Hussein A. Tawbi, MD, PhD

Hussein Tawbi, MD, PhD: Let us go ahead and review the currently available options for patients with B-RAF mutated metastatic melanoma in the first line treatment naïve setting. We've had in hand since 2011 immunotherapy with checkpoint inhibitors and targeted therapy. From an immunotherapy perspective, we have single agent PD-1 antibodies both Nivolumab and Pembrolizumab as single agents who have shown excellent response rates in the order of 35% or more. And excellent PFS usually about six months of PFS and durable responses that we now know at five and six and seven years of about 40, 42% of patients will have an overall survival benefit. We also know that with the monotherapy of Pembrolizumab and Nivolumab, we do experience about a 15% grade three for adverse events. All of the adverse events are immune mediated. We also have two different combination immune checkpoint therapies that are available. The one that we have the longest history with is the combination of Ipilimumab and Nivolumab. With Ipilimumab being the anti CTLA-4 antibody, that was first FDA approved as a single agent in 2011. The combination is highly effective. It gives us response rates of about 55%. It gives a median PFS of about 11 months. Again, at the seven-year update from Checkmate 067 had a median overall survival of about 72 months. Excellent again options for our patients. The combination of Ipilimumab and Nivolumab is usually highly effective in specific subpopulations as well, which we'll discuss a little bit later. Like patients with brain metastases, high LDH levels, patients with liver metastases. Patients with B-RAF mutations seem to derive more benefits from the combination over a single agent PD-1. We also have a new combination in hand that's been FDA approved now since March of 2022. That's the combination of Nivolumab and the anti-LAG-3 antibody Relatlimab. That combination also known as Opdualag which is actually the generic name as well for the combination is also highly effective. It has shown to be better than single agent PD-1 in a head-to-head phase three trial, RELATIVITY-047. It showed improvement in progression-free survival with a hazard ratio of 0.78. A 22% decrease in the risk of progression or death over single agent PD-1. Response rates are around 43% compared to 32% for the single agent Nivolumab. The overall survival is still relatively early. The hazard ratio is 0.8, indicating a decrease by 20%, but was not statistically significant. The combination of Ipilimumab and Nivolumab to go back to that had a grade three for adverse events of about 59%. Whereas with Nivolumab and Relatlimab, we see a grade three for adverse events rate of only 21%. Again, the quality and the kind of incidence of the toxicity in terms of being immune related, is all immune-based. We don't see any kind of off target toxicities with these agents. But again, the quality and the pattern of the toxicity with Nivolumab and Relatlimab is more consistent with that of the single agent anti PD-1. Now, if you have a B-RAF mutation, immunotherapy is not the only option available. We have targeted therapy with B-RAF and MEK inhibitors. To be clear, we do not use single-agent B-RAF inhibitor almost ever, because we have evidence that the combination with a MEK inhibitor is more effective and actually better tolerated. If the patient has a B-RAF V600 mutation, we can treat them with one of three different combinations. B-RAF inhibitors and MEK inhibitors together. It's either Vemurafenib and Cobimetinib, Dabrafenib and Trametinib, Encorafenib and Binimetinib. The mechanism of action for all three are very, very similar. Again, the B-RAF inhibitor target the activated B-RAF mutated protein. The MEK inhibitors target the downstream of B-RAF. The three combinations are quite similar in efficacy. They give a median PFS of about 10, 11 months with Dabrafenib, Trametinib and Vemurafenib, Cobimetinib. The combination has a numerically longer PFS of 14.9 months, but it was a separate different study done at a different era. I don't consider that to be evidence of any improved efficacy. All of them give about the same response rates of about 65 to 70%. Again, all of them have a shorter duration of response than immunotherapy. Again, you heard the median PFS is in the order of about a year. In terms of toxicity, the three combinations differ significantly in terms of toxicity. Dabrafenib and Trametinib is known to cause a lot of fevers. That's kind of the most relevant toxicity. That's what we deal with the most commonly. It's usually easy to manage, which we can discuss later. Typically with the dose interruptions or dose reductions. Vemurafenib, Cobimetinib is a combination where the toxicity it can cause some fevers, but really skin toxicity is more relevant and we see a lot of photosensitivity. Also some significant rashes. Encorafenib and Binimetinib is a combination that has kind of low level of toxicities across the board, but still has all of the different types. Meaning you can still get skin toxicity, you can still get fevers. We also see some GI toxicity with this combination with both some LFT elevation and actually also diarrhea is one of the side effects. Generally speaking, again, relatively similar efficacy. Different profiles of toxicity, which tends to be the kind of the determinant of which combination we use. When it comes to the first line setting, that is the compendium of what we currently have. Again, to briefly recap, single agent anti PD-1 antibody. The combination of Ipilimumab and Nivolumab, the combination of Nivolumab and Relatlimab or one of the three B-RAF and MEK inhibitor combinations.

Videos

Subject matter expert provides a comprehensive overview of available first-line therapy options for patients with unresectable or metastatic melanoma and a BRAF mutation.

First-line Therapy Options for Patients with BRAF-mutated Metastatic Melanoma

Hussein Tawbi, MD, PhD: Hello. My name is Hussein Tawbi. I'm a melanoma medical oncologist at MD Anderson Cancer Center. I'm professor and deputy chair of the Department of Melanoma Medical Oncology and co-director of the Brain Metastasis Clinic here at MD Anderson Cancer Center. What we're discussing today is a case of an unfortunate lady in her 40s, specifically a 47-year-old lady who presented with a 2.2-millimeter primary melanoma of the skin of her left thigh. On history, she did report the history of prior tanning bed use. She was an excellent performance status. After a wide local excision and a sentinel lymph node biopsy, she was found to have two positive inguinal lymph nodes. At least one of them had a two-millimeter deposit. Then proceeded to have a systemic staging with a CT of the chest, abdomen, and pelvis that did reveal one lesion in the right lower lobe of her lung. She has one metastatic lesion to the lung that measured 1.8 centimeters. We did proceed with a biopsy that did confirm this to be metastatic melanoma. As part of her staging, as we do for all of our patients with metastatic melanoma, we do image the brain. In fact, her brain MRI was negative. We did test her serum LDH level, which showed an elevated LDH at 456 international units. We did also perform NextGen test sequencing, and she was found to have a B-RAF V600E mutation. The patient is presenting to discuss for treatment options with us.

The typical patients that we see presenting with de novo metastatic melanoma fits into I would say a couple of categories. I wouldn't say that there's one type that is the patients that present to us. We do have as you may know, generally metastatic melanoma and melanoma is a disease actually of the elderly. Typically we find patients that are in their 60's who are presenting with their first diagnosis of metastatic melanoma. The segment of the population that's seeing the highest incidence increase is actually older white males. This is kind of a typical situation. We also experience unfortunately because of melanoma being a disease that can affect younger individuals especially after prior significant sun exposure, like tanning bed or kind of just generally a lot of prior childhood sunburns as well. We also see a younger patient population occasionally show up. This particular patient, that 47-year-old, I would say to your question is very consistent with the typical patient population that we see.

Hussein Tawbi, MD, PhD: For all patients that present with melanoma, I would say stage three and above we really highly recommend performing mutational testing, at least for the B-RAF mutation. Then ideally NextGen sequencing that not only identifies the B-RAF mutation but can identify a couple of other potentially targetable genes. Within the standard of care, we only have B-RAF and MEK inhibitors that are available for patients that have B-RAF activating mutations. But we also have actually an FDA approval for a very small segment of melanoma patients. Namely patients with NTRK fusions. There are two drugs, Entrectinib and Larotrectinib that are FDA approved for that population. That requires also you know a specific an NextGen sequencing. I do recommend doing that. However, across the board, the B-RAF mutation is the most consistent and relevant mutation that I recommend for all patients with at least stage three melanoma. In terms of other biomarkers that do matter, melanoma PD-L1 testing is not very relevant or important. It is not something that I obtain on my patients. If a patient comes in that has already been tested for PD-L1 status I consider it a variable of interest, but I almost never base my decision solely on a PD-L1 expression. We also care in melanoma, especially in the metastatic disease setting about LDH level. As you heard about this lady, we did check LDH because it is a prognostic marker. I wish we had predictive markers, but LDH is not very predictive as much as it is prognostic. The patients that have a higher LDH levels typically have worse outcomes overall. We know that for those patients, we may want to consider being generally kind of more aggressive.

Hussein Tawbi, MD, PhD: That's a great question. In the adjuvant setting, I do. Today's discussion is not focused on that population. Just to be sure in the stage three setting, we have to make sure that patients are aware of all of the options that are available to them. As you'll hear later in our discussion today, until a couple of years ago we used to really struggle between whether we should treat our patients with targeted therapies upfront or systemic therapies upfront or immunotherapies to be specific. I have to say that with recent results from DREAMseq that we were going to discuss soon, that has become less relevant. We generally start our patients on immunotherapy, and therefore we don't have to wait for the result of the B-RAF mutation. But ideally, we would have it in hand as soon as possible.

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Hussein Tawbi, MD, PhD reviews a case study of a 47-year-old woman with BRAF-mutated metastatic melanoma and discusses his approach to workup, including biomarker testing, for patients with the disease.

A 47-Year-Old Woman with Metastatic Melanoma

Hussein A. Tawbi, MD, PhD, director of Melanoma Clinical Research and Early Drug Development in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, discusses why melanoma responds so well to immunotherapy.

Hussein A. Tawbi, MD, PhD, discusses why melanoma responds so well to immunotherapy.

Hussein A. Tawbi, MD, PhD | Authors

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First-line Therapy Options for Patients with BRAF-mutated Metastatic Melanoma

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