone either way. You could have reasonably put someone like this on BRAF/MEK inhibition, or you could have put them on immunotherapy. It all depends on the patient’s individual choice that makes the difference.
TARGETED ONCOLOGY: Is the durable response for this patient typical for a patient with a low disease burden? Would it be safe to tell the patient to stop therapy if she is in stable, complete remission?
Weber: With BRAF/MEK inhibition, it’s always tough to decide when to stop therapy. With almost all targeted therapies of this kind in solid tumors, you should basically treat them until they progress. So I would not feel comfortable telling someone like this, if they were tolerating the drug well, to stop treatment. Durable response would not be atypical for someone with a low disease burden, or a moderate disease burden and a normal LDH who has what looks like just a modest amount of total disease.
TARGETED ONCOLOGY: How do we factor in this patient’s LDH, sites of disease, and age, in predicting the likelihood of achieving a durable response, as she experienced?
Weber: Usually the younger patients will have V600E, rather than V600K, which means they have a greater chance for a long-term response. And, with the low LDH and the modest disease burden, those are the patients who will do well long term.
The high disease burden patients always get treated with BRAF/MEK inhibition upfront to get that quick response, but those are often the patients who, because of their disease burden, don’t do well in the long term. It’s ironically the lesser disease burden patients who usually get immunotherapy. But, when treated with BRAF/MEK inhibition, they can do very well for a long period of time.
In the third case, the patient was a 43-year-old African American male, who presented to his primary care physician with a lower extremity edema lasting several weeks. Upon exam, he was seen to have multiple enlarged palpable groin lymph nodes bilaterally. The patient’s ECOG performance status score was a 1. His LDH levels and liver function test results were elevated. He had no history of cancer.
A physical exam did not show a primary melanoma lesion. A PET/CT scan showed multiple metastases in the liver and multiple intra-abdominal lymph nodes that were enlarged; a biopsy of a groin node was performed. Genetic testing revealed a BRAF V600E mutation. Treatment was then initiated with a combination of BRAF and MEK inhibitors.
TARGETED ONCOLOGY: What factors do you consider when determining the initial treatment for patients like this who are symptomatic, have a high LDH and disease burden, and have a BRAF mutation?
Weber: In a patient like this who is symptomatic, most people would agree that you would be committed to going with BRAF/MEK upfront, though some would consider an ipilimumab/nivolumab (Opdivo) combo upfront because you can see deep and rapid responses, but often we will go with BRAF/MEK upfront.
TARGETED ONCOLOGY: Would you consider switching to immunotherapy after achieving a good response?
Weber: Absolutely. The dirty little secret is that a lot of doctors will give 8 weeks of BRAF/MEK and, hopefully before they develop a resistance, will then switch to immunotherapy. Usually, it would be nivolumab and carry on from there after that initial induction of BRAF/MEK.
Interestingly, if you could re-introduce BRAF/MEK, if there was a long interval where you had no evidence of progression, say on the immunotherapy and then 6 months, a year later, you could switch back to immunotherapy—that’s still an open question.