Dr. Maughan gave me an update from last month's ASCO GU symposium in San Francisco regarding possible future therapies that I might be needing if and when my mono immunotherapy stops working and my tumors resume growing. Many such therapies are being tested in clinical trials; none have yet been FDA approved. One of the most promising is enfortumab vedotin, an antibody drug conjugate that delivers MMAE, a microtubule disrupting agent, to tumors expressing Nectin-4, a protein found on most urothelial cancers. When given to patients who have progressed after having mono immunotherapy, there was a 42% response rate (EV-101 study, NCT02091999). EV and pembrolizumab (a checkpoint inhibitor similar ot nivolumab) is also being tested (EV-103, NCT03288545).
Coincidentally, in the past week I have been exchanging emails with a woman whose husband recently was diagnosed with metastatic urothelial cancer. She came across my blog and reached out to me with questions. Here are our thread (edited to remove specific identifying information).
[March 3, 2019 at 7:03 pm]
Ken, I read some of your blogs and am glad that you found a immunotherapy that works for you. My husband (58) has TCC. After neoCIs/Gem, then 1. did surgery to remove left kidney/ureter PT3; 2. found CIS in bladder 3; and 2 weeks ago found small nodules in lungs PT4. We just shocked. My husband has the option of Keytruda or a trial: Enfortumab Vedotin Plus Pembrolizumab. I wonder how did you decide to go Nivolumab and do you have any tricks to respond it well. D[March 3, 2019 at 9:11 pm]
D: Thanks for your note. I'm sorry to hear about your husband's Dx. In my case, my distant mets were confirmed by FNA biopsy in 2014. No checkpoint inhibitors had yet been FDA approved at that time, so I enrolled in a clinical trial for Opdivo (nivolumab), starting in early 2015. I was fortunate to have had a complete response, which lasted nearly three years. After my mets returned, my doctors recommended that I resume nivolumab to see if it worked before trying a combination therapy. Right now I've got stable disease, and am continuing with monotherapy infusions every 4 weeks. I'll stick with nivolumab as long as I don't have active tumor growth. I know of no tricks on how to make it work better -- it either works or it doesn't. When the time comes when single agent immunotherapy stops working (and in my mind it's not if, but when), then I'll look at combination therapies, such as Enfortumab Vedotin Plus Pembrolizumab (EV+P). I have the good fortune of being followed by clinicians at NIH, Hopkins, as well as Huntsman in Utah, so I will draw upon a number of opinions before making that decision. So far, I'm keeping the combination therapy options in my back pocket to use when single-agent immunotherapy no longer works.[March 3, 2019 at 9:38 pm]
As for your husband, has he had a biopsy to confirm the nodules are metastatic TCC? Is it expressing PD-L1? The treatment may differ depending upon the answers. Once you have the data, discuss your choices with your husband's onc, and consider getting a second and perhaps third opinion if you can. I'd defer to the consensus of the doctors' recommendations. Pembro has been FDA approved for solid tumors with certain genetic anomalies. If you husband's tumors have those anomalies, it's a good treatment option. The data are available for you to make an informed assessment. The EV+P trial has less available data, although early results are promising. My understanding is that immunotherapy typically is offered first, and if that fails, EV+P may be an option. Going straight to EV+P is a more aggressive therapeutic choice. Getting information about the genetic profile of your husband's tumors could help the decision, but it ultimately boils down to whether you want to try immunotherapy alone (as I have, since so far it's working for me), or jump straight to the combination therapy. Ken
Ken: Thank so much for your email and your opinions. You have done great jobs to work with so many good doctors. I just wonder if traveling to different clinics would cause some stress? Feb 2019 CT Scan shows 5 solid nodules in lungs (largest 1.7 cm), while no biopsy, CT Scan report says "compatible to Lung Metastases" comparing his Oct 2018 CT Scan (none) and his Dr thinks so too. When asked PD-L1 test, his Dr said, there is no need because patients with "unqualified" PD-L1 still respond to Keytruda. Thank you to ask these questions, we'd better to check these things before Keytruda. D[March 3, 2019 at 11:35 pm]
D: I personally found great comfort in seeking multiple opinions. But I'm an unusual patient in that I like to read the medical journals and keep current on fast-moving developments regarding metastatic urothelial cancer (mUC). I don't know where your husband is being treated at -- I believe that talking to an oncologist at an NCI center is important. If your husband has already been to an NCI, and if going to different clinics would add stress to you and your husband, then don't do it.[March 4, 2019 at 12:08 am]
Checkpoint inhibitors such as pembro (or nivolumab) only work if the tumors are expressing either PD-1 or PD-L1. That's why some doctors (and drugmakers) like to test for those proteins. But those tests are not uniform, for two reasons. First, there is no standard test for those protein levels. Second, those proteins not immutable. They can come and go. A patient can be tested for it, and be negative, yet still respond to a checkpoint inhibitor. But knowing that your husband's tumors tested positive for those proteins suggests a greater likelihood that he will respond to monotherapy. That knowledge may influence your treatment decision.
With tumors growing as rapidly as they are between 11/18 and 2/19 as shown on the scans, however, it's important to start treatment quickly. If getting a biopsy or other answers to my questions would slow things down, then I'd lean towards starting therapy ASAP. In either treatment option that you have identified, your husband would be getting pembro, an immunotherapy checkpoint inhibitor. That's important. Immunotherapy is his best bet for mUC. The question you have asked is whether to have monotherapy, or add in Enfortumab Vedotin at this time. The answer may be influenced on how you and your husband want to have the option for additional treatments if this one fails. Maybe it's important to both of you to know that if pembro alone does not work, you can go to EV+P. Or maybe you want to skip monotherapy and take the more aggressive approach and try EV+P now.
Living with mUC for nearly seven years has taught me to be patient and view my mets as a chronic issue. There's no cure for mUC. The goal of any of the therapies that I've had, or that your husband is considering, is to slow the progression of the disease. I expect that at some point my nivolumab montherapy will stop working, and I'll have active tumor growth. When that happens, I'll try a combination therapy. I have a list of about a half-dozen (including EV+P) that I'll discuss with my doctors, plus anything else they can think of. We'll discuss the pros and cons, and we'll pick one. If it works, I'll ride that horse until it no longer works. If it doesn't work, I'll try the next one. Meanwhile, I'll live my life as best I can and be grateful for each day. Ken
Ken, Again, thanks so much. My husband's oncologist is at an NCI. We will travel to another NCI for 2nd opinion. We will look into possible PD-L1 test, while starting therapy soon. My husband is at a stage of finding a proper med to survive. He will work with a good nutritionist on his diet. I believe if UC patients can hold on for a few years, new medicines will come out to cure them. Your opinions and experience are really helpful and thank so much for this. D[March 4, 2019 at 9:24 pm]
Ken, Well, I am sorry to bother you again with questions. But only when you have time. (It seems our Drs do not give much information, in general. We do not push because this is the only decent NCI in our area) But this time, we did try to ask our doctor about PD-L1 test, but he said NO. Here is the answers from our doctor.[March 6, 2019 at 11:45 am]
1. Do I need PD-L1 test, No, I don't think the predictive power of PD-L1 status is such that we should be using it currently to make treatment decisions. The two principal options are chemotherapy and immunotherapy, and recent chemotherapy didn't do much. So even if PD-L1 were low, I would recommend immunotherapy (or a clinical trial).or any other test prior to starting Keytruda? If so, I had biopsy 11/6/2018 and could sample from it be used?
answer: No, because some pts with negative PD-L1 still respond so we do not use this for a go/no-go decision
2. I understand that Keytruda could still work even if I had a low PD-L1. BUT if my PD-L1 was in fact quite low, would an alternate medication then make more sense? So should my PD-L1 therefore be checked?
answer: No, I don't think the predictive power of PD-L1 status is such that we should be using it currently to make treatment decisions. The two principal options are chemotherapy and immunotherapy, and recent chemotherapy didn't do much. So even if PD-L1 were low, I would recommend immunotherapy (or a clinical trial).
***
Questions for you:
1. There are several immunotherapy, and they have different requirements of PD-L1. Would a different PD-L1 level point to a different immuno med?
2. I contacted another NCI. But I just do not know how this works with a distinct clinic with regard to infusion, scans, trials?
3. Do we really need PD-L1 score?
4. Our nutritionist said she can help with low PD-L1. Have you heard about this?
5. May I know your list of good combined med trials and treatments, if you do not mind.
Thanks so much, D
D: As I understand it, your husband has already decided to get immunotherapy (Keytruda). With that decision already made, I understand why your doctor says no new PD-L1 testing is needed.[
To answer your specific questions:
1. No. The 6 different FDA-approved checkpoint inhibitors work using similar mechanisms. All require the tumors to express PD-L1 to work. Some manufacturers have suggested that their drug be used only on patients that test positive for PD-L1, but since there is no agreement on how to test for it, plus the fact that PD-L1 comes and goes, makes the current testing less useful. In my original response, I was wondering if your husband already had been tested for PD-L1, or other genetic testing. Which specific checkpoint inhibitor your husband gets (Keytruda, Opdivo, etc.) isn’t as important as the fact he’ll be getting immunotherapy.
2. Getting second opinions is not easy. To the extent you can stay local, it’s easier. For contact info, see https://www.cancer.gov/research/nci-role/cancer-centers. Ask your doctor who he would recommend. But I would not delay treatment if getting a second opinion would take a while.
3. No, since it’s already been decided that your husband is going to get immunotherapy. I can understand why the doctor says a PD-L1 test is not necessary. The question was whether to add EV at this time, or wait.
4. I’m not aware of any studies supporting the idea that a specific diet can enhance PD-L1 expression. This review article from last year is a mishmash of ideas showing how little is known about diet in assisting the fight against established cancers (as opposed to certain diets helping to reduce the risk of developing certain cancers, which is irrelevant to those of us who are already stage 4). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859494.
5. My list is in one of my blog posts from about 6 months ago, I think. EV+P is at the top of my list - it has low side effects and promising benefits. Cabo+Ipi+Nivo is another option, but toxicity risks are greater. Ken
Ken, Thanks for your help. We like your idea to try a med first, and keep the combined meds later. Just pray for miracles. Best wishes to you and your family. D
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