This webinar will review the molecular basis for the different types of targeted therapy, including immunotherapy, for periocular and orbital tumors. Through understanding the molecular basis, the mechanism for resistance and side effects with this class of medication will become clear. We will discuss the possible future use for targeted therapy and what some of the current limitations in neoadjuvant or adjuvant use are. Specifically, this will include the issues with margin control with neoadjuvant use of hedgehog inhibition.

Lecturer: Dr. Vivian Yin, Memorial Sloan Kettering Cancer Center, New York, USA


DR YIN: Hello, everyone. Thank you for joining us today. My name is Vivian Yin. I am an oculoplastic surgeon that has a niche or specializes in oncology. And today I thought I would give you guys an update on what we’re using targeted therapy for, and specifically what I think the next step will be, in terms of targeted therapy for periocular and orbital tumors. So to start with, in terms of what we’ll cover today, I think it’s important to learn and understand the molecular basis for how targeted therapy works. Part of the reason for that is: By understanding that, you’ll know what the drugs will be efficacious for, but as well as what the mechanism of resistance and possible side effects. It’s very hard to memorize all the side effects and mechanisms of resistance if you don’t understand how the drug works. We’ll touch a little bit on the combination of treatment modalities, as well as possible future use for targeted therapy, or what’s kind of in the pipeline in terms of research. And then lastly we’ll talk a little bit about immunotherapy. There’s a very new exciting drug that’s now officially approved for use in squamous cell carcinoma. So to get us started, the first question I was gonna ask is: What do you think is targeted therapy? Is it a special type of treatment that prevents the formation of cancer, meaning carcinogenesis? Is it a molecule used to label cells with radiation to decrease the potential for side effects? Does it work on all individuals, especially those that are elderly or immunocompromised? Does it target a specific mutation or pathway in cancer to prevent proliferation or progression? So I’ll give everyone a few more seconds. Okay. So it looks like most people are picking that it does target a specific mutational pathway. So that is what the definition of targeted therapy actually is. It does not prevent the formation of cancer. It actually is a mechanism where it prevents proliferation, and we’ll talk about some of the other stuff, and the reason why I included this in the first question. So the official definition of targeted therapy is a drug that blocks the spread or growth of cancer by interfering with specific molecules. So these molecules are referring to, maybe, transmembrane proteins, or maybe a specific activator or cytokines, and it blocks that pathway from being able to propagate, which is what helps cells grow, as well as progress, as well as spread of cancer, meaning metastasis. So I’ll show you two pictures of cases that would trigger someone — or I hope would trigger someone — to think along the lines of non-surgical treatment. So on the left there on the screen is a gentleman who had a neglected basal cell carcinoma, and on the right there is a recurrent squamous cell that has gone from the eyelid into a large orbital mass, which is causing the globe to be displaced superiorly and medially. This is where targeted therapy becomes part of the discussion, and this brings up the next point, which is: Targeted therapy is used for advanced cancer. It’s not meant to be used for little basal cells or little squamous cells that are surgically excisable. So the first pathway I’ll talk about, which is implicated in basal cell carcinoma, is the sonic hedgehog pathway. Now, sonic hedgehog, which is this cute little animal on the right, is the way this mutation or pathway is named, because when there’s a mutation in this pathway, drosophila or fruit flies form this particular weird banding that you see — can people see my pointer? Right here, where it kind of looks like the spikes on a hedgehog. And that’s the reason why, when scientists found this mutation, causing this abnormal differentiation and migration of cells, they thought it would be cute to name it sonic hedgehog. Now, why do we care about it? Because this pathway has been shown to be in locally advanced and metastatic basal cell carcinomas. So this is the pathway that is the sonic hedgehog. It involves a little transmembrane protein called PTCH, which when it’s not activated, actually inhibits another membrane, which is responsible for sending signals into the cell, to allow the cells to differentiate and proliferate. Now, when that PTCH membrane has a substrate that’s bound to it, this inhibition is released, and therefore a proliferation cascade is sent down into the cells. What Vismodegib does is it blocks the transmission of this protein downstream from PTCH and prevents this proliferation pathway from activating. So we see this gentleman with the large neglected basal cell looking like this, after about three months of treatment on Vismodegib. Now, a couple of things you’ll notice is that: Once the tumor regresses, you end up with deficit of soft tissue, and that’s because what may look like tissue here is actually tumor. So one of the problems or one of the things you still have to address is deficit of tissue, even after you see regression of tumor. And this was the original study that led to the approval of Vismodegib for locally advanced basal cell. This is a watershed plot, and zero means no change. Anything that’s negative means regression of tumor, and anything that’s positive means growth or progression. So as you can see, about roughly two thirds of patients had either stable disease or response with the drug, with, however, still a few cases of progression. And if you look at kind of a big picture point of view, the overall response was about 43%, which may look low at first, but for cancer treatment, this is actually quite magnificent. Most treatment in terms of chemotherapy would achieve an overall response of only about probably 20% to 30%. Now, the second number here, the 21%, is — CR means complete response by biopsy. Meaning that even clinically you don’t see anything on the surface. If you biopsy that site, there’s also no microscopic tumor there. So if we want to talk about success and be stringent about success, complete response is what we would be looking at. Now, 13% of the patients did progress, which tells you that this drug, like all other cancer treatment, doesn’t work on everyone. So monitoring is still very important. What got us really, really excited is actually when we saw the use of this for basal cell nevus syndrome. This is a 24-year-old college student who has all these bumps that look like acne on his face, but this is actually all basal cell carcinoma. And these individuals are known to have a mutation in their germline that causes these formations of basal cell. And patients on this treatment not only have regressions of all these tumors completely, that do not require any surgical treatment. So when we look at the clinical study for this, what they saw was that not only do patients not form new basal cell. The basal cell they had also regressed in size by about 65%, compared to patients that were treated with placebo. So in 2012, that was when Vismodegib was first approved, for hedgehog inhibitors, for metastatic and advanced basal cell, but there’s a caveat. The caveat is that this has to be recurrent after surgery, or a patient who is not a candidate for surgery or radiation. So keep that in mind as we talk about some of the other uses. The other word of caution I mention to people is that: A lot of time, you see a dramatic response well on drug, but then when you withdraw the drug, a lot of the spots start coming back. People mislabeled this as resistance. This is not resistant. This is actually tumor progression after the patient was not on the drug anymore. If you remember earlier, I mentioned that the drug stops the proliferation cascade. But what the drug does not do is it actually does not kill the cancer cell. So this is not a chemotherapy. This is not cytotoxic. The drug is only good at preventing progression, and the body or the immune system likely takes care of the rest. So when you biopsy sites that look like they’re normal — so let’s say if we pick a spot right here that looks like it’s regressed, if we biopsy that, there is one in six chances that that will actually still show basal cell on the biopsy. Now, I mentioned a little bit about resistance. Although progression after you stop the drug is not considered resistance, there are actually true resistance to Vismodegib. There are a couple of hypotheses about why this happens. The most common one is that it’s likely a mutation in Smo, the second transmembrane protein the drug binds to, that alters the binding site for the drug so the drug cannot bind to it. There’s also some postulation of possible alternative pathway, and when I show you a map of how these pathways interact, it’ll make a little more sense to you. There’s two other theories. One was the Notch modulation. Notch is a parallel pathway, and it’s believed that maybe that interacts with this, so that it almost has an escape mechanism. And then possible upregulation of downstream signal is also postulated. Now, once again, progression after you stop the drug is actually not considered resistance. So let’s move on to this question. The advantage of targeted therapy is that there are no side effects, since it targets cancer cells only. Do you think that is true or false? That’s great. I’m glad that most of you realized it is actually false. All drug therapy has side effects. And targeted therapy doesn’t just target cancer cells. It targets all cells. It just targets a specific pathway. So that will become important in understanding the side effects. So for Vismodegib, there have been two clinical trials that have had long-term follow-up, one based out of America and another one based out of Europe. And by and large there are four major side effects you need to be aware of if you have a patient on Vismodegib. I tell the patient this is nearly universal. The first one is muscle cramps. It typically happens in the lower legs, and it can be severe enough that the patient has trouble sleeping. The other one is alopecia. You saw that all the patients on the drug have thinning or complete loss of hair, of their beards, facial hair, as well as the hair on their head. Dysgeusia is loss of taste. Not weird taste, but complete loss of taste, so everything tastes like cardboard to the patient. And that is believed to be what causes weight loss. Unlike chemotherapy, where the weight loss is believed to be due to cellular changes, this is just due to loss of taste, so they lose weight. Fatigue — we don’t know the specific mechanism, but almost half of the patients complain of that, more in the US trial than in the European trial. Because muscle cramp is the most universal side effect, there was some worry about potential CPK elevation. CPK is a marker for muscle damage or muscle breakdown. So people looked at that specifically, to see if elevation of CPK can also cause kidney issues, as well as health issues and potentially death, if the elevation is severe, and that’s the reason why people looked at specifically whether there was CPK elevations in these events where people have severe muscle spasm. And the bottom line is that there is — the majority of patients do not have CPK elevation. However, there is a subset of roughly about a third who will. And this is not correlated to the grade of muscle spasm. So reports from the patient of how bad the spasm is. Therefore you do have to check this on all patients, instead of just those who have severe symptoms. This is the gentleman you saw earlier. The 24-year-old with the basal cell nevus syndrome. And this is just to show you the degree of alopecia. This is important, actually, with clinical counseling. So before the patients start on the drug, it’s useful for you to be able to describe to them what they should expect in terms of side effect. So usually the wording I use is you’re gonna get thinning of hair, but you don’t become completely bald, so you can still see a little fuzz on this patient’s head. The symptoms do resolve after you stop the drug. But it does take some time. And the first thing to go away is muscle spasm. Which can take anywhere from one to three months. Hair loss and taste come back next, which takes about six months. But for the patient to actually gain back their original weight, it takes as long as a year before that is completely back to to baseline. And the most common thing or the most common problem with the patient on the drug is actually not tolerating the drug. So patients stopping the drug because of the side effects. Because of that, people started looking at… Well, is there a way for us to decrease the risk of that, so the patient could stay on the drug for longer? And one of the things people looked at was: Can we give people drug holidays? Now, drug holiday is not a new concept. We use it for other things like chemotherapy. And the most interesting thing I think from this study was that the most deciding factor, if you look at the number, mBCC means metastatic, laBCC means locally advanced. BCNS means basal cell nevus. So the highest rate of patients going off the drug is depending on diagnosis. You can think about it: If you have metastatic cancer, you believe you’re gonna die, therefore you’re more likely to comply with therapy, even in view of having side effects. But if you have basal cell nevus syndrome, you’re a little bit less likely to stay on the drug, because you feel well, you know you’re gonna live, and therefore the motivation to stay on the drug is less. So this highlights to the clinician, to us, that when you have a patient on this drug, it’s actually very important for you to hand hold these patients and try to get them through the drug therapy and encouraging them, and that actually makes a huge difference in terms of this continuation rate. In terms of efficacy, when you look at the chart below, alternating between 12 and 6 months, versus every 8 weeks, after an induction period, even though it seems like there’s a difference there, it’s actually not statistically significant. The good news is that the efficacy is pretty close, slightly lower, in the absolute percentage, but not statistically significant. So it is safe to give patients drug holidays without fear of completely losing overall response. The other thing that came on approximately five years ago or a few years ago was that there was some reports or case reports of formation of squamous cell carcinoma with patients that were on Vismodegib. Now, they pulled together all the long-term studies between the US and Europe, and looked at: Was there truly an increased risk of squamous cell beyond baseline? Meaning these are Caucasian patients who had a lot of sun exposure to start with. And they found at one year the incidence of squamous cell was not higher for those people who had Vismodegib compared to control. There was no increased risk of forming squamous cell. This is good, considering that some other targeted therapies do have this as a potential side effect. So let’s take a little review of what we’ve gone through so far. In terms of Vismodegib or hedgehog inhibitors in general. So just remember that these are only approved for locally advanced and metastatic disease. This is not meant to treat excisable eyelid BCC. And progression after stopping the drug is actually not resistance. It is the normal mechanism of what you would expect with the pathogenesis of this disease, as well as the way that this drug works. Side effects are the most common reason for discontinuation of treatment, and it is worthwhile to consider intermittent dosing, so as we know, this can obtain a similar response, and you may be able to keep the patient on the drug for longer. There is no increased risk of squamous cell. However, there could be CPK elevation, which does need to be monitored and managed. These are, however, not grade or time-related. So you need to be aware and check that on all patients. Okay. So let’s move on a little bit, on what are the controversies around the use of Vismodegib or hedgehog inhibitors? And one of the controversies is that the FDA approval is for locally advanced disease only. So that leaves the physician in a bit of a conundrum. What is locally advanced disease? Is it surgery that leads to the loss of an eye? Surgery that leads to loss of the lacrimal drainage system? Loss of the entire or half of the lower lid? Or loss of one third of an upper lid? If you pool 100 oculoplastic surgeons, you’re not gonna get to the same conclusion, which leaves things a little bit gray in terms of what this drug should be used for. And just to make things even more muggy, there’s been a lot more talk about the neoadjuvant use of Vismodegib. This is not FDA approved, so if you go down this path, you’re absolutely using the drug off-label, and the patient has to be aware of this. But even if you do decide to try this, how do you know if the cancer will regress with little spots or satellite lesions that are left behind? And how do you decide where to cut, after you treat a patient with Vismodegib? Do you cut on the original edges? If you do, what have you really gained by using the drug ahead of time? And there is also some issue with margin control that I’ll highlight in a little bit. And then the last question is: How long do you treat the patient for? Three months, four months, six months, a year, before you take the patient to the surgery to cut out the rest? So there has actually been now two retrospective studies looking at the neoadjuvant use of Vismodegib. Neither of these are prospective, and the numbers are pretty small. One is a study out of MD Anderson and the other out of Europe. Both of them only had eight patients, and both had pretty similar pathological complete response. So about 60% or so. The follow-up are also relatively good. So ten months to a year. However, you’ll notice that the duration of treatment is quite variable. So for the MD Anderson study, the mean duration was 14 months, although in Europe the study was only 6 months. And if you look at the range in brackets, it’s even more variable. Why does that matter? I’ll highlight that with this case of mine. So this was a 65-year-old lady who presented with a neglected right basal cell in the right medial canthus. It invaded into the lacrimal sac. This was a poorly differentiated cancer. The pathologist could only call it advanced carcinoma with basaloid features. They weren’t comfortable calling it basal cell. The patient wanted to try Vismodegib instead of surgery alone, which would have involved extensive surgery and would have caused the patient to be uncomfortable due to dry eye from loss of eyelid. You can see on the CT that it’s involving a big enough area within the orbit that excision would be quite difficult. After even four months of being on Vismodegib, you see flattening out of the edges. There is no ectropion, because this was all tumor before. With the tumor gone, the eyelid doesn’t have enough soft tissue to maintain its structure, and there’s less soft tissue density compared to before. At this point, based on a protocol of my colleagues in Michigan, four months is usually when peak side effects occur. So at this point we decided to take the patient off medication and take her to surgery. First it’s kind of hard to decide: Where are you gonna check your margins? I thought: Let’s check around the original margin. So we did the entire thing and thought we had cleared the margin. This is what the patient looked like immediately post-op. However, this edge that was originally read as negative or no cancer came back positive. And when we decided that we were gonna go back in and clean this out again, a lot more of that initial area ended up being positive. So this is what prompted us to go back, the box in white. The blue represents to 4, and this was positive. These little islands that you can see, that is deep actually to the surface of the skin — the red corresponds to this. Once again, little pockets of basal cell. The yellow corresponds to the corner picture. And then the purple represents to the bottom left here. Now, if you kind of… So there’s more basal cell here, as you can see. These little speckles are inflammation. Here it’s a little bit of inflammation here. It’s actually discontinuous. So is this representing potentially satellite regression? Or is this just difficulty in judging where the basal cell is, because of the inflammation that occurs with Vismodegib? These are still questions we don’t know true answers to. There have been lots of debates between oculoplastic surgeons about the concept of satellite regression. This was a case from the MD Anderson paper. You can see they’ve marked out their resection margins at three spots. So the question becomes: Is this representing satellite regression? Are we doing the patient a disservice by going ahead and treating them with Vismodegib first? However, it’s not all grim. So this was another patient with a recurrent — multiple recurrent basal cell carcinoma. So he presented to me with a recurrence in the medial canthus, into the lacrimal sac. You can see on the corresponding axial CT here, it’s almost a perfectly nodular involvement of the lacrimal sac. And then after two months of being on therapy, he had to be taken off therapy, because of liver enzyme elevation. So he was tolerating the drug, but he was starting to have systemic side effects, so we had to stop the drug. However, even between the original and two month, you can see that this little bump is now gone. But on CT, there still seems to be maybe some thickening of the lacrimal sac mucosa. Is that cancer? It’s hard to tell. So at around two weeks later, we took the patient back and did an unblock excision around the entire sac, and besides mucosal inflammation, he had no residual cancer in the entire specimen. So it’s really hard to judge which patient is gonna respond and which patient is not. And how long do you treat a patient for? The first case was on therapy for four whole months and still had lots of residual cancer. The second was only on for two months. If you look back at that study of intermittent dosing, in terms of response, or degree of response, you kind of get a vague feeling that the treatment kind of plateaus somewhere around here. Probably around the four to six month mark. And the last thing I’m gonna mention is just that there may be other combination therapies that may be coming up as potential better use, instead of using Vismodegib neoadjuvantly than with surgery. And this is something I think everyone should consider, which is a combination of Vismodegib with radiation. This was a North American study with two sites, MSK being one of them, and California — San Francisco — being the other. All patients had locally advanced — not just limited to the periocular, but of all head and neck basal cell. They received induction of Vismodegib for twelve weeks, then had concurrent Vismodegib and radiation. The radiation for this study was 50 grey, not an insignificant dosage. But some would argue lower than conventional treatment dosage of 65 for head and neck cancer. The reason we thought of combining this is that Vismodegib is a radiosensitizing agent. So just like the whole concept of using chemotherapy to sensitize to radiation, we’re using Vismodegib as a sensitizer. This was a locally advanced medial canthus BCC, with the lacrimal sac involvement. So you can see tumor invasion into the retroorbital space here. And with the combination of radiation and Vismodegib, you can see the nice cosmetic results from this surgery. I think we can all agree that if I try to cut this out, there’s not gonna be as cosmetically pleasant of an eyelid contour as this. And on the imaging, there’s also complete regression of the tumor. So something to keep your eyes out for. Now, in terms of neoadjuvant hedgehog, I think the optimal duration likely will end up being somewhere around six months. More studies still need to go on to confirm this, but that’s probably hypothetically where we need to go, if we ever want to consider neoadjuvant use. Margin control is very difficult, because of the amount of inflammation that goes on. So if you are gonna resect afterwards, consider special handling, and maybe even not using frozen section, and using rush paraffin, like what we do for melanoma, which is how I handle these cases now. And the last thing: Consider the role of radiation, either as a consolidation along with Vismodegib, or adjuvant treatment after. So let’s take a break and switch gears a little bit. And move on to the next pathway that we’re gonna look at. So in terms of cutaneous squamous cell carcinoma, It has been associated with which targetable mutation? BRAF mutation, EGFR overexpression, PTCH mutation, or RAS mutation? So there is a pretty good spread. So it looks like the majority of people think it’s a RAS mutation. The second most common is EGFR overexpression, followed by PTCH and BRAF. The most common is EGFR overexpression. There has been some RAS mutation noted in cutaneous squamous cell, but it’s not that common. Maybe sporadically PTCH mutation, and there has not been any BRAF mutation seen in squamous cell carcinoma. So let’s talk about EGFR overexpression. This was the oldest targeted therapy, not necessarily for cutaneous. For other malignancy. But for cutaneous squamous cell, EGFR overexpression has been seen at over 78%. Also in actinic keratosis, which makes sense, because many people believe it may be a precursor for squamous cell carcinoma. You’ll see this is actually quite complicated, with multiple intermembrane proteins involved. And downstream from it, there’s some crossover between RAS and MAP kinases. And I’ll show you a little bit later on the crossover with BRAF, and that may be why some of you thought BRAF is implicated. So this was the lady I showed you earlier, with the recurrent squamous cell, involving a large portion of the orbit. Pushing the eye superiorly and medially. Here is axial scans of that same patient, after starting on Vismodegib. You can see how the proptosis and globe displacement has improved significantly, and the decrease in size of the tumor on CT scan. However, you’ll notice it’s not gone. So this was a patient treated on EGFR because of her age and comorbidities, that we’re just trying to have control of disease. We’re not aiming for regression. But this gives the patient a lot more comfortable of an eye and function of the eye. Interestingly, EGFR inhibitors are actually not approved for cutaneous squamous cell, even though we talk about it and use it quite a bit. There are two categories of EGFR inhibitors. They can be a tyrosine kinase inhibitor, a small molecule inhibitor, and these are probably the more favored drug, because of ease of administration. So it’s a pill a day. There are two of them. Iressa and Tarceva are the brand names. Gefitinib and Erlotinib are the generic games. And they’re for lung and pancreatic cancer. Cetuximab was the first one approved for colon cancer, not even for lung, but it’s also approved for head and neck squamous cell carcinomas. So this is not cutaneous, but mucosal squamous cell carcinomas of the sinuses. And these have classic side effects. This lady with the acne-like rash on her forehead and face, this is an acne-like or actinoform eruption that if you have a patient walk in like this, you almost immediately know they’re on an EGFR inhibitor. It’s most common on the face and trunk, rarely on palms and sole, and it can happen in two to three days. The mechanism of the side effect is what we call on-target side effect, meaning it’s a direct result of the drug working the way it’s supposed to. And what it does is it diminishes the proliferation of basal keratocytes in our cell and decreases cell turnover, and that’s what forms these acne-like rashes. There’s also upregulation of inflammatory cytokines, and I believe there might be some alteration in maturation, as well as neutrophilic infiltrate that is part of the cell turnover mechanism. It’s way more common with antibody-based EGFR inhibitors, rather than with the tyrosine kinase small molecules, but it can happen with both. The other classic sign that is relating to us in ophthalmology is trichomegaly. This is not trichiasis. This is lashes growing out of normal follicle sites, but they are long, they are irregular, and they’re very coarse. It can happen most commonly with lashes, but it can happen with brow as well. And this is because of terminal differentiation of these follicles, that is also controlled by EGFR. Erlotinib and cetuximab have been shown to be more common to cause this, but the incidence is still only around 10% to 12%. This occurs a little bit later than the actinoform rash. About 10 weeks. It can happen with weekly or biweekly dosing, and goes away about a month after you stop the drug. In terms of management, most of the time we just ask the patient to trim or help them trim their lashes. In terms of actinoform rash, sun exposure has been known to worsen it, similar to what we know with acne. You can treat this with topical steroid, or the same thing you can use for garden variety adolescent acne. Metronidazole, clindamycin, and erythromycin have been tried, as well as tetracycline, doxycycline, and minocycline. Dose reduction is incredibly rare, mainly because if patients are on this drug, it’s quite effective, so we try to mitigate the side effects and help the patient stay on the drug, rather than reducing the dose or drug discontinuation. But those options are in your back pocket if you need them. The use of doxycycline and minocycline has been associated with decrease in the grade of severity of the rash by as high as 70%, both doxy and mino and tetracycline. So that’s probably what I would use as first line for this type of rashes. The last aspect that we’re gonna look at is the use of immunotherapy. So we mentioned earlier that squamous cell carcinoma is actually an off-label use for EGFR inhibitors. I’m about to tell you something that is on-label use, that is relatively new, and exciting for squamous cell carcinoma. So PD1/PDL1 is a ligand receptor that interacts with others in our immune system. These are non-cancer-specific. These are just normal aspects of our immune system. Where PDL1 binds to PD1, and that interaction prevents the T killer cell from killing the tumor cell. Now, if you block this interaction between the tumor cell and the T-cell, the T-cell then is able to recognize the tumor cell as something that is foreign, and therefore able to kill that cancer cell effectively. So the tumors are really smart, and that’s why they develop these PD1 receptors, to try to prevent our immune system from attacking it. So moving on to immunotherapy, the next question for us to think about is: Is immunotherapy better tolerated and safer, compared to the targeted therapy that we mentioned above? This is a common question, because immunotherapy is kind of the hot topic now, since its first introduction for the treatment of metastatic melanoma. So I’ll give everyone a few more seconds to weigh in. Okay. So two thirds of you think that this is true. That immunotherapy is better tolerated, and a third thinks it is not true. So let’s see. So before we get into answering that question, this is to show you how dramatic, and why there is such excitement, both in the public and in the press about the use of immunotherapy. So this PD1 cemiplimab is actually specifically approved for locally advanced cutaneous squamous cell. This is from one of the advertisements from the company that makes this drug. To show you how dramatic the response could be, even with just six weeks of treatment. So all these little lumpy nodules on this patient’s head are all lobules of cutaneous squamous cell. And you can see almost near complete regression of them, even after a mere six weeks of being on treatment. And this is another watershed plot. You’ll notice it’s very similar — you’ll think that it’s replicated from when I showed you the Vismodegib watershed plot. And even the numbers look largely similar. And this is something that we’ve noticed very interestingly with targeted therapy. Is that the response seems to be almost replicated of each other. So the objective response with PD1 inhibitor is also around 47% to 50% of patients. The time to response was relatively short. So like you saw in the last patient, about six weeks or less than two months before you see response. About half of the patients have — sorry, about 81% of the patients have overall response, which is quite promising for, once again, for cancer drugs. Just to show you an example of one of the patients of mine — this was a 100-year-old who had multiple surgeries with Mohs, multiple radiations, radiation chemotherapy, more surgery, and once again recurred, and still is left with this large squamous cell carcinoma involving the nose, as well as the medial canthus. This is her after three months on pembro. Now, pembro is another PD1 inhibitor. It’s not the one that is approved for cutaneous squamous cell, but it acts with a similar mechanism as the others. You can see the regression of the size, and also kind of this angry-looking edge has now flattened out. However, the patient still has a large defect. This is the septum that you’re looking at, that’s eroded through the side of the nose. But this is a very good response, and much better than what you’ll see if we had treated this patient with chemotherapy. Now, in terms of side effects, for immunotherapy, this is probably one of the things that doesn’t get talked about a lot. So immunotherapy is actually more toxic, or has more serious toxicity and mortality than the previous targeted therapy I’ve mentioned. So EGFR, as well as Vismodegib. So death has been seen with immunotherapy, and in the study for cutaneous squamous cell, the one that led to its approval, there were actually three deaths, or 5%. These three patients, two of them were in their 90s, and the mechanism of death involved pneumonitis, and hypercalcemia, in these two 90-year-olds. The third is believed to be possibly not related to drug, however, in clinical studies like this, we have to include them in our analysis. And the most common side effect is an immune mediated response with inflammation. So you can have pneumonitis, inflammation of your lungs, you can have cellulitis, inflammation of your skin, hypercalcemia is something that we really worry about in these patients, and patients can also have pleural effusion, because of this immune response. Almost every single patient, pretty much 100% of the patients, will get side effects of any grade. So other kind of quote-unquote inflammatory things is that they can have severe watery diarrhea, almost like a colitis appearance, they get severe fatigue and nausea, they can also have a non-specific rash through their entire body, because of this immune response. So if anything, I would say immunotherapy is probably more dangerous in elderly patients, and therefore we don’t really consider it unless you’re really stuck and there’s no other available therapy. So in summary, the take-home that I hope you’ve gotten from this is that targeted therapy inhibits cellular proliferation, but not the initiation of cancer, through, typically, blocking a pathway that is mutated and constitutionally activated through a small molecule. There are monoclonal antibodies, as with EGFR inhibitors, but the majority of the therapies coming on the market are small molecular. The approval of this drug is for locally advanced cancer, not for small surgically resectable cancer, even if the patients just say I don’t want surgery. And besides being better tolerated, all have potentially dangerous side effects. And the efficacy in immunotherapy actually requires the patient to be immunocompetent. So if you have a patient who is post-kidney transplant, let’s say, and wants to be on the immunotherapy, the efficacy is different than what you saw in those studies, and you have to take that into consideration, and consider alternative therapy. So with that, I will see if… Perfect! We have 15 minutes left. So I’ll see if there are any questions. Oh, while you type in your question, I’m just gonna answer some of the questions that were sent in with the registration. So I don’t treat retinoblastoma. I know that was one of the questions. And I don’t treat intraocular melanoma. So I’m gonna skip those questions. If you want to email them to me and for me to forward them on to some of my colleagues who do treat it, I would be more than happy to. In terms of topical therapy for basal cell carcinoma, I’ll first talk about — there was a trial with topical use of hedgehog inhibitor. I deleted it for the sake of time. But the bottom line is that it has not been shown to be very effective. I think the response rate was somewhere around 13% for complete regression, which is much lower than what you could get with systemic treatment of Vismodegib. The belief is because it’s a penetration issue. Basal cells tend to be kind of bulky, and the penetration of topical therapy is unknown. In terms of using Imiquimod, an immune modulated or immune pathway mechanism for basal cell, if it is small and superficial, possibly. There’s not enough study on the use of Imiquimod for basal cell. Most of the studies come out of Durham, and if you look at the design of the studies, they’re not very strong, and that’s why we tend to treat BCC primarily with surgical excision if possible. The exception of course is if there’s orbital involvement, or if it’s locally advanced, meaning a large surgical area which would lead to difficulty for giving patients a very good functional result. In those cases, I tend to go next to targeted therapy. Rarely do I use radiation as a first line for basal cell anymore, because of the toxicity that radiation can cause. Especially for periocular radiation. You will end up giving the patient an uncomfortable eye anyway. So in view of those two side effects, I think surgery is more definitive. In terms of 5FU for ocular surface squamous neoplasm, I do use it. 5FU is more toxic than interferon, which is probably the preferred treatment for SSN now. So my number one choice if the patient can’t be covered for the drug, since it is quite expensive, would be using interferon. And then as a backup, if the patient cannot afford it, then I use 5FU. The dosage I use is 1%. Because 5FU is quite toxic — not as much as mitomycin C, but it still can be quite toxic to the ocular surface, I use it for one week only, then give a patient a three week holiday. So that can decrease the side effects and increase the tolerance so you don’t have as many cases of limbal stem cell deficiency. Lymphoma — so I did not cover lymphoma, because lymphoma is still a disease treated predominantly with radiation and chemotherapy. There’s no specific targeted therapy for it right now. For large conjunctival — backing up a little bit, lymphoma is not a surgical disease. So even if it’s a large conjunctival lymphoma, we do not treat this with excision. We treat it with radiation. And the dosage you need for lymphoma is — what I’m talking about is MALT lymphoma. It’s quite low. So MD Anderson recently put out a study, last year or the year before, looking at low dose radiation. So 4 grey, twice. A total of 8 grey only, two sessions of 4 grey, and that’s shown to be efficacious in treating lymphoma. So even if it’s a large conjunctival, you can still irradiate it. If the patient has diffuse large B-cell lymphoma, then you may choose to up that dosage to possibly 10 or 20 grey, depending on the degree of response, and if it’s systemic, you go the route of chemotherapy, but definitely not surgical excision for these cases. There was a question of rhabdomyosarcoma. I’m not sure what the question is. If the person who asked this question wants to clarify — what about rhabdomyosarcoma they want to ask. In general I would say the treatment of rhabdomyosarcoma, if it’s isolated to the orbit, would be surgical excision. There’s some debate between sarcoma doctors and oculoplastic surgeons, like myself, on whether you should do complete excision, versus just doing an excisional biopsy. My rule of thumb for that has been: If you can safely excise the entire thing, then you do so. And the reason or the advantage of that is that: The patient will end up getting a lower dose of radiation and chemotherapy. If you don’t excise it completely, they end up being in category 4 of the sarcoma protocol, and they get a much higher radiation and chemotherapy dosage, which increases the side effects that the patient will experience. So let’s see if there are any other questions. So I’ll give a minute or so for everyone to type their question in, if there’s any. And then I’ll leave my cell phone… Email on. So I’ll leave my email address on there. So that if you have any questions that you’re too shy to ask now, you can email me. Okay, so if there’s no questions, I want to say thank you for being with us here today, and thank you for your attention!

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August 9, 2019

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