Pavlick Covers Research in BRAF Wild-Type Metastatic Melanoma

Anna C. Pavlick, DO, MS

Anna C. Pavlick, DO, MS

During aTargeted Oncologylive case-based peer perspectives live discussion, Anna C. Pavlick, DO, MS, explained to a group of physicians best practices for the diagnosis and management of patients with metastatic melanoma. Pavlick, co-director of the Melanoma Program and assistant director of the Clinical Research Education at NYU Perlmutter Cancer Center, discussed treatment options between immunotherapy and targeted therapy based on the case scenario of a patient withBRAFwild-type metastatic melanoma.

CASE:

June 2010

A 73-year-old Caucasian man presented to his physician with a right periauricular pigmented lesion, 21-mm in diameter. His medical history was notable for arterial hypertension, dyslipidemia, hyperuricemia, and hypothyroidism, for which he has been medically treated. He is a nondrinker and former smoker. He had a right nephrectomy in 2002 for retroperitoneal hematoma and consequent chronic renal insufficiency. He otherwise maintains full autonomy in his daily activities and personal care.

He underwent surgical resection of the periauricular lesion. A lymph node biopsy was performed and positive, but the patient opted out of complete lymph node dissection. A metastatic workup was negative. Pathologic assessment revealed an ulcerated melanoma that was Breslow index 2.1 mm, Clark level IV, and stage pT3bN1a.

Since his surgery, he remains active and continues golfing 3 times per week.

Targeted Oncology:What are your initial thoughts on this case?

Pavlick:When it comes to metastatic melanoma, cutaneous melanoma, 50% of patients’ tumors will harvest aBRAFmutation when they metastasize. ABRAFmutation, is a driver mutation, meaning we have a mutation that we have medicines for to shut off the driver. But what happens when the patient isBRAFwild type? Well, you don't have that target and 50% of the patients are going to have metastatic disease. What do we do with them and how do we manage them?

[This patient] underwent the resection of this lesion, lymph node biopsy was positive, and the patient said, “No way, I'm not going for a neck dissection.” I think what is important and what is missing in this is how positive was that lymph node? Was the lymph node microscopically positive or was it macroscopically positive? Because what you would recommend now in 2019 is different than what we would have recommended 5 years ago.

If we have a microscopically positive sentinel lymph node with less than 2 mm worth of tumor in it, or just focal clusters of melanoma cells, based on [the MSLT-II trial which] random­ized patients who had a microscopically positive sentinel node to either full-neck dissection or observation, we found that if that patient had a microscopically positive node, they did not need to have a complete neck dissection or axillary dissection. That helped us to determine if we have to put people through a completion lymphadenectomy of that drainage base and, based on a microscopically positive node, the answer is no.¹

But what happens if you have a macroscopically positive node? It's still not palpable, but you send it to the pathologist, the pathol­ogist opens it up, and you have this big, poor, black ugliness inside. The MSLT-II data do not justify not doing a neck dissection or axil­lary dissection. If you have a macroscopically positive node, the answer is yes, you should offer your patients a complete lymph node dissection. They can refuse, but you still have to offer it because standard of care is still to dissect out that basin.

He had an ulcerated melanoma of 2.1 mm. It's a pT3b, T3 because it's 2 mm, B because it's ulcerated. N1a tells us that it's microscopically positive, because if it was macroscopically positive it would be an N1b. His metastatic workup was nega­tive, so he has stage IIIa melanoma.

Targeted Oncology: What would you use to treat this patient?Pavlick:In the dark ages, 20 years ago when I started doing this, we would give patients interferon for a positive lymph node. Somebody like this, you could either offer observation or, based on the data looking at adjuvant PD-1 therapy, you can offer them a PD-1 inhibitor. Both pembrolizumab [Keytruda] and nivolumab [Opdivo], are FDA approved as adjuvant ther­apy for patients with stage III disease.^2,3Whether it’s A, B, or C doesn't matter.

Targeted Oncology: How do you determine risk for this patient and what is his diagnostic work up?

This patient opted not to have a dissection. You know he’s at risk because he has nodal disease, ulceration to his lesion, and an intermediate depth. He’s not 1 mm, he’s not 4 mm, he's somewhere in the middle.

Melanoma has become much more complicated with the AJCC [American Joint Committee on Cancer] 8th edition. But we should be using the most up-to-date [edition] because the most common FDA treatment recommendations are based on the newer staging. We know this patient has a positive node and we know he had an ulcerated intermediate lesion. What are we ordering for his metastatic workup? PET scans are poor at picking up tiny little brain lesions, but absolutely get a PET scan if you can get it paid for by insurance. [Order a] PET scan and a brain MRI. Most insurances will pay for a baseline PET scan for melanoma. Try getting another afterward and you’re pretty much out of luck. If you can’t get a PET scan, [get] a CT scan of the chest, abdomen, and pelvis and an MRI of the brain—that is completely acceptable.

What molecular tests would you order for this patient? Would you order PD-L1 testing?  

Remember the gentleman had a periauricular lesion and it’s in a sun-exposed area. The most common cutaneous mutation isBRAF, so we orderBRAFtesting. Next in the sequence isc-KITbecause it occurs in areas of excessive sun exposure, especially in areas that have solar elastosis. There is a higher frequency, but the frequency is still only about 20%.

Melanoma is different than most cancers. You want to know your PD-L1 status when it comes to lung cancer because if you have a low PD-L1 score in lung cancer, you are probably not going to respond to immunotherapy. When it comes to cutaneous squamous cell carcinoma and melanoma, you don't need to order PD-L1 testing because we know that the higher your PD-L1, the higher the chance that you are going to respond. Even with low or negative PD-L1, we still have patients who respond so we don't ever exclude them.

Would you consider adjuvant therapy in a patient such as this?

The answer is yes, you can, but do you have to? Let’s go back and think of all his other issues. He has hypertension, he has 1 kidney, and he has an elevated creatinine [level]. We know that adjuvant therapy is going to consist of a PD-1 agent and either nivolumab or pembrolizumab can cause nephritis. I'm not saying [don’t use it], but I think this is a discussion because it's preventive for adjuvant therapy. You need to have a good discussion with a patient regarding the potential for toxicity, and document that you had this discussion.

It’s important that when we talk about any kind of immu­notherapy, we make sure people understand that the endocrinopathies are permanent. I can’t stress that enough, because I had an 80-year-old gentleman [to whom I commu­nicated this while his daughter was in the room]. He became an insulin-requiring diabetic at the age of 80. We fixed his metastatic melanoma, but I made him a diabetic and he was upset because he had to give himself insulin every day.

What can happen if this patient hasBRAFwild-type disease and is then treated with a BRAF inhibitor?

The COMBI-AD trial [of dabrafenib (Tafinlar) and trametinib (Mekinist)] looked at patients who hadBRAFV600E- and V600K-mutated stage IIIB and IIIC melanoma [NCT01682083]. That is not this patient. This patient isBRAFwild type, which is not applicable. The 1 thing you never want to do is treat aBRAFwild-type patient with aBRAFinhibitor, because if the patient isBRAFwild type and you give a BRAF inhibitor, you are going to accelerate the metastatic disease in that patient. Make sure you know what that patients BRAF status is before you give a BRAF [inhibitor]. I had a patient who came in from [another institution], and the way the BRAF report was written was cryptic. The patient wasBRAFnegative and had brain metastases, but they were being given dabrafenib and trametinib for the treatment of their brain metastases. This patient hadBRAFwild-type disease and died. He went from 5 brain metastases to more than 50 metastases in a matter of 4 weeks of being on the wrong therapy.

What do you think of the use of the CTLA-4—target­ing agent ipilimumab (Yervoy) versus the PD-1 inhibitor nivolumab?

Ipilimumab was the first immunotherapy that we had. Something was better than nothing. When we looked at ipil­imumab in the adjuvant setting, response rates were still only about 20% and toxicity was significant. Once we had PD-1 inhibitors, we compared ipilimumab with nivolumab, and nivolumab had a much higher response rate. Patients did much better and had way less toxicity, so nivolumab supplanted ipilimumab as adjuvant therapy.⁴

Then, in the pembrolizumab-versus-placebo trial, the PD-1 inhibitor won out over doing nothing for stage III disease.5

Your treatment options for patients with stage III disease include either monthly doses of nivolumab [or pembroli­zumab]. [With nivolumab], we used to give 240 mg every 2 weeks. I’m an advocate of 480 mg once a month with respect to patient quality of life. They don’t want to see you every 2 weeks, we don’t want to see them every 2 weeks, and they do just as well on an every-4-weeks schedule as they do every 2 weeks. Or you can give them pembrolizumab and split the difference and see them every 3 weeks. I don't think 1 agent is superior to the other.

CASE (continued):

On routine follow-up, the patient presented with moderate asthenia that limited his daily activity, without other relevant clinical symptoms (ECOG performance status of 1). His physical examination was unremarkable. His laboratory findings included: urea, 70 mg/dL; creatinine, 1.76 mg/dL; aspartate aminotransferase, 59 IU/L; alanine aminotransferase, 52 IU/L; gamma-glutamyl transferase, 363 IU/L; alkaline phosphatase, 204 IU/L; lactate dehydrogenase (LDH), 820 IU/L.

A full-body CT scan revealed presence of pulmonary and hepatic nodules and an MRI of the brain revealed no evidence of brain metastases. He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications. Pathology revealed metastatic melanoma and mutation testing revealed aBRAFwild-type tumor.

What is this patient’s prognosis?

This is a patient who is going to get immunotherapy. We are not going to give chemotherapy, not for melanoma. The response rates to chemotherapy are only about 10% to 15%. Response rates to immunotherapy, whether you have aBRAFmutation or not, are about 65%, irrespective of LDH. Stage IV melanoma has a 65% response rate with combination therapy.

I think last year I signed 9 death certificates and 5 of those patients died from melanoma. It is a totally different ball game [compared with 10 years ago]. Prognosis, despite the elevated LDH, is still good. You still have a 65% response rate and if you can get people to respond to immunotherapy, many times their responses can be durable.⁶

What role does aBRAFmutation play in deciding treatment?

We are talking about people who have lung metastases, liver metastases, bone metastases, and brain metastases. [Even though a patient has a]BRAFmutation, it does not mean [they are receiving]BRAF-targeting drugs because when we did the immunotherapy studies—looking at ipilimumab plus nivolumab versus ipilimumab versus nivolumab in a phase III trial—we randomized patients based on whether they had aBRAFmutation or not. Response rates absolutely do not differ whether you have or don't have aBRAFmutation.⁷

Do you think that immunotherapy should be given over targeted therapy?

Patients who respond to immunotherapy have a high chance of having a durable response of 3 years, 5 years, and I even have patients who are now at 15 years because they were on the first immunotherapy trials. For some patients, [immunotherapy can translate into cure], but like I said, few of us are going to tell their patients they're cured. We're going to tell them that they have a nice 30-year remission.

If you have aBRAFmutation and you use BRAF drugs, it is different because these drugs work quickly. If you have a patient who essentially has melanoma that’s out-of-control and growing like wild fire—BRAF drugs in the presence of aBRAFmutation is where you want to go when you have high-volume disease, rapidly progressing disease, or a patient who's sick who you need to salvage quickly. The down side to BRAF inhibitors is that many patients don't have the durability of response. They’ll respond for somewhere between 9 months and 24 months, but then you're back to square one. We try and use them by getting the disease under control, and we’re trying to figure out now, How do we add in immunotherapy? We are looking at trials that are incorporating immunotherapy with BRAF-targeted therapy to try to enhance the durability of responses.

If you start with aBRAF-mutated tumor and you give targeted therapies, then the patient progresses, it is harder to get them back under control with immunotherapy. That’s why, if given the opportunity to start with the immunotherapy, we start with immunotherapy. Then if they progress, we go to BRAF inhibitors because when patients progress after being on BRAF inhibitors, their tumors usually take off at the speed of light. They progress quickly when you inhibit the driver mutation, the tumors shut down; but when it comes to immunotherapy, we have to start recruiting T cells. We have to get the persons’ immune system to become active and it doesn’t happen quickly. For some people, it can take 3 weeks, for some it takes 6 weeks or 12 weeks, but if you have a cancer that's multiplying quickly, sometimes you don't have the luxury of time to wait for that response. That's why if you don't have a melanoma that's on fire, start immunotherapy. If you have the fire and you have aBRAFmutation, use what you have to use.

What combination therapy can you suggest for patients with metastatic melanoma?

We published results of a large trial in theNew England Journal of Medicine. When we did the study, we looked at combination ipilimumab and nivolumab. Ipilimumab was 3 mg/kg and nivolumab was 1 mg/kg. Patients were stratified into being asymptomatic or symptomatic. The favorable group is the asymptomatic group. These are patients where you just did the MRI and you found they have brain metastases. Patients had to have at least 1 brain metastasis that was cm and that that was our target lesion. They could have had other systemic diseases or not, and they were then given 4 cycles of full-dose ipilimumab plus nivolumab. They had a repeat MRI after 2 cycles. [The intracranial] response rate [was 57%] in asymptomatic patients without any radiation.⁸

It’s the same thing if you look at the study of patients who hadBRAF-mutated melanoma and brain metastases that looked at the dabrafenib plus trametinib. Again, there was about a 50% disease control [rate] in the central nervous system as long as the patient had thatBRAFmutation — you’re on dual targets.⁹

How does performance status play a role in treatment?

I think with our therapies it’s different if you have someone with an extremely poor performance status but they have aBRAFmutation. I don’t think it’s crazy to think about treating them. If you have someone withBRAFwild-type disease, [noBRAFmutation], and a poor performance status, you have to think about whether or not they would truly benefit from getting immunotherapy because you get a lot more systemic toxicity than what you do with immunotherapy. You also have to be good at response. I never say never, but you have to do it on a patient by patient basis to see whether or not you think they're going to benefit.

What treatment should this patient get?

If the patient is symptomatic and sick, you want to be able to treat them quickly. The more comorbidities [translates to] more risk factors, but that doesn’t mean you can't get immunotherapy or targeted therapy.

The options that you have for this patient are immunotherapies. The question becomes: Do you offer this patient combination therapy, or single-agent nivolumab or pembrolizumab? Sifting out the data, single-agent pembrolizumab or single-agent nivolumab is going to give you a response of about 50%.^4,5Giving patients combination therapy is going to give you a response of about 65%, so you have to weigh it out: Is that 15% worth it? If you're going to incur such toxicity to someone, is it worth giving them 2 agents? We used to always hesitate to give the full dose to seniors because I’