AEs from Immunotherapy monotherapy for BCG-Unresponsive NMIBC

Raoul S. Concepcion, MD, FACS: Let's go to case number 2. This is immunotherapy monotherapy for BCG unresponsive non-muscle invasive bladder cancer. So in this particular case, we have a 76-year-old white female with documented non-muscle invasive bladder cancer that has been biopsied, improving carcinoma in situ. She received 2 induction rounds of BCG, repeat biopsy. Basically showed a continued presence of carcinoma in situ in the bladder, multiple therapies and tested positive for MSI and started on pembrolizumab [Keytruda] 400 milligrams IV every 6 weeks. Initial labs all within normal limits. TSH was a 1.2 with the range of normal being 0.3 to 4.2 after 3 infusions. She started to have severe fatigue, constipation, and joint weakness. Repeat TSH level at that point was 20.7, which the provider thought was immune mediated thyroiditis and was started on a steroid taper for 4 weeks. Symptomatically became better prior to the next infusion. TSH was repeated at a normalized 2.4 left on Liba thyroxin, steroids weaned, and the patient now continues to be on pembrolizumab 400 milligrams every 6 weeks.

So Mercedes I'm going to pump this up to you to lead this off. So again, this is sort of a new area, especially for the urology world. For the medical oncology world, it is probably an old hat, especially with pembrolizumab. I know Dr. Stratton has given a lot of immunotherapies. Especially if you're in clinical trial, Mercedes, your thoughts on the immune-mediated, thyroiditis? How this patient would be managed – anything else that you want to add to this?

Mersadies Orr, CRNP, FNP-C: My experience with [pembrolizumab] is limited right now. I do have 1 patient currently on treatment. Luckily, I have not had to manage any thyroiditis. It seems like they never treated appropriately. Systemic corticosteroids are typically recommended for any immune response while on treatment. In my experience, most often the side effects that patients have complained of have been very mild, including itching. The patient had, severe itching, but no rash. Other than that, I've been really lucky and my patients have thrived. But with any complaint or new side effects, I would often just interrupt therapy, and consider whether or not a steroid is indicated. Oftentimes I'm thinking things like pneumonitis, etc. I haven't had any patients have issues with their thyroid. We also don't monitor the thyroid or the TSH often. We may get that at a baseline before we start treatment, but that's not something that we're checking routinely throughout treatment.

Raoul S. Concepcion, MD, FACS: Dr. Stratton, what's been your experience with the checkpoint inhibitors?

Kelly L. Stratton, MD, FACS: Since the approval of pembrolizumab for CIS, we've used it for a lot of patients and it's generally very well received after these patients have been on BCG therapy for multiple courses. The opportunity to try something different that doesn't result in the diarrhea and urinary symptoms that they're accustomed to has really been beneficial and patients have really liked it. I have had a different experience with [pembrolizumab]. I have had several patients who've had thyroiditis. Different than this case, I have not had to use steroids in any of those patients. Generally, they have asymptomatic hyperthyroidism during the inflammatory portion. And then as their TSH starts to go up, then we just start them on a thyroid replacement therapy. Typically, we'll have the patient either make an appointment with their primary care physician, or we will refer them to an endocrinologist because generally they're going to be on thyroid replacement therapy from there forward. And most patients can continue to receive treatment. Like this patient, we immediately shifted to the 6-week treatment regimen because it lines up very nicely with our cystoscopies. So patients will get labs every 3 weeks and infusion every 6 weeks and a cystoscopy every 12 weeks. And we have seen that work very well for patients.

Raoul S. Concepcion, MD, FACS: Is that the recommended monitoring for PDL-1 inhibitors, every 3-week labs?

Kelly L. Stratton, MD, FACS: I think that that may be a little on the conservative side of monitoring. We started out during the Q3 week dosing and so we developed our monitoring pathway during that time. And so when we were able to spread out the infusions, we just made a decision that we would keep monitoring their labs intermittently. Thyroid function is something we measure at every infusion and that way, it helps us stay on top of it. We have had a patient who we thought was experiencing myositis and it was actually profound hypothyroidism that had led to their myositis. And so, it's a treatment where you must be aware of the potential side effect profiles, be willing to check for thyroid function, thyroid levels, treponens, or symptoms of hypophysitis as well.

Raoul S. Concepcion, MD, FACS: Kelly, you bring up a great point. And I think all of us, as we try to approach advanced cancers with the multitude of therapies, all mechanistically different, we've obviously embraced the addition of making sure that we have medical oncologists, radiation oncologists, advanced practice providers, but with these immunotherapies and all the itises, the role of the endocrinologist all of a sudden also has become very prominent. I mean, have they become more involved essentially with many of your patients on an IO?

Kelly L. Stratton, MD, FACS: We have gathered a list of consultants who are friendly to immunotherapy patients. So, an endocrinologist, a nephrologist, neurologist, gastroenterologists. And so just having one of each has really made our life a lot easier. And I can't overemphasize how helpful it is to have a pharmacist who can help you through some of these side effects as well, like when you start a high-dose steroid regimen, it's very nice to have them help you taper that patient down as you transition them to an endocrinologist.

Raoul S. Concepcion, MD, FACS: Have they been more involved in your multidisciplinary tumor boards and cancer conferences as well?

Kelly L. Stratton, MD, FACS: Yes. I mean, a lot of times at the tumor board, we're talking about starting a patient on treatment, but throughout the course, they really can jump in and help you get through some of these side effects and help manage the other medicines that the patients are taking and really tease out some of the potential concerns between the GI toxicity and potential pulmonary toxicity or any of the other inflammatory side effects.

Raoul S. Concepcion, MD, FACS: That's great. Kumar, I would suspect that [you have] the most experience with immunotherapy from the medical oncology-specific perspective. Give us your insights and what you've learned over the years and addressing what Mercedes and Kelly have talked about are the various itises that clinicians need to be worried about, incorporation of different specialties that traditionally may or may not have been part of our regular cancer management platforms and how you've been able to accomplish this at a very large community practice that's very active.

Sukumar Ethirajan, MD: So most of our patients are in the hospital outpatient department setting. So, the day-to-day infusions are managed there. I haven't seen any major issues with that. I have actually done a couple of home infusions of pembrolizumab, [which was] well tolerated patients. And in fact, older patients tolerate them well. My view of this is what Dr. Stratton mentioned: You need a good team. A team where you can identify any issues as early as possible. So a good communication with the patient as often as he can, as early as he can. And then identifying the issue. In this case, it's a thyroid. Though the [National Comprehensive Cancer Network (NCCN)] recommends watching DSH every 4 to 6 weeks, I don't think I want to wait that long. I agree with Dr. Stratton, 3 weeks is good, and sometimes they're not symptomatic. It may be subtle. Here it says constipation and fatigue, joint weakness, sometimes it's weight gain without explanation.

So a constant monitor, either the nurse visit or the advanced practice provider or a patient's family member, or a target, all these health as a team number. But this is a multi-system side effect profile. And the good team health early detection and management is very important. A good monitoring plan is very important and some of the older patients have higher comorbidities. Of course, the bladder patients are excluded and then she had the prednisone, which there are more toxicities in older patients, which we need to be very careful because of either perforation or complications or other things. Again, the key is communication monitoring and a team approach.

Raoul S. Concepcion, MD, FACS: Is home infusion becoming more and more popular these days? Tell us a little bit about that.

Sukumar Ethirajan, MD: Well, there are a couple of things going on. Pembrolizumab is not there yet, but if you looked at home infusion of chemotherapy with COVID, that put that in the spotlight. There's a couple of papers from Penn Medicine and then Philadelphia Jefferson, where they're able to transition their patients to home infusion therapy. And they are a good team to take care of it as far as administration, follow-up. So there's already studies out there.

I personally, in my practice, have had a couple of infusions at home. Well tolerated. Not the first dose or the second. After we know that the patient is stable and doing well because these things can go on for awhile. I have a renal cell patient who's getting this for more than 3 or 4 years now. So there are patients who go long term. They're stable, there's no side effects. We have a close monitor. But patient selection is probably more important.

Having said that, there are a few changes in the market space which might become very important. And one of them is, of course, that the drugs are very expensive, especially commercial plans or at-risk plans, they're saying that if it's stable, why can't we give some of these at home. And Medicare just passed home infusion as a part of the most recent 21st Century Cures Act. They opened up the possibility of home infusion therapy. Pembrolizumab is not in that top 10 drugs. In fact, chemotherapy didn't make it there, but it's a matter of time. Once we get comfortable doing these as an outpatient and we have stable patients, and these are long-term treatments after the first 3 or 6 months, if you have a good team, there's a good chance that you can expand it into the home site. I see that happening all the time. Not today, because it's not there on Medicare yet, but there are commercial payers who are moving into the space of providing home infusion therapies. So, it's not too far from there.

Raoul S. Concepcion, MD, FACS: Mersadies, just a quick question. Again, you're in a unique situation where, like Dr. Ethirajan's group is a large LUGPA member practice in Kansas City where he is the medical oncologist, and contrasting to Dr. Stratton, who obviously is in an academic institution, [with a] multidisciplinary approach. But- but Dr. Stratton was also one of the few urologists in the country that has used a lot of immunotherapy himself. what has been your feedback, if you will, in your particular group, where you have a lot of urologists, you have a dedicated medical oncologist. Do the urologists who are active in your advanced prostate cancer center, are they scared of some of these newer therapies, especially with the immunotherapy, and are saying, "Oh, thank God we have Dr. Hamilton," or are they kind of embracing this?

Mersadies Orr, CRNP, FNP-C: Well, I do think that we certainly benefit from Dr. Hamilton, everybody agrees on that. But, in our advanced prostate cancer clinic, if a patient is started on any oral therapy or immunotherapy, that is all managed under the supervision of Dr. Hamilton. So she is the only provider administrating [pembrolizumab] or [nivolumab (Opdivo)] or chemotherapy. So our urologists are not currently administering the immunotherapy at this time.

Raoul S. Concepcion, MD, FACS: So the burning question for probably some of the viewers that are out there, Dr. Hamilton... And there's only one Dr. Hamilton who is managing all these patients, how does that affect when patients call in after hours and call on the weekends? How do the urologic providers basically handle that? That is one of the big things that often comes up in clinical practice, especially in LUGPA member groups, and Dr. Ethirajan, you can comment on this as well. That’s always the pushback from the urologist, is I don't know how to manage those patients.

Mersadies Orr, CRNP, FNP-C: Right now, Dr. Hamilton has myself and a PA. So we help manage our patients. And our practice is primarily prostate cancer, so we have very few kidney and bladder cancer patients right now because of exactly that. Having the coverage in the hospital to manage those patients and also take calls, luckily, our patients on immunotherapy have done great, but they all have access to an after-hours number that would get them directly to Dr. Hamilton.

Raoul S. Concepcion, MD, FACS: So she basically doesn't take any time off?

Mersadies Orr, CRNP, FNP-C: Yeah. Or if she does, she has myself and [the PA] but, because we have such limited kidney and bladder cancer patients right now, that hasn't been a major issue. I can see it being in the future as we grow.

Raoul S. Concepcion, MD, FACS: As patients live longer with all the various therapies, there's going to be anywhere from 5% to 15% of advanced prostate cancer patients that may be candidates for immunotherapy. And again, I think that's one of the reasons why we have to embrace these therapies, just like chemotherapy, is that there is a population out there, even in prostate cancer, that are going to need this.