Anal cancer developments: Dr. Eng (2022)

Manju George 0:00
Hi, everyone. Welcome to DocTalks. Today we have Dr. Cathy Eng with us. I’m Dr. Manju George, the Scientific Director of Paltown, the nonprofit that supports Colontown. And we’re very pleased to have Dr. Eng with us. Usually I do an introduction of the speaker, but I’m not doing int this time. I am inviting her to tell us about her life’s work. And how she got into doing work on anal cancer and all the many activities she does professionally. Welcome, Dr. Eng.

Dr. Cathy Eng 0:31
Thank you so much for inviting me. I am delighted to participate in this recording. I have known, obviously, Manju for many years. As many of you know, I also treat a lot of colorectal carcinoma, but one of the other malignancies I treat is anal cancer. And the reason that I ended up treating a significant number of anal carcinoma patients is when I was starting out my career, just by chance, previously, in my training, I used to take care of head and neck patients. And so it’s a very similar treatment pattern for these patients and similar drugs are utilized. And so I was very comfortable seeing these patients. And that’s kind of how my career started. The reality was that the majority of patients do present with early stage disease. But for patients with metastatic disease, there were really no options when I started out my career. And basically, I just started extrapolating data from other more common squamous cell cancers and started utilizing them in my metastatic patients. And that’s how I kind of got started. So I’ve been doing this for 20 years. I take great pride in it. And I have had some wonderful patients over the years and I’m very fortunate to be able to conduct a lot of my work over these years. And I am the Director of the Young Adults Program here at Vanderbilt Ingram Cancer Center, which is really to provide resources and support and information to keep patients informed, those between the ages of 20 and 45 years old, and really just make them understand that they are not alone and help them.

Dr. Cathy Eng 2:16
So I’m gonna go ahead and get started if that’s okay. So these are all my disclosures, which also include disclosures for colorectal cancer. It was just very hard to differentiate it all, so I just listed all of the disclosures in fairness.

Dr. Cathy Eng 2:29
I love this picture. It is an article I was interviewed for in 2016. And I thought it just really demonstrates how challenging it is for patients to talk about anal carcinoma just because it’s really the cancer no one wants to talk out. People are sometimes ashamed. People presume that it’s associated with promiscuity. And that’s not the case. The reality is that the majority of patients who develop anal carcinoma is because of having a history of HPV in the past, and that comprises about 95% of all of our patients.

Dr. Cathy Eng 3:10
So this is the incidence of anal cancer and it is still considered a rare malignancy because it is less than 10,000 cases per year. But when I started my career, the numbers were much smaller and it rises by 2.6% per year. And globally, it is also an issue as well. These are the numbers in just the United States. They haven’t documented the new numbers yet for 2022. I checked online just this morning. And the median age of diagnosis is 63. The average patient is going to be a Caucasian female. That is the most typical patient that you’ll see in your clinic.

Dr. Cathy Eng 3:51
The majority of patients will present with early stage disease. And then there’s going to be a smaller minority of patients that present with distant metastatic disease, or they may have had earlier stage disease, unfortunately, developed recurrent disease that has metastasized. And so that’s a smaller proportion of patients. But as you can see here, the five year survival is about 30%. If you catch it early, the best news about this malignancy, as many of you may know, is that we can treat it with concurrent chemotherapy with radiation treatment. And if you have an excellent response, you can avoid surgery, and that is what is the unique aspect of this disease.

Dr. Cathy Eng 4:33
I did want to talk about risk factors. I didn’t include that slide, but just in case some people were not familiar with risk factors associate with anal carcinoma, as I mentioned earlier, the majority of patients will present with squamous cell carcinoma, that’s 90% of all anal cancers. The majority of patients will have a history of HPV in the past, or human papilloma virus. As many of you know, there’s a now, the 9 valent vaccine that is available to prevent HPV associated malignancies and that would include anal cancer. There are 100 plus different subtypes of HPV. The 9 valent vaccine includes the nine most common subtypes to prevent this cancer. Other risk factors, there is a linear association with tobacco use. There is an association with sexual promiscuity. There is an association also as an increased risk factor with having a patient that’s immunosuppressed, whether it be organ transplant, so kidney transplant, cardiac transplant and then also patients that are HIV positive. So those are some additional risk factors for developing anal carcinoma.

Dr. Cathy Eng 5:46
As I mentioned earlier, salient facts about anal carcinoma is the majority of cases are associated with HPV. And as mentioned earlier, the majority of patients will present with earlier stage disease in which we will provide them combined chemoradiation therapy to allow sphincter preservation and to hopefully avoid surgery. And this is provided with curative intent. The problem is if you have to go to surgery, which is actually recommended if there’s evidence for current disease, you will end up with a permanent colostomy and obviously that is a quality of life issue for several of our patients. Risk factors for potentially failing are the tumor progressing through concurrent chemoradiation therapy is based upon data from a large trial published in 2012 by Jaffer Ajani, my former colleague at MD Anderson, which noted that a tumor that’s greater than four centimeters or having lymph node positive disease, those are risk factors, unfortunately for developing either recurrent disease or not responding to chemoradiation therapy.

Dr. Cathy Eng 6:57
These are the pivotal trials that have been previously conducted. And really the reason I want to show this to you here is that the original pivotal trial was actually noted incidentally and only involved a study of 28 patients, the so called Nigro regimen. And this is where the dose of the radiation therapy was only 30 Gy. As you can see here, based upon subsequent studies, the dose of the other radiation sensitizer drug which is Mitomycin C ranged anywhere from 12 to 15 milligrams per meter squared. And actually nowadays most of us use 10 milligrams per meter squared. And this is given on the first and the last week of radiation therapy in combination with 5FU. For any of you that have been exposed to Mitomycin C, you may understand that it’s significant impact is basically on the bone marrow and patients end up having extremely low white blood cell counts, so they can suffer from fatigue. Radiation dermatitis is pretty significant for these patients even though this can cure the patient of their cancer. But Mitomycin C is a tough drug to tolerate.

Dr. Cathy Eng 8:09
One of the most pivotal trials that was completed by the radiation therapy group, RTOG 98-11, looked at another option which was to compare to another regimen that may not have the same side effects as Mitomycin C on the bone marrow but it has other side effects, which would be cisplatin. And this study involved over 600 patients. It was a one-to-one randomization, although the investigational arm here was a little unique. Not only did they look at utilizing a different drug, other than Mitomycin, they looked at cisplatin, but they also looked at if it would help by giving a couple of cycles of treatment before, so chemotherapy by itself for a couple of cycles, before even initiating chemoradiation therapy. And the primary endpoint for the study was what we call disease free survival, meaning time to tumor growth. So we’re hoping that the patient will remain disease free. And so basically, the primary endpoint was to make sure there was no evidence of recurrent disease. And what they actually noted at the end of the day, is that the cisplatin arm, unfortunately, was not superior. And it also made it a bit complicated because they had these two additional cycles of treatment before initiation of chemoradiation therapy. Also, it’s very, very important to note, all the prior studies before did not allow HIV positive patients and as we all know now, the medications for HIV patients is fantastic. It keeps our patients healthy, they’re able to endure their treatment. And now we often include them in our clinical trials. But these former pivotal trials did not allow HIV positive patients.

Dr. Cathy Eng 9:48
This is the biggest study ever completed. This is from the UK group. It is called Act II and it really is a true head-to-head comparison of 5FU and cisplatin versus 5Fu and Mitomycin C. For those of you that may have known my career at MD Anderson, we traditionally gave cisplatin on a regular basis to our locally advanced patients. And we felt very comfortable with that. But the majority of people in the United States, many physicians use Mitomycin C because that is considered the standard of care and cisplatin, I’ll show you the data here, cisplatin was not determined to be superior, as the hope for the primary endpoint of this study that they were hoping to achieve, but it was basically found to be equivalent. So to date, Mitomycin C and 5FU still remain the standard of care for the majority of patients. This study also did not allow HIV positive patients at that time.

Dr. Cathy Eng 10:40
And I just want to show you some really important aspects of this trial because this was the largest trial to date for the early stage anal carcinoma setting and there were a lot of lessons to be learned. So basically, once again, this was the first head-to-head comparison of Mitomycin C and cisplatin. But the goal was to demonstrate superiority for cisplatin. And basically they showed equivalence. The complete response rate was 90%. And the partial response rate was basically about the same. So basically, the two drugs are equivalent. The other thing they noted is that if a patient had a delay in their radiation treatment, meaning that treatment was held for one reason or another more than a couple of days, as you can see here in green, if you had completed your therapy between 38 to 42 days, which would be standard treatment, your survival was actually better in regards to locoregional control. And if they extended the radiation for greater than the 42 days, meaning that they had some significant delay for some reason and held your treatment with radiation therapy, in fact, that can impact your benefit of response to complete cure. And although this was not statistically significant, you can definitely see the display in the curves here. And we do not recommend that any radiation therapy be held for any prolonged duration other than maybe one or two days. In my experience, if a patient is having significant radiation dermatitis at their bottom, because of the radiation therapy, I’ll likely hold the chemotherapy if needed, rather than holding a delay in radiation treatment, because radiation for this kind of cancer is really what cures the patient. The chemotherapy is just meant to enhance the radiation. And that’s what’s really important to understand, and also the doses of the chemotherapy we give to patients while receiving radiation therapy are not full doses that we would give to a patient with metastatic disease to work throughout their whole body. The doses provided during radiation therapy are just enough to enhance the radiation treatment. The other big factor learned from this trial and why it is so pivotal is that we learned that patients can actually continue to respond to therapy for up to 26 weeks after the completion of radiation treatment. So previously, if you had not had a complete response at 8 to 12 weeks after completion of radiation treatment, they would automatically take you to surgery and you would lose your sphincter and you would end up with a permanent colostomy. We have now learned that you can actually have a delayed response to treatment. And as long as the tumor is not growing or causing any pain or any other issues that would be abnormal during the recovery phase following radiation treatment, we recommend close surveillance. So regular follow ups with your surgeon who would then do a flexible sigmoidoscopy or a proctoscopy to evaluate your anal sphincter to see how well you’ve responded as well as diagnostic imaging, including CT scans, or PET scans if needed. So here basically demonstrates to you as long as you’ve had a response, and ideally, you’ll have your response earlier in your 26 week surveillance, but basically what we’re trying to say is don’t rush, don’t presume you’re not responding. If the tumor appears to still be there, just give yourself time because you have up to 26 weeks to have a response before your surgeon will make that decision that you need to go on to surgical resection. And from my personal experience, I give my HIV positive patients a little bit more time because they need a little bit more time to heal than the non-HIV positive patient in my experience.

Dr. Cathy Eng 14:29
And these are the toxicities associated with chemoradiation therapy. As you can guess, radiation dermatitis is a major issue, fatigue, drop in blood counts obviously because we are radiating your pelvis. The chronic toxicity associated with radiation therapy are what concerns us. Bowel dysfunction, sphincter control, obviously change in fertility. There’s a potential risk of insufficiency fractures, which are hairline fractures of the hip. Obviously sexual dysfunction, erectile dysfunction, vaginal radiation fibrosis, change in menstrual cycle obviously for women. For our women, I have always historically worked with radiation doctors that provide a vaginal dilator for patients to reduce the risk of radiation fibrosis. And I think that’s really important to keep in mind. Urinary dysfunction. And obviously there is the potential rare risk of leukemia with receiving Mitomycin, which once again, extremely rare, though.

Dr. Cathy Eng 15:29
So what we have now noted, I think I showed you this slide earlier with the dose of the radiation was at 30 Gy, so really low dose, but now we’re going up, for some of the patients, up to 45, 54, 59 Gy. So, why are we using so much more radiation therapy, especially in the setting for early stage disease, meaning a small tumor. So anal carcinoma is a bit unique, because it’s one of the few tumors that you’re staging is based upon the size of your tumor. So if you have a tumor that’s less than two centimeters, that’s great. So that’s an early stage tumor, as long as you don’t have any lymph node involvement. So this is an ongoing trial. I think that’s extremely important. This is the DECREASE trial, which is being led by Jennifer Dorth, who is a radiation oncologist at Case Western, and it’s looking at specifically small tumors, no lymph node extension. And the intent is to reduce the amount of radiation, going back to the smaller doses that we were still able to provide adequate care of patients with complete cure. So it’s a two-to-one randomization. In this setting here, two-to-one for the investigational arm, not only reducing the dose of radiation therapy, so hopefully reducing the toxicities, but also only providing one single dose of Mytomycin. So then hopefully, the patient won’t have to go through all those extremes of toxicities associated with Mitomycin. And so this trial is ongoing. We hope people will enroll.

Dr. Cathy Eng 17:02
There is another trial. So I mentioned to you earlier that patients are at risk for not having a successful response to the radiation therapy if they have a large tumor greater than 4 centimeters or significant lymph node involvement. This trial, EA2165 led by Lakshmi Rajdev has finished enrollment. This was a very, very successful study in regards to enrollment because it was an unmet need. And this is looking at the role of immunotherapy. And as many of you know, immunotherapy is now considered part of the care for metastatic patients. She saw our data from our trial, as well as other trials that were ongoing, I’ll share that data with you in a little bit, and decided to apply it earlier to those patients at high risk of recurrence. So those with bulky tumors, those with significant lymph node involvement, and basically providing nivolumab once a month for six months following the completion of chemoradiation therapy versus standard observation. So we all look forward to the results of this trial. And so hopefully, we’ll have the results in a couple of years.

Dr. Cathy Eng 18:12
Now, what about the patients with metastatic disease? So about 10 to 20% of patients will present with metastatic disease upfront at presentation, and then another 10 to 20% of patients, unfortunately, will develop progression of disease despite having earlier stage disease at diagnosis, and then unfortunately, they will progress. So as I mentioned earlier, when I started out my career, there was really no well known treatments for patients with metastatic disease. And what was going on in the literature was the very, very small studies. As you can see here, these go back to the 80s. I mean, very, very small groups of patients. Small case reports were reported, but no one was really focusing on the metastatic patient population, and pharmaceutical companies at that time, were not interested at all. And I’d love to see what Manju would like to say about that, because they thought anal carcinoma was a rare cancer. And at the time, they were well aware that early stage patients usually were cured. But as I mentioned, there were those patients with metastatic disease though and what were they to do? And so what I decided to do was I looked at my own experience before when treating head and neck cancer patients during my fellowship, and I started looking and extrapolating data from other more common squamous cell cancers, cervical cancer, lung cancer, head and neck cancer, can we use some of those drugs? And would they benefit patients with metastatic anal carcinoma? And so that’s really where a lot of my career has started trying to find options for these patients. So I looked at CARBOPLATIN-TAXOL and 5FU cisplatin. This was a retrospective analysis I completed when I was faculty at MD Anderson Cancer Center, and I noticed that there was benefit for these patients. Subsequently, four years later on, Dr. Kim, reported on DCF, he completed a phase two study, which was looking at a triplet regimen and he actually had some very significant responses as well. And then, once again, I’ve done some other retrospective studies looking at other agents. And then now, pharmaceutical companies are beginning to understand there is benefit in trying to find new options for these patients, as well as the fact there’s amazing patient advocacy groups that are trying to get the information out to patients to consider participation in clinical trials, and to get pharmaceutical companies to realize that HPV associated malignancies exist, and that a drug that has benefit in one HPV associated malignancy may have a benefit in another. So I’m glad to say that we’re getting to see a lot more research in the anal carcinoma patient population, just because there’s greater awareness.

Dr. Cathy Eng 21:05
So these are some of the trials that have been recently completed. I did want to mention this one because it just came out of publication. This I think, was a little disappointing. This is an Italian study. It involved 60 patients, and looked at refractory or patients that have been through multiple lines of therapy, and they looked at the role of immunotherapy plus or minus in combination with anti-EGFR therapy, which in this case, it’s Cetuximab. Cetuximab is approved. Just so you’re aware. You might be thinking, well, why would we use that? Well, Cetuximab, I’ve previously published on it before, retrospectively however, in patients, I had seen at MD Anderson, but also because it is FDA approved, at that time, in surgically unresectable metastatic head and neck cancers. And so there was a thought that maybe this would help this patient population. But unfortunately, this trial I was disappointed to see, immunotherapy did result in a response rate of about 10%, which is pretty standard. But the addition of the anti-EGFR therapy or Cetuximab in this setting only improved the response rate by an additional 7%. And oddly enough, the survival for this patient population was not as favorable versus the single agent immunotherapy. At least that’s what’s reported. And I was wondering if it was an error in their documentation, but this is a publication and they reported 7.8 months, so that’s not very favorable for the combination. I presume it’s due to toxicities. Now, basically you should be aware that we have published formally on a phase II trial. As I mentioned to you earlier, I had looked at the data from the patients I was seeing in my career at looking at 5FU and cisplatin versus CARBOPLATIN-TAXOL and noted there were some promising activity. And several of us got together as part of The International Rare Cancers Initiative. And I brought this to light and Sheilah Rauh created this international trial, which has now created the new standard of care. So this is a head-to-head comparison. It did allow HIV positive patients. It was one of the first studies to allow HIV positive patients, we’re very happy to see that, and these were for newly diagnosed metastatic anal carcinoma patients. And the primary endpoint here was response. It’s not a phase III study. It was a phase II study just to get some information to see what would be the best backbone for a chemotherapy regimen to move forward for these patients to create new treatment paradigms. And so basically, what we noted was they were very similar in response, between 57 and 59%, for the two chemotherapy regimens. The main thing was that there were less side effects though in the carboplatin, weekly Paclitaxel arm. Some of you may know Paclitaxel has Taxol and so what they noted is in fact, it had less side effects. When you’re looking at overall survival too, it also appear to be in favor for the combination of carboplatin and weekly Paclitaxel or Taxol as you may know it. Now, keep in mind, this also uses a more traditional schedule of cisplatin and 5FU which is once a month. And that regimen is very tough. That’s a traditional schedule based upon the way it used to be used in gastric cancer. Some of us that practice regularly and use 5FU and cisplatin as part of a regimen for metastatic anal carcinoma patients have adopted a different schedule. I use it every two weeks. So I split the dosing in half and I find it to be very successful and not as toxic to patients. Because unfortunately, cisplatin has a lot of nausea, as many of you may know. So this has created the new standard of care for the chemotherapy backbone for our metastatic newly diagnosed patients. So I’m very glad to say I participated in that trial. Now, what about the role of immunotherapy? As you know, HPV is commonly associated with this malignancy. So the thought process was, obviously can we provide immunotherapy in this patient population, this virally driven malignancy, and see if this would provide benefit.

Dr. Cathy Eng 25:15
This was the original study involving Pembrolizumab. It involved multiple different types of cancer.

Dr. Cathy Eng 25:22
I’m just going to show you the numbers specifically from the anal cancer cohort. And Pembrolizumab, as you know, can be given every three weeks or every six weeks in patients. And here the response rate was the primary endpoint here. And they noted about a 10% response rate for these patients and these are patients that have had at least one prior line of therapy. Now, unlike some of the other cancers, for anal carcinoma, it does not appear to be definitive whether or not the patient has to be PDL-1 positive or programmed death ligand one positive for the benefit of Pembrolizumab. In other cancers, there has been an association with outcomes. But for anal carcinoma, the data has not been strong enough to say that you should not receive it if you are PDL-1 negative, or positive for that matter.

Dr. Cathy Eng 26:19
And this was the data from their trial that they presented. So definitely some benefit of response for some patients.

Dr. Cathy Eng 26:28
And prior to that publication, we also conducted our own trial, which was a national trial. It was a small study looking at the sister drug nivolumab in metastatic anal carcinoma patients as well. This was given every two weeks. This was a small pilot study that we worked with the NCI and I was very glad to say it was a positive study and the NCI was very supportive of our efforts.

Dr. Cathy Eng 26:54
And I’ll show you the data here, which I think many of you are familiar with. So this was done mostly at academic institutions, in all fairness. We actually had a pretty high response rate of 24%. Granted, once again, this is a smaller number of patients, versus the the finalized pembrolizumab data. The median time to progression or time to tumor growth, or what I call progression free survival is 4.1 months, and then the overall survival was about 11.5 months. So whenever we have a patient with metastatic disease, we talk about progression free survival or time to tumor progression. You’ll commonly see PFS utilized in the terminology for clinical trials, and basically means time until tumor growth. And we follow a very strict criteria called RECIST Criteria. So you have to have basically a certain percentage, these are international criteria that are created, in regards to response, as well as if you’re considered progression of disease, that is also pretty standard criteria. Just so you understand the terminology here.

Dr. Cathy Eng 28:06
And I want to show this to you because this is actually one of my patients. She was on study for about a year. And as you can see here, she had a significant response with just single agent nivolumab. And this trial enrolled extremely quickly because it was an unmet need. I think we finished enrollment in less than eight months for this trial, which was unheard of at the time, but clearly demonstrated to the NCI that patients needed options. And they listened and I thought it was great. Subsequently, Pembrolizumab and nivolumab were actually then inserted into the NCCN Guidelines for approval to be utilized for metastatic anal carcinoma patients. They are not FDA approved, but they are on the treatment guidelines. They are not FDA approved because these were small studies in a rare patient population. We have gone on to try to look at other combinations to see if there’s additional benefit.

Dr. Cathy Eng 29:00
We did a pilot study as well. This was led by Van Morris, who is a wonderful faculty member at MD Anderson who I’ve had the pleasure of continuing to mentor him. We looked at the combination of a different immunotherapy agent atezolizumab, just different competing company, in combination with Bevacizumab. So Bevacizumab is a standard drug utilized in colorectal cancer. It’s basically focused on the blood supply of a tumor. Prior studies have indicated that the two, in combination, may have additional benefit. However, in this case, in this pilot study of 20 patients, they only noted a response rate of about 10% as well. Sorry, 19 patients were evaluable. We enrolled 20 total. So a bit disappointing, I think. I think we were hoping obviously for a much better response rate than the 10%. And why is this? There has been some very nice data for the combination in hepatocellular carcinoma or liver cancer. But for anal carcinoma as a squamous cell cancer, this combination has some benefit but not as significant as we had hoped. The progression free survival here was very similar to the single agent data of nivolumab of 4.1 months and the median overall survival was 11.6 months. So once again, I showed you the data from nivolumab alone.

Dr. Cathy Eng 30:29
Here’s the Atezolizumab in combination with Bevacizumab and Bevacizumab can be associated with bloody nose and remote risk of bowel perforation. The main side effect though is hypertension, about a third of patients. And here, if you look at the data, there’s really no additional benefit for the addition of Bevacizumab here.

Dr. Cathy Eng 30:51
So here I wanted to highlight I think what’s the most important data here for this lecture is basically I want you to be aware of the trials that are pending results and ongoing studies.

Dr. Cathy Eng 31:03
So the NCI was very supportive, as I mentioned, of nivolumab, our first study, and they recommended we added ipilimumab, which is the CTLA4 inhibitor, which is, as many of you know, is FDA approved in melanoma. And this trial actually is just about to be finished. It’s basically nivolumab plus or minus ipilimumab. And this is on a low dose of ipilimumab. So hopefully less toxicities and hopefully increase benefit of response. We are just shy of closing the study and looking at the final data. So I’m very, very happy. I look forward to those results. And I’m hopeful, I hope we’ll see. And then also you should be aware now that obviously because of other malignancies again, and once again, this is how I work, I try to extrapolate data from other malignancies when I’m dealing with a rare cancer to see how I can incorporate some of that data.

Dr. Cathy Eng 32:00
So there was data already in lung cancer, which demonstrated that there may be a benefit by doing platinum based therapy in combination with immunotherapy. So not only myself, but here’s our investigator, Dr. Kim again, who as you saw earlier on the table I provided he had this regimen of a triplet, so DCF and here he’s combining it in combination with a atezolizumab immunotherapy in newly diagnosed. This is a phase II study in squamous cell carcinoma patients. It is a two-to-one randomization. So it’s enrolled 99 patients and it actually finished enrollment last year. And he also allowed HIV positive patients. He calls this study the SCARCE study. And hopefully we’ll see some data here. So I look forward to seeing those results as well.

Dr. Cathy Eng 32:50
There is an ongoing phase I study I should mention. This is specifically for HPV16. It’s a cell based vaccine. This study was on hiatus for a little bit because they were evaluating their data and my understanding from one of my colleagues is that this is reopening in combination now with immune checkpoint inhibitors. So I look forward to seeing how that also will turn out. These are for all HPV positive patients. So not just anal carcinoma patients. This includes head and neck and cervical, etc. So it’s an all comers for HPV.

Dr. Cathy Eng 33:27
Now, last but not least, it’s the first time I’m so glad to say in the metastatic setting, we actually have two phase III trials for our patients with metastatic disease, newly diagnosed. So this is, as I mentioned to you earlier, I worked with Sheilah Rauh on creating the backbone and defining the backbone for metastatic anal carcinoma patients. She is in the UK. We tried to write the study together. But unfortunately, as you can guess, it’s difficult to conduct an international study through the NCI or our NCI and their agency. And so we’ve done two parallel studies. They’re being conducted separately. So she is working with the pharmaceutical company. And she has this immunotherapy agent called retifanlimab. Retifanlimab as a single agent was also evaluated largely in Europe. I think there were three patients in the United States that enrolled when it did open and it had also demonstrated very similar response rate, I think about between 10 and 12%. So she is also looking at the combination of carboplatin plus Paclitaxel or Taxol, as many of you may know it, once again. It does allow HIV positive patients. This is a one-to-one randomization with this immunotherapy agent to see if the combination with immunotherapy is superior to chemotherapy alone. And this is largely an ongoing study in the UK with a few select sites the United States.

Dr. Cathy Eng 35:03
Now in the United States, I’m very, very delighted to be running this study. And once again, it’s a culmination of the work that I’ve done and research for my metastatic anal cancer patient population. Here, this is a two-to-one randomization. So a two-to-one chance that you may be randomized to chemotherapy. So I have a typo there on the title. I apologize. Carboplatin plus Paclitaxel, with nivolumab versus chemotherapy alone, and the patients will then go on to maintenance nivolumab after completing a maximum of six months of treatment. So both of the studies, the European study as our own, they both will allow continuation of the immunotherapy following the completion of the chemotherapy regimen. And here we also allow HIV positive patients. This is a two-to-one randomization. We hope to enroll 200 patients and thus far we have a little less than 45. So I’m very excited. And I’m very grateful to many patients participating in this trial because once again, this is an NCI sponsored, first time phase III study supported by the NCI for this patient population. So I’m delighted that we have this as an ongoing study. I did want to mention I know Immunotherapy is approved for multiple malignancies when looking at tumor mutation burden. However, for anal carcinoma, we have not found that tumor mutation burden has any bearing in regards to response with immunotherapy. Because this is largely a virally driven disease due to HPV, so it’s not so much reliant on the tumor mutation burden. We are looking at the role of HPV circulating tumor DNA in metastatic anal cancer. Once again, circulating tumor DNA has been evaluated in small studies for anal cancer patients, but the largest studies have been largely conducted in head and neck prior to anal carcinoma. So we are incorporating this into our trial as well at this time. And this is just some of the work that’s been done by our French colleagues. So we’re delighted to see that there may be some use for HPV circulating tumor DNA in the future. So once again, we really want to encourage people to participate in the phase III trial EA2176. We’re also very, very proud to say we are supported by the Farrah Fawcett Foundation who has given us a grant to support the HPV circulating tumor DNA work with Sysmex and obviously very grateful to ECOG working with the NCI to support this trial. So, in conclusion, there’s no definitive evidence that PDL-1 expression is predictive for immune checkpoint response in anal carcinoma. HPV circulating tumor DNA is a promising biomarker. And so we hope that at some point, it may be considered a standard of care if there is some promising findings after our study is completed. Chemotherapy upfront is the standard of care for metastatic disease. And the combination with immunotherapy is being investigated and always enroll to a clinical trial whenever possible, especially in the setting of a rare cancer, because that’s the only way we can move the needle forward. So that’s the end of my lecture. And thank you so much for your attention. And I’m open questions Manju.

Manju George 38:20
This is a great presentation, so much information. And I have to confess that I have very minimal understanding of anal cancer. So some of these questions may not be the best.

Dr. Cathy Eng 38:31
Okay.

Manju George 38:31
But my first question would be that you said that early stage cancer, the main treatment was radiation along with the chemo on top, right.

Dr. Cathy Eng 38:40
Uh huh.

Manju George 38:40
Mitomycin or 5FU. So why is that not at all done in metastatic cancer? How’s the local disease controlled?

Dr. Cathy Eng 38:49
Yeah, so 5FU and Mytomycin C, we use the low dose for the radiation. But unfortunately, 5FU and Mytomycin C for metastatic disease would be very difficult to tolerate, because it really knocks out the bone marrow. And so it will drop the white blood cell count significantly. It’s not a drug that you can give long term. And also there is a rare instance of pre-leukemia or MDS associated with Mytomycin. So yes, I know some people wonder like, if it works with early stage disease, why can’t we utilize it in metastatic anal cancer? And I think it’s because it would be really toxic and difficult to endure, you probably could only give maybe one or two cycles.

Manju George 39:32
Okay. And then my other question would be when anal cancer metastasizes, where does it go?

Dr. Cathy Eng 39:41
Great question. Great question. So it actually can go to multiple places. Most common is liver, lungs and bone in my experience, and obviously the lymph nodes in the pelvis. I have seen instances for long term survivors, meaning that they’ve been fighting with their cancer for many years, they have metastatic disease and they’ve been in treatment for a long time. So are thrivers. I do find that those patients that are long term thrivers are also at risk for getting brain involvement. So that is a unique difference about anal carcinoma in my experience. And I also have seen because it’s a squamous cell cancer, I’ve also seen dermal metastasis, so skin skin lesions.

Manju George 40:28
Okay. And then you said that the staging is basically based on the size of the tumor. So I mean, again, I’m going to the basics. In metastatic disease, then do you see like larger tumors locally? Or, you know, how does that work?

Dr. Cathy Eng 40:42
So, I would say the majority of patients when they present with metastatic disease, I would say probably 80% of the patients when they present with metastatic disease have multiple sites of disease involvement. There are a smaller percentage of patients that may only have a few sites of liver involvement. In that setting, I like to utilize radiation therapy because, keep in mind, this is a radiation sensitive tumor. So instead of sending the patient to surgical resection for the liver, I have also utilized stereotactic radiation therapy, I’ve used Y90. And I’ve had several patients that remain still cancer free, without having to go to surgery, as long as their primary tumor obviously has been addressed with either surgery or chemoradiation therapy in the past, but the majority of patients, though, I would say probably 75 to 80% will present with multiple sites of disease involvement. Does it have to be a bulky tumor at their bottom. No, unfortunately. But a lot of them do have a lot of lymph node involvement, where there’s a lot of spread that way and in that fashion.

Dr. Cathy Eng 41:54
Okay, so basically, what you are saying is that it’s not that the tumor grows really big locally before it invades?

Dr. Cathy Eng 41:59
Correct. But you still get metastasis everywhere. Yeah, you don’t have to have a large tumor in order for it to metastasize. But definitely those tumors that are larger and that have lymph node involvement are the ones that are more likely not to respond completely to concurrent chemoradiation therapy for early stage disease. And I do want to mention for patients with metastatic disease, if at any point, you’re still having bleeding or pain in your bottom, I definitely would still recommend you meet with a radiation doctor if you’ve not received radiation therapy in over a year, you meet with your medical oncologist and you meet with your surgeon because you may still benefit from treating the primary tumor, especially if it’s causing you symptoms. Even though you may have metastatic disease elsewhere, hopefully, I like to try to get the disease under control as best as possible with full chemotherapy. And then if I feel that the patient has had a very nice response, but yet their primary tumor is more problematic then I will address the primary tumor with chemoradiation therapy, and then I can always go back to chemotherapy.

Manju George 43:10
Okay, that makes sense. And you know, I’m always thinking about it in terms of rectal cancer, right? Like with chemoradiation, so that’s why my questions are like that. And my next question would be now that you’re using immunotherapy, is there any benefit in using radiation and immunotherapy?

Dr. Cathy Eng 43:29
Great question. So if I’m correct, I didn’t show some of the ongoing European studies, but I believe there’s a small European study, I don’t know if they finished enrollment, looking at the role of immunotherapy with radiation treatment. We have not historically looked at that in anal carcinoma, because, as you know, the data in rectal cancer was not as successful as I think we had hoped. There’s always a lot of interest in looking at radiation therapy with immunotherapy because everyone talks about this abscopal effect, if you radiate this one side, it will work throughout the whole body. And I have to say, many of us still have not really seen an abscopal effect and because there are obviously some toxicities that may be associated with immunotherapy and radiation therapy, I think it’s really hard for the majority of patients with early stage disease, they will be successfully cured. And so it’s kind of hard to get people to change the medications utilized as radiation sensitizers because they’re so successful. But I’m sure that we’ll have more data in the future, I suspect.

Manju George 44:43
Okay. And again, like what you said, because the medications along with radiation are so toxic, it is kind of part of what to do with metastatic disease and what else to add on to radiation probably.

Dr. Cathy Eng 44:59
Yeah, so that’s why5FU and cisplatin, as I mentioned, is a regimen that I had used for earlier stage disease for many years. And the only reason it’s not utilized on a regular basis because it was never found to be superior. All the trials were designed for superiority but actually it’s less toxic if you give it with radiation therapy, so I utilize it in some patients because if you think about it, the patients that are at risk for anal carcinoma, some of them are immunosuppressed patients. So to give them Mitomycin C on top of that, which can knock their immune system down further, that may be somewhat detrimental obviously to a patient with a low CD4 count. So I have utilized cisplatin as an alternative to Mitomycin C for radiation therapy for patients that are either elderly, extremely elderly, really concerned about their immune system or they’re immunosuppressed due to low CD4 counts from their HIV. So I do try to look at other alternatives outside of Mitomycin and I often consider cisplatin if it’s reasonable, as long as the patient’s kidney function is within normal limits, because I’ve had good success with that as well.

Manju George 46:12
Okay, okay. And then my other very naive question is what is the prognosis and overall survival for a stage IV anal cancer patient?

Dr. Cathy Eng 46:27
Yeah. So I didn’t show you the additional data I collected. I think you saw the data from the treatment study from INTERACT, which showed a little over 20 plus months for median survival. You know, I think it’s really important for patients with limited metastatic disease that they really talk to their doctor to see if there’s additional treatment optionssuch as stereotactic radiation therapy, or surgical resection. I didn’t even mention it, there was an older study, which originally said that if you have metastatic squamous cell cancer from any origin, you should never undergo resection of your liver because it wasn’t beneficial. And I completely disagreed with that, because that doesn’t apply to all squamous cell cancers. And I’ve shown that those patients should meet with a liver surgeon if they have liver limited disease, or they should meet with the radiation doctor and their medical oncologist. The median survival historically has not been fantastic for all patients. But I’ll be very honest with you, there are many patients that I’ve worked with over the years that have lived several years beyond the median survival that was previously reported. So I think we are making impact and I’m hopeful that we will continue to increase the five year overall survival, which currently for all stage IV patients, all comers is roughly about 30 to 34%.

Manju George 47:58
With respect to vaccines to prevent anal cancer, even the cervical cancer vaccines that are available, would that help?

Dr. Cathy Eng 48:07
Yes, because now the age has been extended to I think, 45 or 48, for the HPV 9 valent vaccine, so I would highly encourage individuals to get vaccinated and to get their children vaccinated. Because keep in mind, this is a cancer prevention vaccine. And I think that’s really, really important. And thank you for bringing that up. It’s really, really important to encourage people to get vaccinated. Because this is a virus associated with head and neck cancer, penile cancer, cervical cancer, and unfortunately, anal carcinoma and vaginal cancer, right? So we want to make sure that we try to prevent this cancer by starting now at the point of vaccination. It does extend up to the age of 48, the majority of people will get HPV in their younger years when they’re sexually active in their teenage years to 20s. And then all of a sudden, I just showed you the median age of anal carcinoma as 63. So there’s this lag time, and as we all know, as we get older, our immune system gets compromised with time as well. And so I think it just, unfortunately, puts individuals at risk, because some people don’t think about it, about their HPV that they had, you know, 30 or 40 years ago, but in fact, that’s extremely important. And so it’s really, if they can spread the word, get vaccinated, get your children vaccinated, so they don’t have to ever be diagnosed with this malignancy. That would be extremely helpful, For some patients, the treatment for anal carcinoma patients is desperately needed because it’s a quality of life issue for some of these patients, because some of them have these large tumors of their bottom that are not healed and they have a lot of pain associated with their tumors. And they may have open lesions because of where their malignancy was diagnosed. So it’s a big quality of life issue as well. So I always feel for these patients, because sometimes it’s very, very challenging for them in regards to their quality of life, because of where their disease is presenting.

Manju George 50:24
Thank you so much for your continuous work on this rare cancer and it looks like you have a substantial volume of work that you’ve done to improve the quality of life and to bring better curative therapies for them. So thank you for sharing all of it.

Dr. Cathy Eng 50:45
Thank you so much for having me. I’m very, very delighted to have you interview me for this, and I really, really hope that this will educate many patients as well as providers and caregivers. And hopefully we can make a bigger impact in the future for these patients. Thank you so much for doing this. I know this isn’t your specialty, but I’m very, very grateful. Just because we really want people to know that there are trials and hopefully we will get a new standard of care. Fingers crossed.

Manju George 51:17
Yes, yes. And thank you for tirelessly working towards it.

Dr. Cathy Eng 51:21
Thank you so much, Manju. I really appreciate you. Have a great weekend.

Manju George 51:26
You too. Thank you. Bye.

Dr. Cathy Eng 51:28
Bye.