April 2015 – Maui Derm

Botulinum Toxin: Science and Evidence Data, Dose, Duration, Dogma

April 17, 2015

Joel L. Cohen, MD

In this presentation, Dr. Cohen discusses the neuromodulators that we commonly use and how to best apply the science and evidence into clinical practice. Dr. Cohen spends about 40 percent of time in practice doing Mohs surgery and the other 60 percent is dedicated to aesthetics.

It’s important to remember that we typically don’t focus in one area but rather treat assess patient’s full face and multiple regions, and we tend to use a combination of therapies/treatments (neuromodulators, fillers, lasers, and other energy-based devices such as radiofrequency and ultrasound). Clinical research is important to us, as clinicians, for a number a reasons — not only does it allow us to see what products are coming up on the horizon, but it affords us the opportunity to experience these therapies first-hand in clinical practice.

Currently, we have three neuromodulators approved for aesthetic use; onabotulinumtoxinA ((Botox), abobotulinumtoxinA (Dysport) and incobotulinumtoxinA (Xeomin). The important concept here is that these products are probably more similar than they are different.

BTX-A On-label Aesthetic Uses

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Of note, when you go to other countries, especially in Europe, you will see a different spectrum and wider-spectrum of approved aesthetic indications for these products.

We know, from clinical data, that botulinumtoxin can make patients feel better about themselves and can help them outwardly convey their inner emotions more appropriately. Many patients want to delay the outward appearance of aging as well as simply “look their best”. (Finn, Cox, Earl. Social Implications of Hyperfunctional Facial Lines. Dermatol Surg 2003;29:450-455.)

A double-blind, randomized, placebo-controlled health outcomes survey conducted by Dayan and colleagues analyzed the effect of botulinumtoxin type A injections on quality of life and self-esteem. The researchers found that the injections result in improvements in quality of life (QOL) and self-esteem. Additionally, botulinumtoxin-naïve patients demonstrated greater improvements in QOL and self-esteem than participants previously exposed to botulinumtoxin. Moreover, botulinumtoxin-familiar patients demonstrated sustained improvement in QOL and self-esteem as compared to botulinumtoxin-naïve patients, even when injected with placebo.

All of the approved botulinumtoxin type A products have a 150 kD botulinumtoxinA core neurotoxin protein. Incobotulinumtoxin (Xeomin) lacks the accessory proteins that are naturally produced by clostridial bacteria, which Botox and Dysport maintain.

When you look at the clinical studies, remember that there are different comparisons and different endpoints. Non-inferiority studies tend to compare two products at very specific time points. One noninferiority study compared incobotulinumtoxinA to onobotulinumtoxinA at four weeks and 12 weeks, as assessed by investigators, a panel of independent raters, and patients. This study demonstrated that incobotulinumtoxinA is equally as effective as onabotulinumtoxinA in the treatment of glabellar frown lines and both products were well tolerated — at the specific timepoints studied. There are; however, issues with non-inferiority studies. Because there are two time-points, there may be a missed evaluation of the duration of efficacy and a “waning effect.”

If you look at different demographics of your study cohort in some clinical trials, you’ll see that in some studies it’s really reflective of what we do in clinical practice; however, in other studies, it may not be – such as a disproportionate number of patients being quite young. These are issues that need to be considered when we’re looking at overall responses and comparisons among different products.

We also need to think about “low-powered” comparisons. In a comparison of two botulinum toxin type A preparations for the treatment of crow’s feet (Prager, et al), there were only 21 patients in this study. This may not be enough to tease out any major differences between the products in terms of the number of patients studied.

So, in short, there are 3 botulinum toxin products available in the US. It’s very difficult to make direct comparisons. These are different products and we need to consider the fact that the dosing can be different and the studies can be designed differently in terms of non-inferiority, demographics and power as well as an evolution of different study endpoints (2-grade improvement versus 1-grade).

We are beginning to see a shift towards more stringent primary endpoints. A randomized, double-blind, placebo-controlled phase III trial, conducted by Hanke and colleagues, investigated the efficacy and safety of incobotulinumtoxinA in the treatment of glabellar frown lines using Composite Endpoint Treatment Success (CETS), i.e., looking at a two-grade improvement. If you look at how often physicians saw a two-grade improvement versus patients, you will see about 48 percent.

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Remember that it’s difficult to compare data as previous studies often used a one-grade improvement; therefore, demonstrating a larger responder rate and a longer duration of treatment.

The pivotal trial with Botox for the lateral canthal lines required at least a two grade improvement from baseline on both the investigator’s and subject’s assessment of CFL severity at maximum smile using the 4 facial wrinkle scale. At day 30, we see a responder rate of 25.7%. Dr Cohen states that we know we have seen higher responder rates than this; however, because there has been a chance in the way in which the FDA wants this to be assessed, i.e., patient and physician composite scores, the numbers are lower.

What about conversion ratios?

Again, remember that these are different products and we need to look at them as such. Various studies have looked at the concept conversion ratios, but that may be difficult to compute in clinical practice. Regulatory agencies worldwide have recognized that these products are not interchangeable.

Some Other Things to Consider…

When we look at patients, specifically speaking about the lateral canthus, not everyone needs the exact injections that were used in clinical trials. There have been studies, dating back to 2003, looking at different patterns of injections and the way that different people look. It’s important to identify these features in your patients and individualize therapy. When Dr Cohen looks at a patient and he/she is superior dominant, he may give more of the neuromodulator up high, and a little bit less in the middle or below. Keep in mind that on that same horizontal is the bunny line and the contraction of the nasalis. Also along this horizontal is the pharmacologic brow lift.

If we understand the anatomy that the orbicularis oculi pushes our brows down and the frontalis lifts them up, then if we inject the one site where you’re getting the maximum pull down below the lateral, you may see better improvement in the lateral brow lift we can sometimes see when we treat the lateral orbicularis oculi.

Drs Cohen and Dayan conducted an open-label, randomized, dose-comparison study of botulinum Toxin Type A in the treatment of dermatochalasis. They found that a single-site injection of botulinum toxin type A in the lateral infrabrow can offer effective treatment for mild to moderate upper eyelid dermatochalasis—with perhaps a couple of millimeter lateral brow lift at best.

We know that when we look at patient’s brow positioning, there are some that should not be injected with a neuromodulator in the off-label area of the forehead. There was an important article that was published in JAMA Dermatology last year that looked at not only a grading scale for dermatochalasis, but it also discussed the factors associated with dermatochalasis. (Jacobs L, et al, 2014) From a grading scale, there are four categories for sagging eyelids (mild, moderate, severe, very severe). Specific risk factors associated with sagging eyelids include, age, male sex, lighter skin color, smoking status and higher BMI. In many cases, people “blame” genetics for sagging eyelids; however, we can see that there are things that we can do to intervene to help reduce the risk.

Combination Delivery

After the approval of Radiesse with in-office adding of anesthesia in the same syringe, some physicians began to use the same adaptor to combine fillers and neuromodulators. Dr Cohen doesn’t feel that this is a good idea; in fact, he believes that it probably does not save time, leads to an unstandardized mixture, and likely leads to less precise injections – as there are simply some areas where you don’t want toxin but you do want filler. So combination in the same syringe of toxin and filler in Cohen’s view is not a good idea, but combination of toxin and filler in their respecitive different syringes is still a good concept.

When it comes to the lower face and the area around the mouth, a study conducted by Carruthers et al indicated that both physicians and patients saw a greater improvement when the patient was injected with both the hyaluronic acid dermal filler and a neuromodulator. (Carruthers A, et al. Dermatol Surg. 2010;36:Suppl4:2121-2134.

And other studies have shown synergy with the combination treatment of different regions with toxin and filler. A 2003 study of Botox plus Restylane demonstrated that if you inject patients with Botox and then have them come back for Restylane, it has a longer tissue residence time in terms of filler and correction than if you injected Restylane alone (18 weeks versus 32 weeks.)

Dosing

Many of us have seen an overall change in practice patterns when it comes to dosing. In some areas, like especially the forehead, we have shifted from higher doses of toxin to lower doses in order to achieve a more natural, relaxed look for our patients. In the forehead, for example, Dr Cohen and other colleagues who participated in the more recent PRS journal consensus, now inject about half of the dose they previously used in the forehead — thus creating often a more natural look, simply softening the musculature, and maintaining brow shape and positioning better. There’s a lot to consider with regards to neuromodulators. We have seen where NOT to inject, but it’s important to maintain brow positioning and shape as well as symmetry.

There are very specific grading scales that can be useful in clinical practice and Dr Cohen recommends incorporating them into your regimen. This is helpful when discussing the goals of therapy with patients—for instance, for the forehead “softening of the musculature”.

Growth Factors in Photodamaged Skin: Clinical Pearls

April 14, 2015

Zoe Diana Draelos, MD

Dr Draelos provides us with her clinical pearls on growth factors (GF):

GF are multifunctional peptides active in the picogram range
GF act as signaling molecules between cells by binding to cell surface receptors
GF modes of targeting:
- GF release into the blood stream to reach distant targets (endocrine mode)
- GF diffuse over short distances to affect other cells (juxtacrine mode)
- GF influence neighboring cells (paracrine)
- GF act on the cells in which they are produced (autocrine mode)
GF relevant to cosmeceuticals are epidermal growth factor, keratinocyte growth factor, fibroblast growth factor, platelet-derived growth factor
Epidermal growth factor is produced from macrophages and monocytes, it affects epithelium and endothelial cells stimulating the proliferation of keratinocytes, fibroblasts, and endothelial cells
Keratinocyte growth factor is a small signaling molecule that binds to fibroblast growth factor receptor 2b found in the epithelialization-phase of wound healing
Fibroblast growth factor is a very potent angiogenic factor derived from monocytes, macrophages, and endothelial cells (22 human FGFs identified) that induces proliferation of endothelial cells, keratinocytes, and fibroblasts
Platelet derived growth factor is produced by platelets, macrophages, neutrophils, smooth muscle cells and induces proliferation of smooth muscle cells and fibroblasts
Current controversy exists as to whether growth factors are drugs or cosmetics

Immunotherapy Update

April 7, 2015

Keith T. Flaherty, MD

At Maui Derm 2015, Dr Flaherty, a medical oncologist at Massachusetts General Hospital, reviewed updates in melanoma therapy for advanced disease and how these drugs have impacted clinical care. As we try to build on targeted therapy based on our current knowledge of pathways, we ask ourselves what will be the role of combinations and/or precision medicine-type immune therapy matching strategies. Of note, the therapies discussed are investigated in the metastatic setting first, and as dermatologists, we are considering their use in the adjuvant setting.

Ipilimumab

Ipilimumab was the first entry into the field in terms of a positive phase III trial. Ipilimimab at 3mg/kg, with or without gp100, was given every three weeks for four treatments. Based on the data, there’s no question that ipilimumab outperformed the gp100 vaccine alone. This outcome, at the level of overall survival, demonstrated the efficacy needed to warrant the approval of ipilimumab.

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Ipilimumab was already a ten-year old therapy for which metastatic melonama patients were taking the drug for a few months course of treatment and who are still alive and well. Dr Flaherty states that we knew, when these results emerged, that there may be a truly, durable, lasting effect.

There is a cost to this type of treatment in terms of adverse events (AEs). All of the toxicities associated with this drug come from autoimmune attack(s) affecting the skin, large intestine, endocrine glands, or hepatic autoimmune injury. Why these tissues and not others? There are several theories, but not a firm understanding. If you focus on the ipilimumab monotherapy group, you can look at those who had severe autoimmune toxicity, i.e., you have to stop giving the drug and/or give high-dose corticosteroids to stop the autoimmune reaction. This occurs about 10 percent of the time. Everything short of this autoimmune toxicity appears, in short, in mild or moderate form and basically goes away without any immunologic intervention.

Phase III MDX010-20 Study: Most Common irAEs (Grades 3-5) Over Entire Study

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The idea is that we think we’re unmasking normal tissue tolerance, but in a largely reversible way. About two thirds of patients who receive ipilimumab have some form of autoimmune toxicity, only about 10 percent have enough of it that it creates a truly life-threatening scenario for which we need to intervene. Not all of the toxicities manifest at the same time. Dr Flaherty feels that in major melanoma programs, we have become quite comfortable with regards to counseling patients as far as what to look out for and when to call with suspected reaction(s). Dr Flaherty believes that ipilimumab is a therapy that can absolutely be safely administered.

The other phase III trial that corroborated the effects of ipilimumab looked at patients taking ipilimumab (10mg/kg) plus decarbazine (850 mg/m2) or dacarbazine (850 mg/m²) plus placebo at weeks one, four, seven, and ten, followed by dacarbazine alone every three weeks through week 22. This trial was similarly positive with the addition of ipilimumab. The difference, as shown below, was really not very different from that of the ipilimumab versus vaccine trial.

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The toxicities of the two-drug approach were modestly worse. When the FDA looked across the two data sets, they didn’t feel that the addition of chemotherapy was synergistic; therefore, they went with the previous study and approved ipilimumab as a monotherapy for metastatic melanoma.

In clinical practice, you can look at the pooled data set (below) and feel comfortable counseling patients that they have about a 20 percent chance of walking away with the diagnosis of metastatic melanoma by receiving this treatment (four doses over three months) with time-limited risk of toxicity.

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We have learned that if you “cherry-pick” patients and only treat those with lower disease burden, the rate may be as high as 30 percent.

The PD-1 Pathway

What is the role of the PD-1 pathway in suppressing anti-tumor immunity? How might we think about deploying antibodies that try to intercept this negative immune regulator? We can target on either the PD-1 side or the PD-L1 side [with antibodies]. Scientifically, we would anticipate that this would alleviate the negative influence that the expression of this immune marker on tumor cells can produce in terms of silencing T-cells directly. There was a belief that PD-L1 target is actually safer than PD-1 targeting because you don’t disrupt PD-L2/PD-L1 interactions that a PD-1-blocking antibody would and there is some clinical evidence that this may be true.

Pembrolizumab

Pembrolizumab was FDA-approved in the late summer of 2014. In the pivotal, randomized study, patients who had received ipilimumab and/or a BRAF inhibitor, if they were BRAF mutant, were randomized to receive pembrolizumab 2mg/kg IV every three weeks (ongoing), pembrolizumab 10mg/kg IV every three weeks (ongoing) or chemotherapy. This was a trial that was aiming to show that patients who had exhausted the available therapies could benefit from treatment with pembrolizumab. This data set addresses the unmet need of patients who don’t get a benefit from ipilimumab.

Primary End Point: PFS (RECIST v1.1 Central Review)

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The data (above) is impressive when looking at pembrolizumab compared to chemotherapy at the level of progression-free survival. This is clearly a positive study and very important data for patients who had exhausted all of the other treatment options. It is true; however, that this therapy does not work for all patients and about half of patients will still experience disease progression. The number of patients who have objective responses, again these are patients who have not exhausted all other options, appears to be about 20-25 percent.

Two different doses were investigated in this study (2 mg/kg Q3W and 10mg/kg Q3W). Because there was no difference in efficacy, the lower dose, which is modestly safer, was the regimen that was approved. The toxicity is identical in type with ipilimumab. This type of immune therapy produces the same autoimmune reactions in terms of the affected organs and tissues. The issue is that the severity is clearly lower than that of iplimumab.

AEs of Clinical Interest for Pembrolizumab

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If you look at the Grade 3 and Grade 4 AEs (above), notice how there are only a few autoimmune toxicities in the approved pembrolizumab group (2mg/kg).

For our patients, this is a drug that can be effective and a bit less dangerous in terms of autoimmune toxicities.

Nivolumab

Nivolumab, another PD-1 antibody that was approved in December 2014, was studied in patients who had not received prior therapy. Patients were randomized to nivolumab (3 mg/kg IV every two weeks) plus placebo or placebo plus dacarbazine (1000 mg/m² IV every three weeks). The thought here was that if you were going to conduct a clinical trial that was chemotherapy controlled, you couldn’t include BRAF-mutant patients because you wouldn’t offer them decarbazine as a front-line “cytotoxic” therapy. Patients in this study were stratified based on PD-L1 status.

This drug has a huge impact in terms of overall survival.

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The data demonstrate a one-year overall survival rate of 73 percent. Many practitioners look at the evidence and would like to get PD-1 antibodies in the front-line. Currently, these drugs are approved for second- or third-line.

Progression-free survival clearly improved as well with nivolumab. These are immune therapies, but they have a clear impact on tumor burden as well. About sixty percent of patients have some demonstrable tumor effect.

When you see a response, the likelihood that the response is going to be durable through six and twelve months of follow-up is very likely.

PD-L1 status is an interesting biomarker to which we should pay attention. The overall survival outcome for patients whose tumors express PD-L1 on their surface does better than the control group and the overall population. (see below)

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It is fairly clear that we can do some enrichment by using PD-L1 on the tumor as a biomarker.

Combination Therapy

In the medical oncology metastatic melanoma field, there is a lot of research around the concept of combining PD-1 and CTLA-4-blocking antibodies. Tumor responses in patients receiving nivolumab plus ipilimumab demonstrated that approximately 90 percent of patients responded after a follow-up of about 13 months.

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There is still a group of patients who remain refractory, even to two-drug therapy. This phase I data ultimately launched a large phase III trial and we expect to see the data in June of this year (2015). The combination regimen cannot be given at the full dose of each drug; at least one of the therapies has to be attenuated. The data in the phase III trial is not quite as robust; however, we look forward to hearing the results in June.

When you look at the best available data with PD-1 monotherapy (pembrolizumab), this is actually not bad (below). Dr Flaherty feels that it is still unclear as to whether combination therapy is lifting us to a new plateau. We need more evidence to support that. Regarding safety, in patients who were taking combination therapy at the doses that were taken into the phase III trial, there was a sixty percent rate of severe (Grades 3 and 4) autoimmune toxicity. The results from the phase III data will help us to determine whether or not this combination therapy can be clinically useful.

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Adjuvant Therapy

There is some preliminary evidence on adjuvant therapy as we only have an interim result from a trial looking at ipilimumab monotherapy versus placebo in 951 patients with high-risk, stage III, completely resected melanoma. The primary endpoint was recurrence-free survival. If you focus on hazard ratio, there is about a 25 percent improvement. The question is whether or not this drug is really doing something more effective in the adjuvant setting than it would otherwise do in the overt metastatic setting. This is not clear—we need to see more data, more follow-up, and more overall survival evidence to know if this is a therapy that should be moved to the high-risk, resected setting. This therapy can have significant toxicity consequences, so we do have reason to be concerned.

Toxicities are substantial in the adjuvant setting. Notice the rate of Grade 3 and 4 toxicities. (below) This is the same drug that has a ten to twelve percent toxicity rate in the overt metastatic setting, but more in the adjuvant setting—partly because of the higher dose.

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There were treatment-related deaths in this trial. This is not something that we can take lightly.

Vaccines

From 2010 to 2015, in the metastatic melanoma field, we have run about twelve phase III trials and they have all been positive, except for the most recent of the vaccine trials, a MAGE-3 peptide. Prior to this, we have had three peptide vaccine trials suggesting a detriment in overall survival. We still have not found a way to deploy these therapies. Dr Flaherty states that many of us are hopeful that either by using some biomarker selection strategy or, more likely, using these agents with immune checkpoint antibodies, we may be able to find utility in steering immune responses towards specific epitopes. Currently, there are no ongoing phase III trials.

Conclusions

Ipilimumab was the first-in-class immune checkpoint inhibitor and has demonstrated survival advantage. Long-term follow-up clearly supports survival impact with only three months of therapy. PD-1/PD-L1 is considered “best-in-class” based on higher response rates and better disease control; however, the percentage rate of long-term survivors is unknown. The combination of ipilimumab/nivolumab suggests synergistic toxicity and the question remains regarding synergistic efficacy. The adjuvant role of therapy is still not defined as we only have interim data for ipilimumab at the higher dose.