December 2015, Vol. 4, No. 6

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The Current Landscape in Melanoma Treatment

Interview with the Innovators

An Interview with Jeffrey Infante, MD, of Sarah Cannon Research Institute

Infante_Jeffrey98pxThe COMBI-d and COMBI-v trials showed that treating BRAF V600 mutation–positive metastatic melanoma with the combination of da­brafenib plus trametinib resulted in a significant increase in overall survival and a 33% reduction in the risk of progression or death compared with treatment with dabrafenib alone. In an effort to understand how these data impact the care of patients with metastatic melanoma, the publishers of PMO spoke with Dr Infante, an expert in the field.


PMO Thank you for taking the time to discuss the evolving field of melanoma care, Dr Infante. We’d like to begin our talk today with your definition of personalizing care for patients with cancer.

Dr Infante
I think we’re moving into an unbelievable era of oncology where you’re able to personalize therapies to individual patients, not just based on their tumor type but down to the level of the molecular makeup of their cancer. Our efforts try to match therapies to each and every individual patient, and I’m excited to be a part of that movement.

PMO There are so many options available to patients with melanoma. In an attempt to understand treatment approaches, can you discuss a hypothetical patient with BRAF V600 mutation–positive malignant melanoma and the many options for first-line treatment to include chemotherapy, dabrafenib, vemurafenib, ipilimumab monotherapy, dabrafenib plus trametinib, pembrolizu­mab, nivolumab, and anti–PD-1 plus ipilimumab?

Dr Infante
For patients with V600 mutation–positive malignant melanoma, the good thing is that there are multiple good options. To address the options you mentioned, I’ll start by saying that I never use chemotherapy, and I rarely use dabrafenib, vemurafenib, or ipilimumab alone on initial therapy. The remainder of these treatment options require a lengthy discussion. Having options allows for the art of medicine where we can treat each patient as best we can to meet their needs compassionately while providing the best possible care.

When a patient walks into the office who has a BRAF mutation–positive melanoma that’s stage 4 or metastatic, then there’s a long discussion. I let patients know that there are excellent options, and I break them into 2 categories: there’s targeted therapy based on that BRAF mutation where we could use combination treatments with BRAF and MEK inhibitors; and we also have immune therapy approaches such as PD-1 inhibitors alone or in combination with the CTLA-4 inhibitor ipilimumab.

Another option is to enroll on a clinical trial. We’re working hard to get frontline clinical trials to address unmet medical needs. So even for first-line patients we prefer if they enroll in one of our clinical trials. For instance, there are combination trials ongoing that combine both BRAF and MEK inhibitors with an inhibitor of PD-1 or its ligand PD-L1.

PMO Is combined BRAF and MEK inhibition now the standard of care for patients with metastatic melanoma?

Dr Infante I don’t think there is 1 standard of care. We need to take into consideration the patients and where their tumors are, how they feel, how symptomatic they are, and if they have underlying autoimmune disease such as rheumatoid arthritis or a history of colitis. Further, do they have trouble swallowing pills? Is distance or travel an issue? These are considerations that may sway you one way or the other and allow an art of medicine at the bedside, as there’s not 1 approach.

PMO How do available options compare in overall response rates? And how does that affect your choice of therapy?

Dr Infante In the BRAF/MEK combinations, the response rates can be as high as 60%, and that’s a true partial response, representing at least a 30% decrease of their tumors. The expectation is that the vast majority of patients are going to get some benefit, and only about 20% of patient’s tumors will grow right through the treatment. Although around 6 of 10 patients are going to see a decrease of 30% on their imaging studies, the median progression-free survival is usually somewhere around the 10- to 12-month range, depending. But every patient is different. That’s the discussion I have with folks; I talk about the initial dabrafenib and trametinib studies and let them know we still have 7 patients on this combination from that early phase 1b trial who still come into our clinic 4 years out now.

There are some important points to cover: at 3 years the progression-free survival rate is 18%, so the majority of patients have technically progressed at that point. There are less than 20% who still remain progression free. But the overall survival rate at that time was approximately 40%. There are many patients who we count as having disease progression because they may have a new lesion in the brain or they have a new spot that either gets resected or radiated, and then they maintain their response in the other metastatic sites for prolonged periods of time. To think that 40% of these patients are still alive 3 years out is remarkable.

A lot of effort has gone into trying to understand which patients are likely to have that prolonged overall survival. If you looked at patients who had a low serum lactate dehydrogenase (LDH) level, a few metastatic disease sites, or those with complete response on their scans, the 3-year survival rate could be as high as 60%. This creates a bit of a conundrum in practice, because if a patient is very ill, has very aggressive disease, and is declining symptomatically, we may push for the oral BRAF and MEK inhibitors. But if you’re looking at the patients who get very durable responses with the oral therapies, it’s actually the same patient population that gets durable responses with the immune therapies. Those are some of the discussions you have to have with each individual patient.

We also discuss immune therapy options in detail. The way I talk to patients is if you’re getting ipilimu­mab alone, the response rate across studies has been somewhere in the 10% to 20% range with a median progression-free survival rate of about 3 months. Unfortunately, it’s impossible to predict which patient will gain benefit from the drug. Clearly, if you’re in that 20% that benefits, it is an amazing drug. Fabulous overall survival data have been published showing 20% of patients still alive at 10 years. There are a lot of side effects, and we have to treat a lot of people to help a few; however, if you’re one of the few it helps and you can manage the side effects, it can be a very durable and rewarding treatment. I think the PD-1 inhibitors look better as monotherapies, at least from a response rate and from a toxicity profile perspective. The response rates across studies with the PD-1 antibodies are in the 30% to 43% range, and the median progression-free survival has been around 7 months. But the percentage alive after a year or 2 looks higher than what it would be with ipilimumab; however, we don’t have the long-term follow-up that we do with ipilimumab.

Finally, the ipilimumab plus PD-1 combination is also a very active regimen, and response rates are close or equal to those of the BRAF and MEK inhibitor combination. The phase 3 trial of ipilimumab plus PD-1 had a response rate of 57%, and the median progression-free survival was over 11 months. So that’s a very active regimen, but there are toxicity issues with extenuated immune-related side effects.

PMO Let’s talk about managing the side effects.

Dr Infante When we’re going to start patients on immune therapy, whether it’s PD-1 alone or the combination of PD-1 with ipilimumab, we spend a lot of time educating them on the immune adverse events. My analogy to patients is that we’d like to have a campfire on every cancer cell in your body, but I don’t want a forest fire throughout your body. Usually forest fires are rare; the immune system tends to pick an organ, and we focus treatment on the inflammation in that organ.

A common side effect is skin rashes. Sometimes they’re mild, but occasionally they can be diffuse and need to be treated. Patients can also have significant diarrhea or colitis. We also talk about following their thyroid function, because the longer patients are on these immune therapies, the more likely they are to eventually need thyroid hormone replacement. We watch their liver and kidney function. We talk about arthralgias, with symptoms like rheumatoid arthritis, and potential pneumonitis.

We encourage open communication with the doctors and the nurses because in our experience, acting early on side effects is best. So we’ll often act on immune-related toxicities when it’s an early grade 2 event rather than waiting for it to become a grade 3/4.

Our first line of defense is usually steroids, and depending on what the adverse event is, we frequently use prednisone. We’ll often use 1- to 2-mg/kg prednisone, and if it’s a severe grade 3/4 event, we may even go higher. We tend to use prolonged tapers, the idea being that if you stop the steroids too fast, the fire rekindles. In our experience, it’s better to slowly taper over weeks. Many of the protocols allow tapering of the steroids over 4 to 6 weeks to get your prednisone doses down to 10 mg or less daily prior to reinitiating therapy. We act early with steroids to suppress the immune system, employ a prolonged taper, and really let the fire burn fully out before reintroduction of the medications.

There are occasions where high-dose prednisone may not be enough. With colitis we’ve used budesonide in addition to standard prednisone dosing, and in severe cases patients may need anti–TNF alpha therapy.

The combination of a PD-1 inhibitor with a CTLA-4 inhibitor definitely increases the frequency and severity of the immune-related adverse events. With this combination, about half the patients will have a grade 3/4 adverse event, so that’s enough to hold treatment or to use heavy doses of the steroids to try to calm the immune system down. The data also suggest that 4 of 10 people will not make it through all 4 doses of the combination because of these adverse events. So it’s a significant toxicity increase to take on compared with PD-1 alone, where 1 or 2 of 10 people, or around 15% to 20% of patients, may have a grade 3/4 adverse event where you hold the therapy or have to give steroids. You definitely introduce more toxicity by going with the combination.

PMO What side effects and management strategies are related to BRAF/MEK inhibitors?

Dr Infante
When we are taking care of patients on the BRAF and MEK inhibitors, they’re likely to have a fever. Approximately 6 of 10 will have a fever that is likely medicine-related during their treatment course. In about 2 of 3 patients, the fever is going to be grade 2 or higher and needs to be treated. Fevers usually occur around the 3-week mark, although it’s possible it will occur sooner. Conversely, there are patients who won’t have it for months, and then all of a sudden it’ll pop up. We’ll often try to suppress the fever by giving the patient ibuprofen or an ibuprofen-like medicine and alternate it with acetaminophen around the clock for 48 hours. If the fever is persisting through that, we’ll often hold the BRAF inhibitor. The BRAF inhibitors tend to have a short half-life, so they get out of the body pretty fast, and then we continue the ibuprofen and acetaminophen around the clock for a few days until the fever goes away.

Once the fever subsides, which usually that takes at least 3 to 7 days, you reintroduce the full dose. We try not to dose reduce patients for the fever. If you look at the patients who have fever, it’s only about 20% or so that have 3 or more fevers. In those patients it becomes more of a chronic issue, whereas in the majority of patients, they may have 1 or 2 episodes of fevers throughout their treatment.

PMO Do you dose reduce in those patients who have more frequent fevers?

Dr Infante Yes. If you’re one of those 2 of 10 people where you’re having continued recurrent fevers, there are options. We do dose reduce patients, but it’s usually after multiple times of trying to manage them first. This option would certainly be a last resort.

We’ve used prednisone in some patients to help with that. Steroids often help take the fever away. But there are a few patients who every time they come off the prednisone, the fever comes back. We have a few patients who have been on the medicine a long time who do have to be on a little bit of prednisone, 2.5 to 5 mg intermittently, to help them manage the fevers.

We’re trying our best to keep patients at full dose. We have had patients in whom we’ve decreased the dose of the BRAF inhibitor and the fevers have gotten better.

PMO Are there other side effects to be aware of with BRAF/MEK inhibitors?

Dr Infante Diarrhea can be an issue, so we’ll often use over-the-counter Imodium or Lomotil. We rarely have to dose reduce for diarrhea.

Rash can be an issue. You can get 2 types of rashes, the first of which is a BRAF inhibitor rash that is more of a flat macular erythematous rash. In those patients we would use steroids, either topical or a short course of an oral Medrol dosepack.

Patients can also get the acneform rash of the MEK inhibitor. We knew preclinically that by giving the MEK inhibitor with the BRAF inhibitor you were likely to decrease the clinical rate of hyperproliferative skin lesions and squamous cell carcinoma. There were good preclinical models to show that that was likely to happen and it did in patients, and the combination is better in that sense. One of the unexpected findings was that by giving the BRAF inhibitor with the MEK inhibitor, you decrease the rate and severity of the acneform rash caused by the MEK inhibitors. The rates, when you look at trametinib alone, are in the 70% to 80% range. When you give the combination, that rate falls dramatically with the rash down. For those patients who have acneform type rashes we use topical steroids or a clindamycin topical. For patients in whom it becomes a significant problem, we will use oral doxycycline or tetracycline derivatives.

If we have to dose reduce because of the acneform rash, we would dose reduce just the MEK inhibitor because that’s the one likely to cause that particular side effect.

PMO Can you address the value proposition of the BRAF/MEK-targeted therapies and immunotherapies in terms of cost versus clinical outcome?

Dr Infante This is a complicated question. Honestly, when you walk into the patient’s room, as a physician you’re trying to do everything you can to help that patient. The fact that we now have treatments that can be extremely tolerable for patients, and we’re seeing phenomenal outcomes compared with what we observed 5 to 10 years ago, makes the cost/value issue more difficult to put into context. Cost is a real issue, but when you see how you’re changing the lives of the patients in front of you, it’s hard to put together.

When ipilimumab came out, it was approximately $40,000 per infusion for a total of 4 infusions, and that sounded extremely expensive. But if you think about those 1 or 2 of 10 people who get the very prolonged response, $120,000 to have your metastatic melanoma held in check over many years is actually cost-effective. Now when you’re thinking about the BRAF and MEK inhibitor combinations, both are oral drugs and cost approximately $8000 a month apiece. Over a year’s time, that’s a lot of money, but it improves the patients’ symptoms and provides good quality of life. At this point we don’t know the duration one needs to be treated with PD-1 inhibitors to sustain the immune response. Do we need a year, do we need 2 years, or is it that you have to stay on them indefinitely for them to work? The cost of getting an IV infusion every 2 to 3 weeks for years is definitely going to weigh on the healthcare system. It’s an issue that will have to be tackled.

PMO We’d welcome your thoughts about immuno-oncology in general. Are there enough long-term data to justify the excitement around it?

Dr Infante I am excited about immuno-oncology or immunotherapy as a treatment option for our patients with cancer. I think it has created a paradigm shift, and oncologists are going to need to learn how to give these medications. It’s not going to be just melanoma. It already has FDA approvals in lung and kidney cancer. They’re likely going to have approvals in bladder cancer, and I expect other tumor types will follow. I do think the excitement is deserved.

When the CTLA-4 inhibitors came out, one of the big discussions was that you needed patients who had enough time for the drug to work, that their disease wasn’t so aggressive that the CTLA-4 inhibitors would need more time to get the immune system to check in and really be effective against the cancer. There’s this phenomenon of a pseudoprogression first. So there are some patients in whom the tumors will get bigger before they get smaller. It can take a long time for that to kick in, and then all of a sudden their scans will start getting better, but it could be many months into treatment. If you had a very aggressive cancer, was it worth giving a drug like ipilimumab alone knowing that it’s unlikely to have a rapid decrease in the tumor or a rapid response?

I think that’s changed with the PD-1 inhibitors and some of the combinations of PD-1 and CTLA-4 inhibitors. There are patients who have responses during the first 2 cycles of therapy, and that can be dramatic.

PMO Concerning testing, do you perform BRAF and PD-L1 tests across the board, or is there a particular subset of patients that you’re testing?

Dr Infante In this era of personalized medicine, we’re performing molecular profiling on patients’ tumors earlier and earlier. If a patient has an advanced disease, we’re ordering molecular profiling from the beginning. We’re testing for BRAF mutations, but we’re also testing for others as there may be clinical trial options for these patients if we find other targetable genetic alterations.

It’s worth mentioning that the FDA-approved companion diagnostics to test for BRAF mutations will only pick up the common BRAF V600 mutations, but they can miss some of the variants. A deeper sequencing panel can pick up variants that are missed with the standard testing. We had a patient who was BRAF negative by the standard FDA-approved test, but we found a BRAF V600 mutation on a deeper sequencing or next-generation sequencing approach, and the patient has been on treatment now for 2 years.

Also, we had 2 adjuvant BRAF trials in which we were testing adjuvant patients who had stage 2c or stage 3 melanomas. There was vemurafenib versus a placebo after resected stage 2c or 3 melanoma and then there was a dabrafenib/trametinib, so the combination of a BRAF/MEK inhibitor versus placebo trial if you had stage 3 melanoma or higher that was resected. Those studies have finished accrual, and we are waiting on the results. Now, I’m not treating patients off of a trial in that setting, so currently I’m not testing the BRAF status unless they have advanced disease or are likely to progress imminently.

I think the PD-L1 story is evolving in melanoma as well as in other tumor types. The most data behind this came from the phase 3 ipilimumab versus nivolumab versus the combination of ipilimumab/nivolumab trial. In that trial, if you received the combination, your response rate was 57%, but if you were PD-L1 positive, your response rate was 72%, and if you were PD-L1 negative, it was 55% rounded. Then if you looked at the median progression-free survival, if you were PD-L1 positive, it was 14 months for the combination, but it was 14 months for PD-1 alone. So it suggested PD-L1 may be a surrogate member for our “inflamed” tumor, and in that setting a PD-1 inhibitor alone was as good as the combination.

The interesting part is that if your tumor was PD-L1 negative, the median progression-free survival in the combination arm was 11 months versus 5 months in the PD-1 alone arm, suggesting that if you had an inflamed tumor you may be able to just use PD-1 alone, but if you didn’t have an inflamed tumor, then the combination may be a better approach. Somehow the CTLA-4 inhibitor may prime or inflame the tumor so the PD-1 works better.

That was 1 trial, and there are many trials looking at this issue. Are all PD-L1 testing the same? There are different vendors performing the testing using different assays. Is it just PD-L1 status that is important? For an optimal patient selection strategy, information on tumor-infiltrating lymphocytes, certain genetic alterations, specific neoantigens, and total mutation load may all play a role. Right now there are a lot of unknowns to use it as a predictive marker. But I think it will come. In our practice, it’s just not ready for prime time. PD-L1 status may be one of the factors, but it may not be the only factor.

PMO What unmet needs exist in the treatment of patients with melanoma, and what efforts are needed to address them?

Dr Infante It has been incredible to be a part of this movement in melanoma. I think the whole field of oncology is learning from what’s been done in melanoma, where you can have a targeted therapy approach to genetic alterations that are driving tumors and at the same time have this parallel development of new therapies designed to unleash your immune system against the cancer again.

It’s a phenomenal time to practice as an oncologist and treat patients with melanoma, but the worst discussion I have every week is with a patient who has had either the immunotherapies, PD-1 combinations or PD-1, and, if BRAF mutated, the BRAF inhibitors, and there are no options. The numbers are great, but we’re not curing everybody with metastatic or advanced disease, so there’s a lot of work still to be done.

Finally, another unmet need is moving these drugs into earlier-stage disease. The hope is that some of these adjuvant trials really pan out, and that more will continue to be done.

PMO Thank you for your time and insights.

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