First-line use of tepotinib in METex14 NSCLC: A patient-centered journey

Ryan Nguyen, DO – UI Health, Illinois, USA

Rebecca

Carmela

RN: Welcome, my name is Dr Ryan Nguyen, I’m a medical oncologist based out of Chicago. Today we’re going to be talking about the first-line use of tepotinib in METex14 altered non-small cell lung cancer. This is going to be truly a patient-centred journey. Today I’m so honoured to be joined by actually one of my patients and their family member who has been treating with this medication and who I think as made a really profound difference in their care and their cancer journey. I want to introduce Rebecca, who is a patient of mine, and her daughter, Carmela, who has been such a fantastic resource and part of this journey together. I always say that families are such an important part of a patient’s journey. So we’ll be talking about the diagnosis, when I first met them; the treatment course – we’ll be hearing from Carmela and Rebecca about some of the challenges that we encountered along the way and, of course, about some of the joys in their life that they’ve been able to have because their cancer is much better controlled now. So go ahead and get started.

So some of the learning goals are we’re going to review the role of comprehensive molecular profiling in advanced non-small cell lung cancer. We’ll be talking about the VISION trial which led to the FDA approval of tepotinib for patients with METex14 altered non-small cell lung cancer, as well as real-world treatment considerations for these patients.

We’ll start with a case and this is the case of Rebecca. She’s a 72-year-old female and at the time of her presentation she had no smoking history. She was starting to have some shortness of breath as well as some bleeding, some GI bleeding. Admitted to the hospital and, unfortunately, was found to have quite a bit of concerning findings – a pericardial effusion or fluid around her heart, a mass in her left lower lobe of her lung, some thickening in her small bowel and the duodenum as well as a mass in the left adrenal gland. We drained some of that fluid around the heart and biopsied the left lower lobe mass as well as did a small bowel biopsy. All of these came back with metastatic adenocarcinoma likely from a lung primary. We found that the PD-L1 expression was quite high, greater than 95%.

As part of our protocol, at our institution we do molecular profiling on all of our patients. We did send next generation sequencing from the biopsy which showed a MET exon 14 deletion as well as a MET copy number gain. TMB was 4, MSI was stable and the liquid next generation sequencing also showed MET exon 14 deletion. So for patients who have metastatic disease I typically do tissue plus liquid-based testing to make sure I’m maximising my ability to capture these molecular events. During that work up, unfortunately, she also started to develop some right upper extremity weakness and was urgently admitted to the hospital one day. She really had trouble even lifting her arm above her shoulder and was found, unfortunately, to have two new lesions in the left frontal lobe. Underwent emergent surgery with a craniotomy and these lesions were removed. This was also consistent with metastatic adenocarcinoma.

So upon presentation quite a bit of disease. At this point I’d love to hear from both Rebecca and Carmela, when did you first start to feel like something was different or something was wrong? And then what prompted you to seek medical attention?

CA: The day we went to the emergency room, actually, that morning… Well she was previously diagnosed with asthma so the shortness of breath, even the wheezing, was normal for her. So she has been experiencing that for a few months. Earlier in the day of the emergency visit she said she had vomited and then… I’m a physical therapist so I was checking her oxygen saturation, her heart, her pulse rate and she wasn’t desaturating but she was out of breath. So I was checking on her throughout the day and then in the afternoon, later in the afternoon, I asked her how do you feel? She said she was tired. I asked her, ‘Why don’t we go to the hospital?’, she said, ‘Can we not just see the doctor?’ Well, it’s late and there’s no doctor’s clinic available so I brought her. I told her, ‘We’re going to the emergency room,’ and I asked her to put on her socks. She put on one sock and she had to lay down saying that she’s out of breath, she needs to take a break. Alright, so let me help you with your other sock. And then she was fatigued from that activity so I made her go down the steps slowly, even pushed her with her computer chair to the steps. Then when she got down the steps used a dining chair to push her out to the main door and then I had to ask her, you know, there’s no way that we can push you to the car with a dining chair, so she walked.

In the Emergency Room, when we got there, they checked everything. They did the echo. They didn’t know, again, that I was in the medical profession so they were talking about maybe it’s [?? 5:54] or whatever they found – ‘Oh her heart is dancing,’ something like that. It was actually when the doctor talked to us, they said there’s a lot of reasons why there’s fluid around the heart. The last thing that he said was, ‘… or cancer’, but that actually did not come to me as the probable diagnosis of why she was having all of these symptoms.

RN: Yes, she has probably been healthy all her life and never thought about cancer as even a possibility, let alone lung cancer. But we know that this is one of those cancers that can happen in folks even who don’t have any history of smoking. I’d love to hear from both of you what was it like when you were undergoing all those tests and in the hospital. It must have been so scary hearing the words cancer and hearing about a mass and going through all these biopsies and surgeries. What was that experience like for you?

CA: What was that experience, what was it for you? What was it like, how did you feel when going through the diagnosis when we were in the hospital?

RE: When I was already in the hospital I just leave to the doctors what they’re finding. I just listened to their questions and answered them. They said there is fluid in my heart and they have to go into a procedure. So I give in to their suggestion right away.

CA: Well, they had the cath procedure obviously that same… they were actually quick to do it that night. So in and out of the cath lab and in the ICU. I think in the next couple of days, that’s when they did all the biopsies and all the testing. Obviously before we were discharged from that we were informed that it was cancer.

RN: I think that’s at the point… you were discharged from the hospital and then they set you up for an appointment to see me.

CA: Right.

RN: So that takes us to our next step here and this is an algorithm for how I look at and how I treat folks who have a new diagnosis of lung cancer, just like Rebecca. For patients who have advanced or metastatic, because the cancer had spread to multiple places outside the lung. When we first met we talked about how this was stage 4 or metastatic disease and then what I tell a lot of my patients is I think of lung cancer as almost 20 or 30 different types of lung cancer. No two lung cancers are the same, just like no two patients are the same. Because of that I really try to personalise how we come up with treatment options for patients. A big part of that is making sure that we’re doing what we call biomarker testing.

Thankfully, at our institution we have a process where every single patient who has a new diagnosis of lung cancer is getting all these different tests done on their tumour tissue to make sure that we know about all the different options that are available for these patients. So this is something that we just reflexively do for our patients and that’s how we found this METex14 skipping mutation. I’d love to hear from both of you, when we first met in the clinic and we were talking about your diagnosis and then we talked about the biomarker testing result and the METex14 mutation, what were you thinking? How did that concept of hearing about a mutation and targeted treatment, how did all of that sound to you when we first met?

CA: I think I asked you what the options are because, again as you said, it was stage 4 lung cancer. Again, when you hear the diagnosis of stage 4 it’s always critical – like what’s the life expectancy? I think I asked you what’s the prognosis if there’s no treatment done and I asked as well how about immunotherapy, chemotherapy. And then this is when you explained to us all of the genetic testing that was done, the mutation that was the result of the testing, that the best course for my  mother’s diagnosis and for her kind of cancer is through Tepmetko. Because, again, before that we said, ‘Okay, if there is no treatment what is the expectation?’ ‘It will be maybe six months or less, but with medication maybe two years or… we don’t know.’ So that actually was good news, to be honest – better than the six months or less. So having heard about the biomarker testing and it’s easier for the providers, for the doctors, to make a very sound judgement in how they make their recommendations, their treatment plan. So that actually was a chip off the shoulder, at least, after that gruesome diagnosis.

RN: Yes, I think any time I’m meeting patients, or oncologists are meeting patients, it’s always a stressful first encounter because we’re talking about a serious diagnosis of cancer and especially when we’re talking about something like stage 4 lung cancer. Rebecca, I know you were really sick when we first met so things were very serious. I know that I was very worried, Carmela was very worried, you were very worried, everyone was very worried about you when we first started. So I’m so glad that we have this opportunity to have this conversation years later after we first met.

So let me take us to the paradigm for how I treat patients with advanced non-small cell lung cancer. So we brought up a great point that every patient that has advanced non-small cell lung cancer should get that molecular testing and that includes all the next generation sequencing, the PD-L1 testing, we now have HER2 IHC, c-Met IHC. There are so many different treatment options for patients with advanced lung cancer now that you want to make sure you’re testing your patients and you know all the options for them.

However, we know that about half the patients are not going to have a driver alteration, half the patients that I treat for stage 4 lung cancer don’t have one of these mutations like Rebecca has. So, for those patients I really use the PD-L1 score, which is a marker of response to immunotherapy, to stratify how I treat these patients. For patients who have a high PD-L1 I do consider single-agent immunotherapy as an option, especially in older patients like Rebecca or patients who have more comorbidities. For younger patients or for patients who have more disease where I think they’ll tolerate chemotherapy plus immunotherapy, even in the PD-L1 high setting I would consider chemotherapy plus immunotherapy.

Now, for those patients that are PD-L1 low or negative, chemotherapy plus immunotherapy remains our standard of care here and there are multiple FDA-approved options when you’re looking at all these different combinations here.

When we look at patients who have a driver alteration we see that lung cancer has really become the poster child for precision oncology or this thought of trying to match the right drug to the right patient at the right time. So in these molecular tests that we do we’re testing not just for the METex14 but we’re actually testing for all these different mutations here. You can see that the mutations listed in blue all have treatment options in the first line. So, for example, METex14 has treatment options of both capmatinib as well as tepotinib, and all these other mutations here also have multiple treatment options as well. So we’re really in this area of precision oncology where you can really personalise and customise a treatment option for a patient based on the type of molecular alterations you're seeing in their tumour.

We also have other alterations down here that you can see actually have FDA approvals for targeted therapies but these are just in the second line currently, as of the date of this recording. So we do have these patients get up-front immunotherapy plus/minus chemotherapy but in the second-line setting they do have second line treatment options as well.

So, given all these treatment options, Rebecca and Carmela, I know we touched about it a bit in the beginning but I’d love to hear from you, when you hear about cancer, you think chemotherapy, you think radiation, you think surgery, what do you remember about the different treatment options we discussed and how did we come to decide about Tepmetko as the treatment option for you?

CA: I think we were also, when it was presented, what the best is and also this is, again, for us knowing a lot of the side effects of chemotherapy, some of them have really bad side effects like the toxicity, like the paresthesia and whatnot, and all the vomiting after undergoing those and sometimes the weakness after the immunotherapy. She already had a craniotomy, having the less invasive among them all and the better option when it comes to the mutation testing, I think we all agreed that it’s the best course. Actually, the first six months, especially the first six months after the start of the treatment when the CT was done again, my mum was like, ‘Oh my God, that’s how the cancer tumour has shrunk!’ So it was really, yes, we did the right treatment approach, definitely.

RN: So these are all things that I think we all want to think about and take into consideration, it’s not just what’s listed in the guidelines but also the patient’s unique situation. Rebecca was in the situation she was coming out of brain surgery, we think about her age, we think about some of the side effects with some of the treatments. So I really was coming up with not just a personalised treatment for the mutation but a personalised treatment for the patient as well. I think that’s such an important consideration when you’re thinking about all these different treatment options.

So we’ll go into the VISION trial to talk about how did we decide about using Tepmetko for a patient like Rebecca or for other patients who have this mutation. So this was the clinical trial that led to the FDA approval of Tepmetko for METex14 positive non-small cell lung cancer. This was a single-arm open label multicentre clinical trial. They enrolled patients who were EGFR wildtype and ALK negative who had that METex14 and it could have been diagnosed by either tissue or liquid biopsy. So, again, it’s important to note for Rebecca we captured this mutation both on the tissue and the liquid. So it’s really important to try to capture both so that you can maximise your ability to capture those mutations. They needed to have more than one area of cancer and they needed to have a good performance status. Some of the things that were excluded were patients with symptomatic CNS metastases, with clinically significant uncontrolled cardiac disease or if they had prior treatment with any MET or HGF inhibitor. So a patient like Rebecca we had to do the surgery to control the cancer in the brain before we could start Tepmetko.

So this included patients who were both treatment naïve, about 164, just like Rebecca who hadn’t gotten any treatment for cancer before, and they also included about 149 patients who had gotten some form of treatment, whether that’s chemo or immunotherapy before they were put on Tepmetko.

The primary endpoint of the study was overall response rate or the percentage of patients who had their tumour shrink as evaluated by RECIST and blinded independent review committee. They also looked at duration of response as well as best overall response and disease control rate.

In this graph we’re looking at the results of patients who were… the duration of response. So we’re looking at that amount of patients who had a response and we actually see that just under 60%, about 57% of patients, were like Rebecca where the treatment with Tepmetko actually shrank their cancer. 40% of those patients, like Rebecca, had a duration of response that lasted longer than 12 months. You can see here for patients who had a good response, that response lasted on median about 46 months, or around four years, in the treatment naïve group. In the previously treated group that median duration of response was 12½ months.

The key thing here is that the most response happened within less than six weeks. So for a lot of targeted therapies I see pretty rapid responses and in someone just like Rebecca who has a lot of disease I want something that’s going to work fast and Tepmetko I knew was a medication that has a rapid onset and can work very quickly for patients like her.

When we expand this out to all patients for progression free survival, so how long our patient is living without the cancer getting worse, in the treatment naïve group we see that the median progression free survival was about 12½ months whilst in the previously treated group that is 11 months for those previously treated patients as well. Overall survival, so how long are these patients living on average, the median is 21.3 months for treatment naïve and 19.3 months for those patients who are previously treated.

Side effects, this is something that when I start patients on Tepmetko in the beginning we’re always thinking about some of the side effects to expect for. We were lucky in Rebecca’s instance that Carmela is a physical therapist. So one of the most common side effects that I see with Tepmetko is peripheral oedema and especially lower extremity oedema. So something that we talked about from the very beginning was this concept of leg elevation, of physical therapy, of staying active, compression stockings, to reduce salt intake, as ways to try to prevent as well as treat some of the oedema that’s happening. You can see here in green the percentage of patients who have any of these side effects and then in blue is the percentage of patients who have a grade 3 or 4 adverse event. Most of these are going to be grade 1 or grade 2 but you do see some of these grade 3 adverse events here. Some of the other side effects of note are fatigue, nausea, diarrhoea, some abdominal pain or constipation, musculoskeletal pain, dyspnea, cough, rash, pneumonia, pleural effusion.  So a fairly consistent side effect profile that I see with other oral targeted therapies with peripheral oedema being really a class effect that we see in almost all of the METex14 inhibitors.

Going back to when we made that treatment decision, and Carmela and Rebecca talked about this already, but some of the things that I was thinking about when  I was coming up with my treatment recommendations was, number one, we have a patient that has a lot of tumour burden – pericardial effusion, duodenal involvement, tumour mass, the adrenal, the lung involvement, the brain metastases. So this is a patient with a lot of tumour burden so I needed something that if it was going to work I needed it to work fast. I also thought about Rebecca’s age and patient preferences, just like Carmela was talking about. She had just gone through a surgery, they wanted to minimise some of the side effects that she might be feeling from treatment. We talked about response rate and time to response. Then what was unique was that her PD-L1 score was so high at 95%. So, Carmela and Rebecca, do you remember us talking about immunotherapy and immunotherapy potentially being an option for you in the beginning as well?

CA: It was mentioned but we were discussing which one is most effective at that time of considering treatment plan. Again, with all the discussions and all the pros and cons that were mentioned in the clinic, I think Tepmetko was still way more on the prognosis-wise with the treatment approach.

RN: Yes, and that’s exactly it. The PD-L1 score is very appealing and certainly if we didn’t have the METex14 I certainly would have chosen an immunotherapy-based approach. But when I think about how quickly some of these treatments can work, the immunotherapy can take time and I was worried that was time that we didn’t have. So that’s part of why we chose together to go with the treatment that would work quickly.

So tepotinib, or Tepmetko, is an oral tyrosine kinase inhibitor that’s for the treatment of adult patients with advanced non-small cell lung cancer who have this METex14 skipping alteration. One caveat I’ll make here is that I think it’s really important that patients get both DNA- as well as RNA-based molecular testing because sometimes we do find that DNA-based testing can miss some of these METex14 skipping alterations. I’ve actually seen that in some other patients as well, so you want to be double-checking you’re doing DNA plus RNA-based testing. For those patients who are started on tepotinib or Tepmetko, the recommended dose is 450mg orally just once a day with food until disease progression or unacceptable toxicity. So that was another appeal of Tepmetko is that it’s just a once-a-day pill as opposed to chemotherapy, more surgery or radiation. It’s a lot easier from a treatment administration standpoint just giving this medication once per day.

The treatment course and how did we get to the point that we are here today? We started tepotinib, and I’ll say that from my standpoint I noticed a rapid response and a decrease in symptom burden pretty quickly. The shortness of breath got better fairly quickly, the GI bleeding stopped. We did a scan two months after she started treatment and we saw that the pericardial effusion, the fluid around the heart, had gone away. There was no longer any thickening in the duodenum. The mass in her lung had decreased and the mass in the left adrenal gland had also decreased as well. We checked her labs very frequently during those first four months and the main side effect that we were managing throughout this time was the oedema. So she did develop grade 2 bilateral lower extremity oedema but again because Carmela, such a wonderful resource for her, worked a lot with physical therapy, elevation, compressing, and we did use Lasix on an as-needed basis to help try to manage some of this lower extremity oedema.

This is me talking about it but, Rebecca, I would really love to hear your experience. After you started the Tepmetko when did you first start to feel better?

RE: I really can’t remember when I got better but I could feel it every day I got healed because I can do exercise, different exercises, daily.

CA: How about your breathing?

RE: Of course the breathing was getting better.

CA: Was it right away?

RE: No, it’s not right away but I can feel it’s getting better.

CA: How about feeling tired?

RE: I was glad that every time I see Dr Nguyen I’m looking forward to a better outcome of my ailment. So I’m really happy seeing Dr Nguyen because of the outcome of the treatment.

CA: How about feeling tired? After you…

RE: I can’t remember, after radiation, because the time I felt so tired, I had a hard time eating, even until now I had a hard time…

CA: I meant after you started taking Tepmetko.

RE: That’s why I get better. I can feel it, that I’m getting better. That’s why.

RN: Yes, every time I saw you in clinic. I feel like the first time I saw you, just a couple of weeks after starting treatment, I could already start to see you getting stronger, your lungs were sounding better.

CA: And she wasn’t in a wheelchair.

RN: You weren’t in the wheelchair anymore.

CA: Right, she was in a wheelchair usually.

RN: When we first met you were in a wheelchair and now you’re walking on your own every time I see you. So it happened very quickly, right, and, Carmela, I’d love to hear when did you start to notice that she was being more active, that her energy was getting better?

CA: I think her endurance actually got better pretty quickly. Because when she came out of surgery from craniotomy she presented like someone who had a stroke. But even with that you wouldn’t think that the resolution of that or even the progression of her recovery would be quick because she was in a wheelchair. We sounded like tough love every time with her because we were like, ‘Stand. Walk,’ whatever. ‘Wheel yourself in the wheelchair,’ all those kind of things. But her endurance actually was better, she wasn’t wheezing, she wasn’t coughing. So those noticeable things were actually pretty immediate, to be honest. It happened in less than a month after discharge from the hospital because I know she started Tepmetko after craniotomy. So the physical signs and symptoms of the craniotomy was noticeable but what we noticed the most, she didn’t really felt it but the caregivers around her, like, ‘Oh, you’re not short of breath. I know you’re still tired but you can do more, you can sit better, you’re talking without losing…’ like spaced out. She can talk sentences without feeling the need to stop and pause to catch her breath. So that was pretty impressive.

RN: Yes and it just felt, I’ll say, that every time I saw you just better and better. So happy to see that response. We have to do the CT scans but I knew, based on how you were feeling every time I saw you, that the CT scans had to be good.

CA: Right. Yes, because even the progression from the wheelchair to the cane to the new assistive device, going, visiting you, she actually felt good whenever. Because she would ask to walk with her, just the two of you, and then when she comes back, ‘Oh, it was a walk and Dr Nguyen was so happy.’ I’m like, ‘Yes, yes, you’re doing much better.’

RN: Awesome. Speaking of walking, one of the things that impacts walking for these patients is actually peripheral oedema. Again, this is the most common side effect that we see for patients on Tepmetko. This is how we grade the peripheral oedema. So we talked about grade 1, 2 or 3, and part of it really is getting a baseline for what is the patient’s circumference. So I have patients sometimes get those tape measures that they can wrap around the legs, you want to look at the legs as well and see that percent difference. You want to see if there’s swelling, you want to see can you still see the ankle or is there so much swelling that you can’t even see the ankle? And maybe some of those imprints in there. Can you still see the skin folds or not or is it just so swollen that you really can’t see any of that? Then is it impacting patients’ daily life? So grade 1 peripheral oedema, which is a lot of what we were dealing with in the beginning, doesn’t really impact patients’ lives but once it starts getting to the point where it’s so swollen they have decreased ability to walk around, decreased ability to take care of themselves, that’s when we really start thinking about grade 2 or grade 3 peripheral oedema.

I’d love to hear from you, Carmela, was there anything that you felt like you all were doing at home that helped with the leg swelling the most?

CA: I think encouraging her to be more active because I know that one of the visits with you she lost weight and then the following visit you encouraged her, ‘You have to eat because it’s hard for cancer patients to gain weight,’ so she started eating more. Then when we saw you again, like, ‘Oh, you gained weight.’  And then it was like, ‘Well, you have to be more active too to help with the swelling of the legs, swelling of the arms.’ And I know you prescribed Lasix and then we started using the compression socks. But I think what really helped, aside from all of those, was her being more active than her usual just sitting down in a wheelchair watching TV. So standing, elevating the leg, so, yes, that actually limited the amount of swelling that we noticed in the legs.

RN: And being active is such a key part, not just in the side effect management but also in patients who have cancer and their overall prognosis and lifelong trying to stay healthy. It just really helps encourage that blood flow from not being so stagnant.

So from a provider standpoint when we’re managing peripheral oedema, we just talked about a lot of those lifestyle things that Carmela just covered – compression stockings, lymphatic massage, physical therapy, you can try a low dose diuretic like we did for Rebecca. For patients where it’s very symptomatic I would even consider taking a week or two off the treatment and also potentially a dose reduction. So for those grade 1 or 2, which was mostly what Rebecca’s had, we kept the tepotinib at the standard dose. For those patients where you start to have grade 3 you do want to stop the treatment for a temporary time period; if it goes, if it resolves, then you can restart the treatment but if not then you have to keep holding it and I would even consider doing a dose reduction once you start getting to grade 3. Where it’s really affecting the patient’s ability to take care of themselves then that’s a situation where I’d consider stopping it.

Some of the other side effects that we see are GI side effects of nausea, vomiting, diarrhoea. These are common during the first few weeks but typically resolve after that. They help if the patient takes tepotinib with food and bland food or small meals, increased water, can help with that as well. We do see an increase in the creatinine for some of these patients in the first few weeks but this doesn’t necessarily relate always to an impaired renal function. So it’s something where I continue the treatment if it’s just grade 1 or grade 2 but if I do start to notice sharp peaks in the creatinine then I will hold the treatment. We also see that hypoalbuminemia is a class effect from the MET inhibitors as well. This could also be playing a role in the peripheral oedema, so for these patients I do have them get a nutritional assessment. Like Rebecca and Carmela said, nutrition is such an important part of a patient’s cancer journey as well. Less common but sometimes we see them – LFT elevations, pleural effusions and interstitial lung disease. Although those are fairly rare, these are side effects to keep of note.

Just to give you an idea of the treatment course, six months after treatment, we were having a great response but we did a scan and we did see that in the lung mass, as well as the left adrenal mass, that they were slightly growing. So we had a lot of cancer that we were dealing with in the beginning but we had two spots specifically that were growing. So per our discussion we decided, hey, why don’t we stay on tepotinib because it’s working so well but why don’t we do radiation to these spots to try to control the areas where the cancer is growing. So after we did the radiation we did show that there was quite a favourable response.

For Rebecca I’ve actually been following in her blood something called ctDNA to see how much cancer is floating around the bloodstream. You can see that this number was 17% at diagnosis, went down to 8% once we started her on treatment. Once these spots started getting larger you can see it went back up to 9%, we did the radiation, it came all the way down to 3.7% and I’m very happy to say that the most recent one that we just did is all the way down to 0.7%. So quite a dramatic drop from when we first started.

RE: Yes, thank you.

RN: To conclude, some of the take home messages are that comprehensive molecular profiling is key in advanced non-small cell lung cancer. You really want to personalise your treatment to the molecular profile and to your patient. Tepotinib, or Tepmetko, is FDA approved, NCCN preferred option, for advanced non-small cell lung cancer with a METex14 skipping mutation. The oral once-daily dosing does have a manageable side effect profile, especially if you’re going to be proactive about some of those side effects. Then for those patients who are getting a good response but maybe have oligoprogression with one, two or three sites of metastasis, you can consider consolidative radiation to extend the life of that targeted therapy.

I think this medication has made a huge difference in the lives of patients like Rebecca and some of my other patients who are on this medication. It’s led to more birthdays, more dinners, more Sundays at church that I know that she really enjoys. So it’s been a pleasure and an honour to be part of your care. I know all those church Sundays that you tell me about that you really love. So it really has made a huge difference in patients’ lives and so I really hope that this is a treatment option that you all consider for your patients in the future. With that, take care.