Dr Sigrun Hallmeyer Highlights Clinical Achievements and Barriers in Melanoma

Sigrun Hallmeyer, MD, is medical director of Advocate Lutheran General Hospital’s Cancer Service Line, and co-director of medical research at Advocate Aurora Health, in Illinois. In this interview with The American Journal of Managed Care^® (AJMC^®), Hallmeyer touches on several important topics within the melanoma space.

Not only does she detail unmet needs for patients living with melanoma—chiefly, prevention, legislation, and patient education—but she also addresses how socioeconomic limitations can have an adverse impact on patient outcomes, what clinicians can improve upon when treating their patients, and top goals for treating patients with advanced disease.

The interview has been edited for clarity.

AJMC^®: What do you consider to be the largest unmet needs in melanoma?

I would say unmet needs exist throughout the entire trajectory of melanoma: from prevention to early detection to surgical management for locally limited disease, all the way to patients who face more advanced disease or stage 4 or metastatic disease. So if I’m thinking in those 4 categories for prevention, I think we still have a lot of work to do in terms of promoting better legislation for indoor sun tanning.

I think we’ve done a lot of work in exposure to toxins as it comes to smoking and alcohol and other well-known carcinogens, but indoor sun tanning is still something that is very heavily promoted in the United States—in some states more than others. In Illinois, you need to be 18 in order to frequent one of those indoor tanning salons, and you need parental consent before then. That’s a huge legislative achievement. And I would like that to be a federal thing rather than just a local thing.

Another thing that I feel is an unmet need in the prevention strategies is, as we treat our young athletes and people that go to pools and public spaces like beaches and whatnot, it’s probably inconceivable that you would have a daughter or a son in baseball or softball without a helmet or without a cup. But they are out in the burning sun and nobody thinks about sunscreen, and I think that is where we kind of need to move. It’s an unmet need, that protection from sunburn—not necessarily from sun exposure. Sunburn still needs to be understood as a carcinogen, and we need to protect our teenagers and young adults because that’s our highest-risk population for the future development of melanoma. So that’s prevention.

In early detection, I still feel that our primary care physicians and OB-GYN offices, even pediatricians’ offices, don’t do an appropriate job in explaining the ABCDE [asymmetry, border, color, diameter, evolving] rule for the early detection of abnormal moles. Very much like we are so good at explaining when you should call 911, what constitutes a stroke or heart attack, or any type of physical symptom that should not be just monitored but rather be brought to a physician’s attention, I feel the skin is one of the big organs in our body. But we don’t do a good education in our primary care providing offices, so there is an unmet need there.

Then, local management. I often function as a physician providing second opinions, and in that I see often patients who have had inappropriate local therapy. For instance, they had a shave biopsy rather than an excisional biopsy for their primary melanoma or they had an excisional biopsy, but a sentinel lymph node biopsy has not been performed. Or they have been treated for a lesion in a cosmetically very sensitive area, so the face or the décolleté, or the breast maybe or something else, and they were referred to a general surgeon and not to a plastic surgeon. So there’s definitely still unmet need in terms of the appropriate management of local disease, from the initial diagnosis to shave vs excision all the way to surgical treatment.

Lastly, in terms of the unmet need for metastatic disease, we do recognize that we’re a large country and not everybody can have access to tertiary care, not everybody can be treated at an academic center with a melanoma specialist. But when it comes to a diagnosis of melanoma, where over the last decade or so we have transformed a universally deadly illness of advanced metastatic melanoma to potentially curable disease, it is really a question of life and death for these patients. So even if you’re in a remote area, I think that we should really do a better job in educating these physicians and care providers that these patients should really be referred to a melanoma center of expertise, at the very least for a second opinion. Not that they couldn’t get the treatment locally, but it should be supervised by somebody who does this for a living, because grave and ultimately deadly errors can occur if treatment is not administered in a timely fashion, is not administered in a safe fashion. Many of the therapies that we have can have very significant and potentially fatal side effects. Also, sequencing matters. We have lots of clinical trials that show us that immunotherapy up front followed by targeted therapy leads to much better outcomes than the other way around.

Those are the unmet needs that I can put in a nutshell that we have.

AJMC^®: How do social determinants of health impact the diagnosis and treatment of advanced melanoma?

Unfortunately, unmet needs exist across the board for any patient population, but they are significantly magnified when you talk about somebody who has socioeconomic limitations. Again, living in a rural area, but also not speaking English, not having a primary care provider where you can actually go and have a mole looked at, not having health insurance where going to your primary care provider and having a mole looked at is causing significant financial distress.

Then add to that once you have a diagnosis of melanoma, many of the medications that are typically employed in that setting, including surgery and, of course, the oral and the intravenous drugs, place a significant financial burden on our patients. Also, everything that we discussed in terms of prevention, early detection, early therapy for localized disease, and probably, most gravely, for patients with advanced disease, these socioeconomic barriers become magnified and ultimately significantly influence their chance of having positive outcomes.

AJMC^®: What do most practitioners get wrong when treating advanced melanoma?

Not so much in my practice, but more as to what I see when I get involved in the care for second opinions and would like to look back and just say, “Oh, my God, if I could just reverse time and go back in time…” Again, early detection. I see a lot of young patients who have been seen by a health care provider for years and will then say in hindsight that something on their skin had been looking abnormal for a long time. Skin examination—unlike listening to the heart, listening to the lungs, doing all the things that we’re so well trained for as physicians—in and of itself is still, unfortunately, a rarity for most annual physical assessments. That is, I think, a significant thing that I see, where oftentimes diagnoses are delayed and then patients are diagnosed at a much later stage, at which time this disease is much harder to cure.

What I often also see is that patients who were initially treated at an outside facility and had the appropriate local therapy were never referred to melanoma specialists for adjuvant therapy—additional systemic therapy after the surgery to reduce their risk of disease recurrence, it was never discussed, wasn’t offered—and then I see them when they come with stage 4 disease. That’s certainly a big, big issue, not just in my area of practice, I’m sure that that’s a pan-American issue.

Another thing that I’ve identified is, due to the advent of highly active therapy for metastatic melanoma that is accessible to all, meaning clinicians in the United States with different levels of expertise, what is unfortunately still—and we know this from many publications—now chosen as the first line of therapy for BRAF-mutated melanoma is targeted therapy. We now have really good data that that is not the best first chosen therapy; nevertheless, still 75% of patients with BRAF mutations in the metastatic setting are offered this treatment in the first-line setting. So, you have a good question there. Maybe that’s later in terms of adherence to NCCN [National Comprehensive Cancer Network] guidelines, clear departure there. But it is an easier treatment; it’s just pills, people do it from home. Physicians may be more familiar and more comfortable with the side effect profile, unlike with immunotherapy. So that is certainly a mistake that I see that we need to work against: Patients with this particular mutated melanoma should not be approached with a targeted therapy approach first unless there are contraindications for immunotherapy.

One more thing. Once a patient is in active immunotherapy, I see a lot of patients who come for a second opinion who were told that they can no longer receive curative intent immunotherapy because they’ve encountered a side effect. And I see a lot of mismanagement of the side effects of immunotherapy and physicians who don’t have a lot of experience with it or have maybe the wrong experience with it. Sometimes you get burned with 1 patient who had a bad outcome and then you implicate that bad outcome into your future patients and don’t offer therapy or you pull back a lot sooner than would be needed. This is something where I feel often conflicted, because I see patients for a second opinion who have been pulled off of immunotherapy for reasons that I would have never discontinued therapy, and conversely, I’ve had patients continue on immunotherapy where it was clearly not safe; they were coadministered with immunosuppressive agents, which essentially made the immunotherapy not work.

There’s a lot of room for error, and unfortunately that room is often inhabited by colleagues. Not to say I’m not free of error either, but if I’m specifically asked, “Where are pitfalls for this?”, this is a relatively big one.

AJMC^®: What are the top 3 goals in treating a patient with advanced melanoma?

First is cure. Second is cure. And third is cure. We need to approach our stage 4 melanoma patients with intent to cure them. If I would have said this to you 10 years ago, you would probably have said, “I can’t publish that.” That is now a realistic outcome. We have long-term follow-up for many clinical trials, probably most prominently the Bristol Myers Squibb study [CheckMate 067] that looked at ipilimumab and nivolumab in combination. More than 40% of those patients achieved complete remissions, and many of them never needed any further lines of therapy. That’s what I would consider cure now after multiple years following completion of therapy: not being exposed to any second-line therapy ever.

That’s incredible in just 1 year of research. So I think that’s the top goal that needs to be considered for any patient who walks into any physician’s office who has what we would consider a curable entity. They should not be addressed in any other way than, how can I get to this outcome?

AJMC^®: How closely does real-world treatment align with NCCN guidelines?

These guidelines are really tailored to get patients to a curative outcome. This is where we get into what I mentioned earlier, that unfortunately, still many BRAF-mutated patients do not receive immunotherapy as their first-line treatment. Many immunotherapy-treated patients are unfortunately mismanaged when they do experience side effects. Both of those will influence the risk of them not achieving a complete remission and with that, not achieving a curative outcome. So that’s a big deal. And thirdly, in terms of NCCN guidelines, we do know that combination immunotherapy is superior to single-agent immunotherapy. However, most patients who receive immunotherapy still receive single-agent immunotherapy and not combination immunotherapy. That is, again, a departure from the NCCN guidelines, where ipilimumab and nivolumab in the stage 4 setting are really a category one recommendation for the appropriate patients—albeit I’ve seen many very appropriate patients who were still not managed that way.

AJMC^®: How can payers change or improve coverage and diagnosing and treating melanoma?

I’ve been involved with Society for Immunotherapy of Cancer [SITC], Association of Community Cancer Centers [ACCC], and the Melanoma Research Foundation, so I think payers are well suited—and I have great connections already in those arenas, in supporting these organizations. The problem that I see is, oftentimes when industry and payers in that world reach out directly to health care providers or systems, there is a perceived bias.

Ultimately, it’s probably a smarter use of their dollars to work through recognized institutions like ACCC, SITC, and ASCO [American Society of Clinical Oncology] to help fund educational campaigns, to fund research projects that really understand the state of current health care and to move the dial by showing the physicians, “Here are the NCCN guidelines, here is your adherence. There’s a delta we need to tackle.” I think that’s definitely something that I will always say to peers and to industry—that that’s a good use of your dollars, in terms of supporting these organizations that have essentially that shared goal.

I am a really, really big believer in patient advocacy and direct patient education, because I can tell you that the vast majority of patients who find me, for instance, and other melanoma specialists, it’s not because their oncologist is referring them to me. It’s mostly because of word of mouth from, for example, a friend of a patient of mine who had a good experience here or doing their research online, finding us through the Melanoma Research Foundation, or educational resources that tell them they need to at least have 1 appointment with a melanoma specialist to set them up on the right track. In that sense, I do think that direct-to-patient advertisement, if it is not just selling a drug, but is also making sure that this is appropriate in terms of educating the patients in terms of their chance for achieving a curative outcome and what the steps are to get there, is another useful way of spending their dollars.

AJMC^®: For patients who experience treatment resistance, what are the next steps?

Some of this may be a little bit repetitive right now, but obviously see a specialist, because what one physician may deem as resistance may actually not be resistance. We need to be very careful when we use that word. Also, sequencing of therapy is super important. We’ve also talked about targeted vs immunotherapy, single-agent vs dual-agent therapy, and really understanding that even when patients experience either primary or secondary resistance to therapy, they can still be candidates for a curative outcome. Staying aggressive and not introducing hospice at the first sign of a problem, in my practice has paid off quite well. I will also say, referral to specialty centers so we can accrue those patients into clinical trials so we can get them to second, third, and fourth lines of therapies that might be experimental today but may become the standard of care tomorrow.

I will always bring up this example: We were benefiting from a phase 1 clinical trial with a company called Medarex about 15 years ago. It was a very, very open clinical trial with a drug called MDX-010, and it accrued patients with Eastern Cooperative Oncology Group performance score of 3—essentially, very, very ill patients. To this day, I will tell the story that I pulled 2 patients out of hospice to participate in this clinical trial who I really felt were still candidates for additional therapy—but back in the day, we really didn’t have any additional therapy to offer them—and both of those patients were cured. They went through 4 cycles of this then experimental drug, this company was bought by Bristol Myers Squibb, and now this drug is marketed as ipilimumab.

So for those patients, access to a clinical trial was not just life changing, but life saving. This is how we learn; ipilimumab would not have been approved, would not have been studied, if it wasn’t for these patients saying, “Yes, I will participate.”

Resistance to therapy, or “failure to therapy,” just means that we have failed the patient, not that the patient has failed us, and we have to look outside the box. That really means a clinical trial.

AJMC^®: In your experience with cancer survivorship, how do you assist and assess patients who achieve remission?

I have a big interest in cancer survivorship. That’s why I run the center here. And this is a big deal, especially in the context of immunotherapy. First off, we need to understand that not all patients are cured. It’s almost self-explanatory, but I wanted to say it out loud. At least half of our patients, if not more, do die from their disease—specifically, from melanoma—so we need to moderate the expectation. Even among patients who achieve complete responses, there are still a lot of patients who will ultimately relapse and still succumb to their disease. So, survivorship in that setting needs to be defined as not “cured and now you’re surviving and you’re fine.”

Survivorship really starts from the moment that you’ve been told that you have cancer, and so living with cancer is still surviving. As long as you’re not dead, you’re surviving, so the needs of a cancer survivor, and specifically a melanoma survivor, are very fluid and change over a period of time. In the initial stages of diseases, the focus might be on how do we make sure that you tolerate your treatment well, including financial tolerance. How do we make sure that we manage side effects so they don’t become long-term side effects or life-altering side effects? Think about the immunotherapy and the endocrinopathies that we can induce that ultimately will confine patients for the rest of their life to additional medical therapy with, say, steroids or thyroid replacement therapy.

I have 1 patient who developed type 1 diabetes as a consequence of immunotherapy. But hey, he is cured from his melanoma. I saw him recently, and we discussed this whole thing, and he said, “Look, you gave me a disease that I can live with and can get old with, and that I can manage, but cured me of a disease that was sure to kill me.” That’s really, ultimately, the challenge of survivorship: Finding that right balance of patients having access to getting old, and getting old healthy, by managing toxicities short term and long term for those patients.

AJMC^®: What are you working on in melanoma that you are excited to share?

Number 1, clinical trials. That is my world, because I want to move the science forward and I want to have more patients gain access to clinical trials and more patients gain access to the chance of being cured. Everybody can do targeted therapy, everybody can now do single-agent or combination immunotherapy; they’re all FDA approved, they’re out there now. That doesn’t make me special. What makes me tick and get up in the morning and want to see my patients is getting them excited about participating in a clinical trial.

We currently have 6 melanoma trials open, which is crazy. That’s a really big number for a community oncology setting. For instance, we’re studying the margin with for stage II melanoma. In 2022, we still don’t have scientific clarity if a 1- or a 2-centimeter margin is clinically sufficient and appropriate for these patients. Maybe for an outsider, this may not be a very important question, but if you have a melanoma lesion on the face or on a cosmetically sensitive region, 1 or 2 centimeters makes a huge difference in terms of how disfiguring those surgeries can be. Clarifying that is a big, big deal for us, so we’re participating in a clinical trial to hopefully formally answer that question.

Another one, supported by Pfizer, is actually 2 trials that are looking into administering the combination of targeted therapy and immunotherapy at the same time so we can finally get rid of that controversy around what should come first, what should come second. If we can find a way to give both at the same time and get 2 comparable outcomes, maybe that will be the gold standard of therapy in the future without jeopardizing the outcomes for those who have mutations who are currently typically only treated with targeted agents in the first-line setting.

Then it’s all about making immunotherapy better. We’re participating in the Ultimovacs study, a vaccine study that is added to ipilimumab and nivolumab—so making our current standard of care even more effective by inducing a specific immune response against melanoma cells beyond the nontargeted immunotherapy of ipilimumab and nivolumab.

We’re also opening a clinical trial with tumor-infiltrating lymphocytes, or TIL cells, which is also taking advantage of our expertise that we have from our bone marrow transplant program. It’s looking into the world of cellular therapies, which is the future of oncology and of curing more disease, in many minds.

Also, I just recently opened 2 clinical trials that are helping us understand immunologic side effects and finding ways to predict patients are more likely to develop them so we can be find those problems sooner and treat them more effectively, ultimately with the idea to preserve their candidacy for continued immunotherapy and that ever-sought-after goal of curing them without jeopardizing them for diabetes, thyroid dysfunction, or potentially worse outcomes. We’re constantly trying to move the dial forward in order to increase the numbers of patients who ultimately have a curative outcome.

In terms of my clinical arena, we are starting a multidisciplinary clinic right now on Fridays in our melanoma clinic. We’re having our plastic surgeon participate in our clinic, and with that we’re trying to make it a bit easier for our patients. We’re seeing them in postop follow-up, at which time we can discuss the pathology and potential adjuvant therapy at the same time the surgeon sees them for stitch removal and assessment of the surgical healing, and all that. This is more like a clinical advancement, but it gets me excited because ultimately it helps many of our patients who travel quite a distance to our office because of our level of expertise. We don’t have to make them come twice just to have their stitches removed and seen by the surgeon.

Lastly, my cancer survivorship program is always looking into becoming better and more tailored to specific patient populations. We’re looking for specific programs and supportive groups that might be formed in the next year or so that are specific for melanoma patients and their caregivers.