Immunotherapy Management for Metastatic Bladder Cancer


Focusing on immunotherapy management for metastatic bladder cancer, Dr Shah shares notable toxicities, relevant real-world data, and emergent data on maintenance therapy.


Rohit Jain, MD, MPH: So, Dr Shah, moving towards the [adverse] effect[s], as Jeff mentioned, he had hypersensitivity reaction to avelumab, what notable immune-related toxicities do you see and how do you assess for those effects?

Anand Shah, PharmD, BCOP: Thank you. So, avelumab’s toxicity profile is slightly different, and I will comment on the infusion reactions in a couple of minutes. But I do want to talk about general immune-mediated [adverse] effects. So, immunotherapy drugs came into the market in 2011 and they’ve changed the world of oncology, especially in the solid tumor realm. These agents uncloak the cancer cells from your immune system, and they allow your immune system to fight cancer cells. And we run into problems when the immune system not only attacks cancer cells, but also attacks your normal and healthy cells. And [the] areas that we see this happening most commonly [in include the] liver. So, we can see changes in patients’ liver enzymes on their labs. It can affect their [gastrointestinal] tract and we can see patients having diarrhea from the immunotherapy. It can cause changes in their endocrine function, and we can see changes in their thyroid levels, and we may have to supplement their thyroid levels. Skin rash, we often see skin rash with immunotherapy. And then finally, it can also affect the lungs and sometimes we see pneumonitis, which is an inflammation in the lungs.

But really your immune system in your body is active from your head to your toes. So, in theory, these [adverse] effects can happen anywhere. And we have seen rare cases of patients experiencing immune-related [adverse] effects in their heart or in their kidneys. So, it can happen anywhere, but thankfully the incidence of this is low. And getting back to that infusion reaction. So, avelumab does cause infusion reactions and it is recommended to administer with premedications for the first 4 doses. And then the decision beyond [those] first four doses can be individualized for the patients. So, if patients don’t experience any … infusion-related [adverse] effects, then you can take away those pre-medications. But if they do, then the strategies that were utilized in Mr Ehas’ case [are] exactly what we would do generally, which is to either give them an H1-receptor antagonist, such as diphenhydramine in addition to acetaminophen, or we can also slow down the infusion rate, which is what happened in your case as well. Dr Jain, correct me if I’m wrong, but we would not make dose adjustments in this case, we would just slow it down, and I believe that’s what we did in your case, Mr Ehas.

Rohit Jain, MD, MPH: Right. I totally agree with you Dr Shah. There [are] no dose adjustments for immune therapy in general. These are standard fixed doses. And especially in the hypersensitive reaction, adding premedication, slowing down the rate, those are the usual strategies that we will take to mediate those [adverse] effects. But sometimes the immune neurotoxicity could be severe. And fortunately, in our journey with Mr Ehas, we were very lucky we didn’t have any of those issues. So very, very fortunate. When we talk about maintenance avelumab, obviously these are all clinical trials. And when we try to generalize these treatment options, we also have to look at how is the real-world uptake of the treatment? Because sometimes the clinical trial patients are slightly different from the real world because there are some exclusion criteria, which could not allow everyone to go on the trial.

And what we have seen so far [in] all the published data that we have from the real-world utilization is that the paradigm that JAVELIN Bladder 100 [NCT02603432], has created has been accepted and is widely utilized now, and a majority of the patients who are receiving chemotherapy and have a response are being given avelumab. And the response rates are also pretty comparable to what has been seen in the clinical trial. So overall…the standard of care [that] JAVELIN Bladder 100 established and maintenance avelumab is the standard of care now after chemotherapy.

But what next? Now we know that maintenance avelumab is the standard of care, but how can we improve that? And that’s why many trials are ongoing, which are utilizing now…maintenance avelumab as the backbone of treatment. And now we are adding more drugs as a combination approach in this maintenance realm. And to state a few, there’s an ongoing JAVELIN Bladder Medley [NCT05327530], which is a phase 1B/2 trial. It’s a multiarm trial that’s evaluating the safety of avelumab, but it is in combination with other cancer immune therapies in the advanced bladder cancer space. So, this consists of 4 different treatment options or different arms. One is the avelumab alone, one is avelumab with sacituzumab govitecan, which is an antibody-drug conjugate. Then there’s avelumab plus M6223, which is an anti–T-cell immune receptor with IG and ITM domains. And there’s avelumab plus NKTR-255, which is a normal polymer conjugated recombinant human interleukin-15.

Similarly, there’s another trial which is ongoing called as MAIN-CAV study, which is a phase 3 trial where patients are randomized between maintenance cabozantinib plus avelumab vs avelumab alone in patients who have not progressed on prior chemotherapy. TALASUR [NCT04678362], which is an another ongoing single-arm phase 2 trial, is looking at the efficacy of maintenance therapy with talazoparib, an orally bioavailable polyadenosine diphosphoribose and a PARP inhibitor. It’s combined with avelumab, again in platinum-sensitive metastatic patients. We’re looking at overall survival and duration of response.

And lastly, there’s a question which we have been asking, do we need 4 to 6 cycles of chemotherapy? Can we stop early on? And that’s a question [that] is being asked with the DISCUS trial [ISRCTN15750433], which is a randomized phase 2 study in the UK, which is comparing 3 cycles of chemotherapy vs 6 cycles of platinum-based chemotherapy prior to starting the maintenance avelumab in advanced urothelial cancer. So, this trial will help us to understand whether few cycles of chemotherapy followed by avelumab is good enough, or do we need to go through all 6 cycles of chemotherapy? Also, we have to look at what are the other treatment options after maintenance immune therapy?

And at some point, if there is progression, what can we do? And that’s where we have enfortumab if the patient is enfortumab naive, which is an antibody-drug conjugate, which [has] shown a response rate of 40% in patients who have received chemo[therapy] and immune therapy. We have sacituzumab govitecan, which [has] shown a response rate of 27%, again in the third-line or fourth-line setting. We also check for FGFR inhibitor [eligibility] by looking at the receptor status, if the patient is FGFR2/3 alterations, and that allows us to use afatinib as another treatment modality. And when we look at the new investigational drugs, it’s a list of drugs [that] are being tested in different clinical trials, such as a HER2-targeted antibody-drug conjugate going toward more of a biomarker approach if you have a HER2 expression that [an antibody-drug conjugate] can be utilized. And then we are also exploring adaptive immune therapy approach as well as multiple other checkpoint inhibitors in this clinical situation.

Transcript is AI-generated and edited for clarity and readability.

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