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Melanoma FAQ
Experts Answer Frequently Asked Questions on Melanoma Management

Released: March 03, 2021

Expiration: March 02, 2022

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In this commentary, melanoma experts Michael A. Davies, MD, PhD, and Ahmad Tarhini, MD, PhD, answer questions on the management of melanoma posed by the audience during a live CCO Webinar in October 2020.

Adjuvant Therapy

What adjuvant treatment do you prefer for patients with BRAF mutations?

Ahmad Tarhini, MD, PhD:
The efficacy data are consistently strong across the phase III clinical trials for nivolumab, pembrolizumab, and dabrafenib/trametinib. I think these are equally viable options and that the decision should depend on patient preference in terms of taking a pill vs an infusion and discussing the potential toxicities. The PD-1 inhibitors work very well, but there are certain adverse events that could be long-lasting, such as endocrinopathies and hypophysitis. With dabrafenib/trametinib, there is a risk of pyrexia and its implications. Thus, I recommend having a discussion about the risk‑to-benefit ratio for each of these therapies, as well as determining your patient’s preference between a pill or an infusion. That is the best practice today in the absence of a randomized, head-to-head study.

Do you recommend adjuvant therapy for a patient with stage IIIA melanoma who has lymph node metastases < 1 mm (ie, a patient who narrowly misses the cutoff for inclusion in the phase III adjuvant trials)?

Ahmad Tarhini, MD, PhD:
In the phase III trials of adjuvant therapy for stage III melanoma, including KEYNOTE-054 (pembrolizumab vs placebo) and COMBI-AD (dabrafenib/trametinib vs placebo in BRAFV600–mutant disease), participants with stage IIIA disease had to have lymph node metastases > 1 mm; stage IIIA patients were not included in the CheckMate 238 trial. However, patients with any lymph node involvement are included in the approved indication for pembrolizumab, nivolumab, and dabrafenib/trametinib. Hence, I would say that they can be treated. However, I would discuss with them the risk‑to-benefit ratio, making it clear that this is a lower‑risk population. They would not have been included in the adjuvant studies because of their lower risk of disease. Moreover, there are potential toxicities, cost considerations, and the impact on their quality of life and their families, and so on. So, I do not recommend it strongly, and I am less inclined to treat these patients.

How has the COVID-19 pandemic affected your choice of treatment for patients, particularly in the adjuvant setting?

Ahmad Tarhini, MD, PhD:
It has not affected me much, but I have colleagues who have favored dabrafenib/trametinib more because the pill is easier to take and requires fewer trips to the clinic. On the other hand, some colleagues have favored nivolumab or pembrolizumab because they offer every-4-weeks or every-6-weeks dosing, respectively. I think both remain viable options and both can be administered with fewer clinic visits.

Michael A. Davies, MD, PhD:
I think it is clear from studies that have been conducted in the COVID-19 era that patients who are receiving chemotherapy are at increased risk of severe infection and mortality from COVID‑19. We do not see that risk in patients receiving immunotherapy or targeted therapy. In the melanoma world, we have been fortunate to be able to continue treatment for our patients—while minimizing their clinic visits—because we are able to choose immunotherapy and targeted therapies.

When considering targeted therapy, I have seen a preference for encorafenib/binimetinib or vemurafenib/cobimetinib in this setting, because of the much lower risk of fevers. Avoiding fever helps avoid any screening issues associated with COVID-19 safety.

Considerations in Selecting Frontline Therapy

Is there any specific clinical scenario for which you would recommend ipilimumab/nivolumab instead of dabrafenib/trametinib as first-line treatment for patients with BRAFV600 mutations?

Michael A. Davies, MD, PhD:
The clearest indication for choosing ipilimumab/nivolumab instead of dabrafenib/trametinib as first-line treatment is in patients with asymptomatic brain metastases. I think it is difficult to argue that any other regimen has the durable responses and durable intracranial control that we see with ipilimumab/nivolumab in that scenario.

Otherwise, we currently have no head-to-head prospective trials comparing ipilimumab/nivolumab or even single‑agent anti–PD-(L)1 agents vs BRAF/MEK therapy. Something I emphasize with patients with BRAF‑mutant disease is that if we start with immunotherapy and they progress, targeted therapy can work quite well. Similarly, if we start with targeted therapy and they progress, immunotherapy can work quite well.

I talk with patients about the differences in toxicities between these regimens, and I consider the social situation of the patient, particularly for ipilimumab/nivolumab. With the high risk of toxicity that we see with these regimens, it is very important to make sure the patient has a good support system and has access to care in case they experience treatment-related toxicities. Regarding dabrafenib/trametinib, although the rate of toxicity is higher than single‑agent PD-(L)1 agents, we can easily manage those toxicities by holding the drug.

The other intrinsic difference is that we have a track record with immunotherapy. When patients respond to immunotherapy, you can stop treatment and patients will continue to respond. We do not know if you can take patients off of targeted therapy, so this is another distinction between the two. I do think that, as academics, we tend to have a strong preference for using immunotherapy because of this very specific characteristic and the potential for cure, but again, we are still waiting to see the results of some of our ongoing prospective trials to provide a definitive answer to that question.

Ahmad Tarhini, MD, PhD:
I agree. The ECOG‑ACRIN EA6134 study (NCT02224781), which is specifically testing ipilimumab/nivolumab vs dabrafenib/trametinib with crossover at progression will answer this question. This trial is more than two thirds accrued now, so hopefully we will have the data in the next couple of years.

The KEYNOTE-001 trial and a pooled analysis of the CheckMate trials, showed a very short median progression‑free survival in patients with < 1% in PD-L1 expression. Can you comment on this?

Michael A. Davies, MD, PhD:
It is consistent across the data. Although you do not have to have PD-L1 positivity to respond to single‑agent anti–PD-1 therapy, the chances of responding are much higher if the patient is PD-L1–positive. In my practice, I prefer to distinguish between PD-L1 completely negative vs positive rather than a 1% cutoff. Not only are the data more clear with that distinction, but it is easier to ask a pathologist to delineate between positive and negative. What is interesting about ipilimumab/nivolumab is that patients seem to have similar outcomes regardless of PD-L1 status—or at least it doesn’t decrease as much. There are multiple factors to consider when choosing between single‑agent and combination therapies, but when I am on the fence, a PD-L1–negative status may push me toward using the combination regimen because of these data.

Ahmad Tarhini, MD, PhD:
When looking at the full clinical picture of the patient, including the tumor burden and lactate dehydrogenase (LDH) status, brain metastases can also sway us one way or the other.

Michael A. Davies, MD, PhD:
Yes, LDH status is interesting. Although we might assume that patients with high LDH would benefit more from combination therapy vs single‑agent anti–PD-1, we have done the analyses and it does not seem to be that different.

Moreover, when comparing ipilimumab/nivolumab to single‑agent anti–PD-1, the combination seems to provide more benefit in patients who are PD-L1 negative. Intriguingly, in CheckMate 067, the combination also seems to provide greater benefit in patients who have a BRAF mutation. Again, the challenge is that we do not have another study to validate these observations, but these are interesting data

Based on available data, what do you see as the role of triplet therapy with atezolizumab/vemurafenib/cobimetinib?

Ahmad Tarhini, MD, PhD:
Data from phase III IMspire150 trial showed a significant improvement in PFS with atezolizumab/vemurafenib/cobimetinib vs placebo plus vemurafenib/cobimetinib in patients with newly diagnosed, unresectable, stage IIIc-IV, BRAFV600 advanced melanoma. The study met its primary endpoint, with a median PFS of 15.1 months with the triplet regimen vs 10.6 months with vemurafenib/cobimetinib (P = .0249). Based on these data, I think this regimen is a viable option for patients with BRAF-mutated tumors who would benefit from BRAF/MEK inhibition in the first line. This includes patients with aggressive disease and/or high tumor burden, who we are concerned about not responding to other therapies and who need a quick response. In that patient population, where I think we need a response sooner rather than later, I am willing to justify the toxicity risks of the triplet combination.

Michael A. Davies, MD, PhD:
It is important to point out that there was no immunotherapy comparison arm in IMspire150, so it is difficult to know how those patients would have done with immunotherapy. Moreover, the follow-up in that trial is relatively short compared with other studies in this population. The good thing about melanoma treatment is that the bar has been raised; rather than considering response rates or survival at 12 months, we are pushing those questions out to 3-5 years.

Do you believe in the clinical validity of intermittent dosing for targeted therapy?

Michael A. Davies, MD, PhD:
Based on promising preclinical data suggesting that intermittent dosing with BRAF inhibitors can delay acquired resistance, the randomized phase II S1320 trial evaluated continuous vs intermittent dosing of dabrafenib/trametinib in patients with metastatic, unresectable BRAFV600 melanoma. Unfortunately, the clinical trial was completely negative; there was a strong trend for intermittent dosing, resulting in worse outcomes. Hence, at this point, intermittent dosing is not being pursued as a strategy.

Can you comment on the use of “flipped” dosing with nivolumab plus ipilimumab?

Michael A. Davies, MD, PhD:
The approved dose of this regimen is ipilimumab 3 mg/kg and nivolumab 1 mg/kg. In the phase IIIb/IV CheckMate 511 study, investigators compared standard dosing to “flipped” dosing of ipilimumab 1 mg/kg and nivolumab 3 mg/kg in patients with previously untreated, unresectable advanced melanoma. With 12 months of follow-up, the results look promising, including lower rates of adverse events in the “flipped” dose group while maintaining comparable efficacy. However, we need longer follow-up. Moreover, this trial did not allow patients with brain metastases, so we do not have any published data about the ipilimumab 1 mg/kg and nivolumab 3 mg/kg regimen in patients with brain metastases. This regimen is currently under investigation in this population, but at this point, if you are going to use ipilimumab/nivolumab for patients with brain metastases, you should use the approved dosing.

Biomarkers

How do you manage patients with NRAS-mutant melanoma?

Michael A. Davies, MD, PhD:
Because BRAFV600 mutations and NRAS mutations are mutually exclusive, finding an NRAS mutation increases your confidence that you have not missed a BRAF mutation and helps direct patients toward a clinical trial. At this point, we do not have FDA-approved targeted therapies for patients with an NRAS mutation, so in my practice, we treat those patients with immunotherapy. Of interest, current guidelines do recommend treatment with the MEK inhibitor binimetinib in patients who have an NRAS mutation who have failed immunotherapy, even though it is not approved by the FDA. We do know that binimetinib had a higher response rate than chemotherapy in that population, although the responses were generally quite short, with a very small difference in PFS and no difference in OS. Thus, for our NRAS‑mutant patients who have progressed on immunotherapy, we recommend a clinical trial.

Your Thoughts
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For most patients with newly diagnosed metastatic BRAFV600E melanoma, what is your preferred treatment recommendation?
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