Current clinical roles of anti-PD-1/PD-L1 antibodies in first-line treatment for metastatic urothelial bladder carcinoma (mUBC)

DR LOVE: Welcome to Oncology Today: Immune Checkpoint Inhibition in Urothelial Bladder Cancer, a special program focused on current and emerging clinical research. This is medical oncologist Dr Neil Love. For this program, I met with Dr Joaquim Bellmunt from the Beth Israel Deaconess Medical Center in Boston. In addition to this audio podcast, there is a video component with Dr Bellmunt’s slide presentation

To begin, I asked him to review current data and ongoing trials in the first-line metastatic setting evaluating the combination of immune checkpoint inhibitors and chemotherapy.

DR BELLMUNT: There were 5 trials designed a couple of years ago, and we have heard about the results of 3 trials. We have heard about the imVIGOR130 that is using atezolizumab plus chemotherapy versus chemotherapy versus atezolizumab. We have heard about the pembrolizumab study, the KEYNOTE 361, that is in the same design, using pembro versus pembro/chemotherapy versus chemotherapy. And also, we have heard about the DANUBE trial, that in fact, has already been published this one, where we have been testing durvalumab versus durvalumab/tremelimumab here, not combined with chemotherapy, versus chemotherapy. And unfortunately, not one of these trials has provided any survival benefit.

The 2 trials, the KEYNOTE 361 and the DANUBE, are completely negative in terms of PFS and overall survival. The only one that has provided some positive data is the imVIGOR130, using atezolizumab plus chemotherapy. We have seen a statistically significant benefit in progression-free survival, not of a big magnitude, and we are waiting still for overall survival to be mature. So still first-line chemotherapy plus immunotherapy with atezolizumab cannot be used because only PFS has been seen to be positive. We need to wait for overall survival data.

And we’re waiting for 2 other trials using nivolumab and also durvalumab plus chemotherapy.

DR LOVE: That's what oncologists always ask about, because they’ve been through that thing with lung cancer, where the chemo plus IO, and it really works in terms of their practice. It's been so useful. I guess this was very disappointing. But on the other hand, and I’m really curious to know how you explain this, the situation is a little bit different when you use IO maintenance after chemo.

Rationale for the design of the Phase III JAVELIN Bladder 100 trial evaluating first-line maintenance therapy with avelumab and best supportive care (BSC) versus BSC alone for patients with mUBC whose disease had not progressed after induction chemotherapy; FDA approval of maintenance avelumab

DR LOVE: So I’d like you to go through that also, in terms of, first, what was done before the JAVELIN study, what we knew about maintenance? And then of course, the JAVELIN study. And what I really want you to try to explain is why was the JAVELIN study so positive and these other studies of chemotherapy plus IO not? But anyhow, let’s talk about the data first, then you can tell me why it happened.

DR BELLMUNT: So, in fact, as you have mentioned, we were disappointed on this first-line studies combining chemotherapy plus immunotherapy, because we were hoping to see the same thing as in lung cancer, head and neck and other diseases. And then, the point here is that we had 5 immunotherapeutic compounds approved in second-line bladder cancer and the majority were developed in this first-line setting. But the last one to come up was avelumab. And avelumab, impressively, the way that it was studied, it was in the setting of maintenance.

Avelumab was the last to be positive in the second- and third line. And then a study was designed, in fact, based on the concept of maintenance, that we know that chemotherapy is of benefit in lung cancer. And we were thinking that immunotherapy might be also a benefit in patients receiving chemotherapy first.

When we go back and we see the data that we have in terms of using some type of maintenance treatment in bladder cancer, we have a trial using sunitinib versus placebo as maintenance that was completely negative in terms of overall survival and PFS.

We have a trial using lapatinib in patients having HER2 positivity, also was negative. And then I was involved in a trial that we published using vinflunine, and this agent is approved in Europe; is not approved here in the US, where we saw a progression-free survival benefit when giving the vinflunine after receiving chemotherapy in first line.

The way the JAVELIN trial was designed was in a similar way, and this is what I was involved in this trial.

Vinflunine is a third generation vinca alkaloid that was approved for being used in bladder cancer, only in Europe. In fact, the benefit was very, very tiny.

They didn’t decide to license that in US. So, it's not available here in the US. But this trial using vinflunine that is approved in Europe a second-line chemotherapy for bladder cancer was used as maintenance therapy. And the trial was positive in terms of progression-free survival. It was a very short Phase II randomized trial, not powered for survival benefit.

DR LOVE: So, really, that sounds more like a switch maintenance chemo strategy.

DR BELLMUNT: That's correct. It's the same as pertuzumab in — pemetrexed — sorry — in lung cancer. So it's the same approach.

DR LOVE: Right.

DR BELLMUNT: But the approach with immunotherapy was obviously based on the same rationale, you treat the patient with chemotherapy in the metastatic setting and we know that after 4, 6 cycles, you stop therapy and then you wait. And that the majority of patients are going to recur, despite obtaining a good response to the chemotherapy. And the hope here was, let’s see switch, let’s say, to immunotherapy in patients who derive benefit when receiving chemotherapy. And benefit means complete response, partial response, or stable disease.

In the JAVELIN 100, the trial was designed in that way. So patients responding CR, PR or obtaining stable disease, were randomized to switch maintenance with avelumab until disease progression, or best supportive care, the way that we are managing patients — we were managing patients in the past. And obviously, it was quite challenging and risky. The main endpoint for this trial that was decided was overall survival in the intent-to-treat population, although, also in the PD-L1-positive patient population this was studied.

Major efficacy findings from the JAVELIN Bladder 100 trial; antitumor activity observed with maintenance avelumab in various patient subgroups (eg, cisplatin- versus carboplatin-based chemotherapy, complete response versus partial response versus stable disease with chemotherapy)

DR BELLMUNT: So this has been really breakthrough news for bladder cancer. So this trial was presented initially at ASCO as a plenary session, and then it has already published in the New England Journal, did show survival benefit when giving avelumab maintenance versus best supportive care. And the magnitude of benefit is like — the difference in median OS is 7 months. So, it's a huge benefit in terms of survival. Based on that, FDA has approved avelumab as a standard of care as maintenance in this setting. So, patients who received cisplatin or carboplatin, the benefit of avelumab has been seen in both cisplatin treated or carboplatin treated, after 4, 6 cycles if you obtain a complete response, a partial response, or stable disease. If you switch to avelumab — and in this trial, the period of time in between finishing the chemotherapy and starting avelumab maintenance — it was a maximum of 10 weeks. Patients receiving avelumab maintenance, they obtained a survival advantage.

DR LOVE: So, I’d like to go into some of the details of the studies and the clinical implications. But, again, my first question is why? Why do you see such a big bump? I could imagine, sure you could say, okay, there’s some synergy in some way the chemo primes that IO. But also could be the way the trials were done. What’s your thought about why there was such a difference?

DR BELLMUNT: So this has been an interesting question. Is it like priming the tumor with chemo or immunotherapy might lead to a higher benefit? And, in fact, we presented a trial at ESMO this year that was named INDUCOMAIN, that means induction, concomitancy, and maintenance using avelumab, where we use immunotherapy first, followed by chemoimmunotherapy followed by maintenance. And we compared with randomized data to chemotherapy with carboplatin and gemcitabine. We were hoping that giving immunotherapy first, 2 cycles, was going to prime tumors to respond much better to chemotherapy. We were completely wrong.

So, what we have learned in bladder cancer in all these trials that have been presented, that if you start with immunotherapy, you’re going to see that you’re going to lose at least a third of the patients in the very beginning when treating with immunotherapy and monotherapy. Because immunotherapy takes time until you boost the immune system, if that tumor is growing quicker then you’re going to lose your patient. And we have learned that. It's not a good strategy.

And if we move to this setting of JAVELIN, the fact is that patients start receiving chemotherapy. And then, those patients that do respond, likely maybe because of tumor necrosis, like releasing neoantigens, maybe you are, in fact, synergizing or increasing the use of immunotherapy in this immediate maintenance space.

So, the point here is that some patients of this JAVELIN trial in the placebo arm— or in the best supportive arm — sorry — they received subsequent immunotherapy. And despite that, the trial shows a benefit, meaning you need to give immunotherapy sooner, immediately after the chemotherapy in these patients who have metastatic disease and not wait until they progress, meaning don’t wait until the second line, the pure second line. So, in fact, if we see avelumab is like giving the second-line therapy earlier, just not wait for the tumor to come back. And this strategy, as mentioned, did show this huge magnitude of benefit for bladder cancer patients.

DR LOVE: What about if it's sort of a clinical thing, kind of like along the lines of what you’re saying? And I’ve heard there are cases that come up in lung cancer like this, where people are going downhill form the tumor and they visualize the fact that the chemo in the short run kind of slows that process down. So, what about if that's what’s going on? That you start the chemo, you slow the tumor down, you stabilize the patient maybe clinically — I don’t know sick the typical patient is in this situation — and then you really just give immunotherapy to a healthier patient? And maybe it's not, like I said, maybe not a biochemical or antigen thing, but more of a clinical thing that, I don’t know, it allows people to receive immunotherapy? I don’t know. I just find it really strange. And I can’t think of another example.

DR BELLMUNT: So, we’re going to obtain some biomarkers to try to understand a bit more what’s the mechanism of action behind. And, in fact, we presented some data at ESMO. But what you are saying is correct. So one of the things that was presented at this ESMO, they said, well, is there any difference between a performance status 0-1 in these patients? And the point is that PS was obtained at the time when patients were randomized to avelumab maintenance versus best supportive care. And one of the questions I made to the company, in fact I said, well, you need to look for the PS, the performance status, in the beginning. Because maybe you are, what you are saying, patients who are sick, they benefit from the chemotherapy, maybe you make the tumor to go down and then the immune system is getting better. And then it's the time when immunotherapy is work much better. So this is another way just to interpret why immunotherapy is working that well in this setting.

So, there are different therapies. But this one could be one of them. And in fact, I said, you cannot study or compare the performance status after these patients having received chemotherapy. Because it could be that these patients, the PS was worse in the very beginning. And those are — in fact, this is a good clinical biomarker. You are selecting chemotherapy responding patients or chemotherapy benefiting patients to give immunotherapy. In this trial obviously, the patients that did progress were excluded from this trial. And one could say, well, you are enriching the population. No, likely you are selecting those patients who are going to derive the highest benefit when receiving immunotherapy.

DR LOVE: It will be really interesting to see what the performance status was before and after chemo. Because, obviously, chemo is going to cause problems, but maybe they’re going to get benefit from reducing the tumor. Do you think that the typical patient getting first-line setting therapy for metastatic disease is symptomatic from the tumor?

DR BELLMUNT: Well, this is a question that needs to be answered. And, yeah, the point that you are saying is that the one that I asked the company. So we need to know that. We need to see if there is, in fact, a benefit of improving the PS of these patients. We don’t know. So it could be that the — we need to see how much this performance status has changed to understand if this may be a potential explanation why immunotherapy is working in maintenance.

DR LOVE: Interesting. I guess the other thing is, it looked like the patients who had great responses really benefited the same as people who had stable disease or partial response. It didn’t look — right? That's what it showed, right?

DR BELLMUNT: Yes. This analysis was presented at ESMO. And they provide the survival curves in patients who obtained a partial response. The majority of the patients were, in fact, patients obtaining a partial response. This is what we see in their clinical practice, right. And the largest benefit was seen in these patients, patients obtaining a partial response, receiving then immunotherapy. Patients in complete response, there was some benefit, but if you see the hazard ratio and the differences in survival is not that big as in patients obtaining partial response. Obviously, you could say here, well, the fact is we know that there are patients who obtain a complete response with chemotherapy that are long-term survivors. So with chemotherapy alone, we are able just to cure sometimes around 10% of patients. And it may be very difficult to improve this patient population.

So you see the highest benefit was seen in patients with PR, followed by patients on stable disease, and the patients that we didn’t see this huge benefit was patients in CR. But one potential explanation could be this one. But I think that that's not the reason to say, well, if you get a CR, don’t give maintenance. Because you don’t know which are the ones that are going to surprise us by the CR.

DR LOVE: And of course, not that many people have CR. Also, I mean I just think the data in this trial really could be so amazing as you keep looking at it. One thing that's not even IO related, I don’t even know if it's legitimate to even bring up, but if you look at in the control arms, what did you see in the carbo versus cisplatin? I know it wasn’t randomized, but just curious how did it play out?

DR BELLMUNT: So, in fact, the benefit — this is also another super analysis that was presented asking this benefit of immunotherapy is only seen in patients receiving cisplatin/gemcitabine or is also seen in patients receiving carboplatin and gemcitabine. And the benefit was seen in both groups of patients, patients receiving cisplatin/gemcitabine or carbo/gemcitabine. Obviously, the benefit was a bit better in patients receiving cisplatin/gemcitabine, but here, we could say, well, there is a preselection of patients with good prognostic factors in patients receiving platinum — cisplatin-based therapy.

So, patients receiving carboplatin/gemcitabine usually are patients with worse prognosis. So it could be a selection issue.

So this was not randomized, as you have mentioned.

DR LOVE: Yeah, but I’m talking about the control arm. Because the debate that's going back and forth and the belief that carbo is inferior to cis. I’m just kind of curious, I know it's indirect, etc, but in the control arm did the cis patients do a lot better?

DR BELLMUNT: Well, so that's a never-ending question on carboplatin versus cisplatin. We have data in lung cancer. In bladder cancer, there are 4 small, randomized trials. When I finished my residency, I led one of these trials. And it was a 40-patient trial comparing in fit patients, cisplatin versus carboplatin. And we saw, in the trial that I was chairing, the benefit was seen in patients receiving cisplatin. But this has not been seen in all these small, randomized trials. The belief is that —

DR LOVE: Just out of curiosity, in your trial, what were the numbers? You had 40 people. What was the response rate in two groups?

DR BELLMUNT: So the response rate was platinum/gemcitabine, it was — I think it was 50 — yeah, 55%; carbo/gemcitabine, it was 35%. But there was a survival benefit. But yeah, it was 20 + 20. It was very small, Phase II, randomized trial.

Well, in general, the belief is that cisplatin/gemcitabine provides a superior survival in bladder cancer. But we do not have any prospective, randomized trial with the magnitude sufficiently enough just to say definitively, cisplatin is superior to carboplatin. Because now with immunotherapy, maybe those patients that are receiving carboplatin, if they respond not in this huge amount as cisplatin because they receive immunotherapy, in the end the benefit will be the same. And this is what we have seen a bit less of benefit in carbo-treated patients, but still, the benefit is there.

So, I know that people in community hospitals because of issues of giving cisplatin — cisplatin is a tricky drug to be given. So you need hydration, good renal function, audiologic follow ups, so on and so on. And one say well, if the benefit is minimal, likely quality of life matters and it's better for the patient to come and stay in the infusion room like for 1 hour and a half and not 6 hours receiving the platinum with the hydration. And sometimes we need to put that into context in patients that have limited survival expectations, right. So it's interesting to see that the benefit is seen in patients receiving carbo/gemcitabine.

Spectrum, frequency and severity of immune-related adverse events reported in the JAVELIN Bladder 100 trial

DR LOVE: What about tolerability/toxicity in the JAVELIN study? And any comments about — I’ve heard things about infusion reactions with avelumab?

DR BELLMUNT: So in the initial trials with avelumab, the infusion reactions, because of the type immunoglobulin that the monoclonal that is being used, were seen in 20% of the patients. But now that we have learned the best way to give avelumab, if you start giving anti-histaminic medications with Tylenol. So, the infusion reactions were seen in only 11% of patients receiving avelumab. And that the majority were not seen here, meaning that in the subsequent administrations, like giving additional steroids or other medications, we were able to blunt, or —- well, not completely, but in some patients preventing subsequent allergic reactions — infusion reactions.

DR LOVE: Other than that, typical immune-based tolerability issues?

DR BELLMUNT: We saw what we see in the second line and third line, so you see that around in between 3- and 5% of patients can develop like immune related side effects. We don’t see the severe diarrhea that is seen with a CTLA4 inhibitors. So we see sometimes colitis. We see quite frequently thyroid abnormalities. So in these patients you need to check the TSH. Only if the patients are symptomatic, sometimes you need to treat these patients with thyroid replacement therapy. We saw some pneumonitis. But I think that the rate of adverse events that were much more frequently seen, immune-related adverse events than in the chemotherapy treated patients, but there was no warning, saying, well, there are some patients dying because of immune-related adverse events.

DR LOVE: Right. Again, globally, just taking a step back, also from the point of view of the general medical oncologist and all the different things they’re seeing nowadays, particularly as it relates to checkpoint inhibitors, and when you look at it, in a way it sort of reminds me — in a weird way of what happened with ovarian cancer when they used PARP inhibitors as maintenance after platinum-based chemotherapy. And they saw this incredible hazard rate of around .3 or something and nobody exactly could explain it, there wasn’t a comparison to — actually, if you think about it, I guess there wasn’t a comparison to using it in a different way, that's just the way they always did it. But it sort of reminds me of that. And I don’t know if the biology — that reflects the biology or not.

Frequency of FGFR mutations in mUBC; response to immune checkpoint inhibition after disease progression on erdafitinib

DR LOVE: One more thing I want to ask you about — we were talking about subsets of urothelial bladder cancer, what about HER2-positive disease? How does that fit in? And any difference in terms of how these patients respond to immunotherapy?

DR BELLMUNT:  Fibroblast growth factor receptor. So those are the ones that enriched in luminal type of tumors. Those are the ones that we have erdafitinib that is a drug that the FDA approved for treating bladder cancer patients. So in these patients, the general belief in the very beginning was, well, these patients are not going to respond to immunotherapy. Those are luminal type of tumors, don’t give immunotherapy. And, in fact, there has been an analysis in patients receiving immunotherapy where, in retrospect, the FGFR status has been checked and there are patients with FGFR genomic alterations that do respond to immunotherapy. This paper was published in European Urology by Matt Galsky.

And as mentioned, I have a patient that was an FGFR translocated, that is seen in 3% of bladder cancer patients, that those patients are responding pretty nicely to FGFR inhibitors, that received 2 — it was in 2 clinical trials, receiving FGFR inhibitors, a TKI and a monoclonal antibody. And when these patients progressed after receiving and benefiting of receiving these FGFR inhibitors, he received immunotherapy and obtained a complete response. That means that the tumor microenvironment, first, it might change under the pressure of different treatments. And also, we have the point of the tumor heterogeneity. So the tumors are not homogeneous, and maybe one portion of tumor is enriched by FGFR, another portion is not enriched by FGFR and is enriched by these luminal type, that infiltrated type of tumors and then, the patient might respond to immunotherapy.

I think we cannot create a dogma saying, well, patients with FGFR, no immunotherapy.

There is a Phase III trial in patients with FGFR mutations, FGFR genomic alterations, that are randomized to receive erdafitinib, this FGFR inhibitor TKI versus immunotherapy to try to answer the question what’s the best to be given to these patients.

Biologic rationale for combining enfortumab vedotin with pembrolizumab for mUBC; available data with this combination

DR LOVE: So, the last thing I want to ask you about before we go to your 2 cases, is the issue of the combination of antibody drug conjugate plus IO, in particular enfortumab vedotin plus IO. Can you talk a little bit about the rationale for that? What we know about it? And where you think it's heading?

DR BELLMUNT: So this is also an exciting combination that likely is going to change the future in bladder cancer. The results of a trial that were conducted in patients who were untreated, first-line therapy, but unfit for receiving platinum-based therapy. Those patients were assigned to receive in a Phase II trial the combination of enfortumab vedotin plus pembrolizumab.

In this trial that was initially presented at ESMO in 2019, and it has been updated at ASCO, what we saw, but in first line, patients previously untreated, being unfit, response rate of 71, 72%. And we have never seen this before with any type of chemotherapy. And these responses are durable. So the combination of — let’s say this type of improved way of giving chemotherapy. Would have been disappointed with the regular way of combining chemotherapy plus immunotherapy.

But, the antibody drug conjugate, enfortumab vedotin, is using a carrier that is a monoclonal antibody that is targeting the Nectin-4 that is frequently expressed in bladder cancer, but you need not to test for that expression. And this carrier, this antibody, is having a chemotherapeutic compound that is the monomethyl auristatin and this antibody arrives to the tumor cell, is being internalized, and then inside the cell the chemotherapeutic agent is being released. This is the concept of antibody drug conjugate. So it's like an optimized way to give chemotherapy. Using that, combined with immunotherapy, we saw these responses.

Presumably, there is this concept of immunogenic cell death. So with this type of chemotherapeutic agents, ADCs, you induce an immunogenic cell death. And then if you have pembrolizumab there that is going to attract the lymphocytes there, releasing the PD-1/PD-L1 brake, then you see this synergistic event.

This combination that was tested in this first-line, Phase II trial, now is in a randomized, Phase III trial in first line compared to platinum/gemcitabine, carboplatin/gemcitabine versus enfortumab vedotin/pembrolizumab. And this might be the way that we are going to treat first-line setting bladder cancer patients, and I’m like championing to the future. Maybe I’m wrong. But we’re so excited with the results of this combination of pembrolizumab plus enfortumab vedotin. Enfortumab vedotin is approved for being used in third line after having received platinum-based therapy and immunotherapy here in the US, based on the Phase II data. And we have heard in a press release that the Phase III trial comparing enfortumab vedotin versus chemotherapy in third-line setting is positive for survival.

DR LOVE: Wow.

DR BELLMUNT: So it's going to be — yeah, this is only press release. It has not yet been published. So it is a Phase III trial. Patients that have received chemotherapy with platinum, followed by immunotherapy, and then in this third-line setting, randomized to enfortumab vedotin or chemotherapy, that could be paclitaxel or docetaxel. But results, based on this press release, are positive for survival.

So, it's the first time that we see positive data about survival in this third-line setting. And obviously, this is going to be approved for sure worldwide, monotherapy of enfortumab vedotin.

The point is that if enfortumab vedotin/pembrolizumab is being approved, then we’re going to change — what we’re going to do in second line? So if we use immunotherapy in first line, right? So maybe we will need to use other agents to overcome the immunotherapy resistance. So it's going to be — the landscape might be complicated. Or, if we are using, like maintenance avelumab, what are we going to do when the patients progress? We have enfortumab vedotin. But we don’t know what we’re going to do if the length of period since the patient received maintenance — well, I’m talking about the future. When all these treatments are being implemented, we will need to redesign our trials because the patients will be receiving maintenance avelumab. And there is something that in these first-line trials that I have mentioned, avelumab maintenance was not there. And now, you say, this might change the way that we treat bladder cancer in the future.

DR LOVE: I remember saying that 4 or 5 years ago that lung cancer was the new breast cancer because it was getting so complicated. Now I’m going to say that bladder cancer is the new lung cancer because it's getting even more complicated.

DR BELLMUNT: Getting complicated, totally.

DR LOVE: But exciting.

DR LOVE: Let’s just briefly talk about your cases.

So this first patient, I guess you just saw in June for the first time?

DR BELLMUNT: Mm-hmm. Yes. This is a real case. It's a patient that I’m going to see now with finalizing the 6^th cycle of chemotherapy. So this patient had an upper tract tumor with a lymph node that was enlarged, it was positive for urothelial cancer, and a small spot in 1 bone. He has obtained a very, very nice response. So, even we are thinking, even before going to the answers, to use local therapy for this patient. But assuming that this patient is one of these close to complete responders with chemotherapy, the patient received platinum/gemcitabine, the question here is what to do next in this patient that has received 6 cycles, but the disease has responded pretty nicely. And then you ask, we will stop, and we’ll closely follow the patient. This is what we have been doing because, initially, there was nothing there, just doing these patients after even obtaining this good response, consider erdafitinib maintenance if FGFR genomic alterations are presenting in the genomic report. So we obtained a genomic report and we didn’t see any FGFR genomic alterations, but we might assume that if this is positive, are we going to do that?

So, nowadays, we don't have any data that maintenance erdafitinib is of benefit. Who knows in the future we’re going to, also, to have some data? But at this point, we do not have that.

The third option was, well, wait until progression and rechallenge again with carbo/gemcitabine if recurrence is beyond 12 months or cisplatin/gemcitabine. That's something that we have been doing in our patients with metastatic bladder cancer. Patients that obtain a good response and the disease is not progressing before 12 months, we assume that the disease is still platinum-sensitive, and we might consider using again platinum/gemcitabine. Although, some of these patients were included this situation of recurring after 12 months, were included in trials like the KEYNOTE 045, and those patients obtained benefit when receiving immunotherapy. So, nowadays, like there is not data on what we need to do with these patients. Both options are likely good.

The fourth option in this patient that is responding well is, okay, follow up and then immunotherapy when the patient progresses. And this is something that also we have been doing, meaning second-line immunotherapy, that is a standard of care. We have Level I evidence for pembrolizumab based on the KEYNOTE 045. And then the last option is that, based on the JAVELIN 100, in this patient, consider avelumab maintenance.

So the answer is clear, based on the data that we have discussed. So in this gentleman that I’m going to see with scans that likely are going — after the 6^th cycle of therapy, I will offer him avelumab, based on the results of the JAVELIN 100.

DR LOVE: So, what did you tell him to expect, or what will you tell him when you bring this up, the avelumab? Incidentally, do you know how we do consensus conferences? We get 25 investigators and we present cases like this and say what do you do? And if they all say, give avelumab, we call that a consensus. And we’ve done that before, and we know that's what they say. So, when your practice has been changed, there’s absolutely no question. But there are some issues that come up. So, for example, when you tell him what to expect, what interval? How many infusions is he going to get over the next year?

DR BELLMUNT: So that's an important point that you are raising. Avelumab is given every 2 weeks. That means that the patient needs to come to the hospital to receive the infusion of avelumab every 2 weeks, and this is absolutely, obviously, impacting on the quality of life. But I can tell you that this patient was so happy because the results of the JAVELIN 100 came up during the treatment.

DR LOVE: Right.

DR BELLMUNT: And I knew something in the very beginning, and I say, well, maybe if you are not responding, we will switch to immunotherapy, but then when he responded, I said, well, I have good news for you. We have now this trial that giving maintenance immunotherapy, even if you are responding well, you will receive it. And he’s able to accept whatever. So he’s so happy knowing that this is going to happen with immunotherapy in this situation.

So he has seen a response. And he’s happy to receive early immunotherapy, and he knows that he’s going to benefit his survival.

We’ll see. When he is on treatment after 4 or 5 months, likely he is going to complain, because it's reasonable, and say, well, maybe we can extend the periods of time. And the point is that the label is avelumab every 2 weeks. We know that the majority of immunotherapy compounds are now moving to every 4 weeks or every 6 weeks, so pembrolizumab now is approved for 100 mg every 6 weeks. And with the COVID, it has been a huge discovery, the patient’s not needing to come every 3 weeks. Nivolumab, the same. It was every 2 weeks, now it can be given every 4 weeks. Likely avelumab, we will need to find a way just to give every 4 weeks avelumab. And the treatment is until progression. So that's the way that it was designed. But at least this patient 1 year of maintenance.

I think that if a patient is able to receive 1 year with good quality of life, is likely might lead to benefit. The median number of cycles, in fact receive by the patients, was around — I think it's 7, 8 months. But, obviously, the patients who benefit, they continue receiving avelumab.

DR LOVE: So, is your plan in a patient tolerating it, and not having a problem coming in, would you continue it indefinitely?

DR BELLMUNT: Well, that's the way that the trial was designed. The trial is immature. We’re going to see the long-term follow up of this JAVELIN 100. We will know this data, what’s happening in patients who discontinue because of not a good tolerance or because they feel tired. We will see.

And you know that in lung cancer, now there are trials — well, there has been this trial comparing 1 year versus continue up to 2 years. It seems that you need to continue. So, stopping at 1 year is not enough. So, my suggestion will be — this patient I will encourage them to at least try to get 2 years of therapy, of maintenance. But I have no data. This is my personal belief. I could be biased.

DR LOVE: It's really amazing. I see that on June the 2nd, he got his first dose of chemo. So I don’t know how tied in he is and how much he’s following what’s going on in the field. But imagine, he’s getting his first dose of chemo and he hears that this JAVELIN study was presented and now he knows his chance of surviving, if he goes through that route, is going to be a lot better. But amazing how the timing on this thing.

What about a patient who, from the beginning, or may, after a while, says I really don't like coming in here. How would you feel about switching to another IO like pembro every 6 weeks?

DR BELLMUNT: In fact, there this trial from the Hoosier Group, the same design as JAVELIN 100. So patients receiving — well, they receive up to 8 cycles of therapy — were randomized to receive maintenance pembrolizumab versus follow up. This was a Phase II, randomized trial. This trial was positive for progression-free survival, but this trial, a low crossover, so more patients received treatment at the time of progression, and it was a small trial that finally, the overall survival was not positive. It could be like a tight 2 year, so you need to include more patients to find a benefit. I think that may be the case.

So, the point here is what’s going to happen if a patient says, well, I don’t want to come every 2 weeks. I want to receive every 6 weeks pembrolizumab. So I think it's going to be a personal discussion with the patient because this is out of label, the label is for avelumab. Avelumab is a PD-L1 inhibitor, pembro is PD-1 inhibitor. We don’t know the difference between PD-1/PD-L1 in this setting. We know that some people, they say, well, maybe in the adjuvant setting PD-1s are better than the PD-L1s. But, yeah, also a never-ending discussion about that, at least for bladder cancer.

DR LOVE: Although, I have heard people say, like you said, that maybe there’s a difference in the class, avelumab causes an infusion reaction. I don’t know, maybe there’s something slightly different. I guess your high powered executive, 75 years old, functioning well, you want the good stuff, so to speak, that's been proven. But who knows, once you start coming in, maybe it’ll be a little bit difficult. Anyhow, that's the challenge of oncology.

Case: A man in his mid-60s with mUBC, underlying immune disorders and disease progression on platinum-based therapy and on pembrolizumab receives enfortumab vedotin

DR LOVE: So the last thing I want to ask you about is the other case.

I always love cases of people with pre-existing autoimmune problems, or transplants, or anything. And just really some amazing questions that come up. And you had this 66-year-old man, morbid obesity. History of pulmonary — heart failure, but ulcerative colitis, getting 15 mg of prednisone a day and aspirin, who had metastatic disease. So this is not a maintenance avelumab type situation, but it is a situation of a patient with a prior autoimmune problem. And this, I don’t think, is that uncommon. I mean you see all kinds of questions like this. I was really fascinated by what you did. Can you talk about that?

DR BELLMUNT: So, in fact, this patient, the first thing that you need to ask the patient is for how long have you been on this treatment? When was the last episode of ulcerative colitis? And in this case, this patient, he didn’t have any recurrence in the last 5 years. So, then, some of these patients are receiving steroids chronically because someone prescribed those, and no one paid attention to that. And maybe he could even, part of this morbid obesity could improve, like tapering down those steroids. And this is what we do in these patients.

So he was checked with a colonoscopy. We tried to taper down the prednisone progressively. And then at that the point that the prednisone was less than 10 mg, then we discussed with him the risks and benefits of giving immunotherapy. So the patient was having metastatic disease, and we know that after chemotherapy, this patient has limited survival expectation. For immunotherapy, we know that there are 20% of the patients responding to immunotherapy in second line, and half of these patients have long-term responses deriving benefit long term. So it's an option to say, well, we know what’s going to happen if we don’t give immunotherapy. And if we give immunotherapy, you have the chances of responding and you have the chances of your immune disorder likely recur.

And the studies have shown that 50% of the patients with underlying immune disorders, there’s going to be a worsening of these underlying autoimmune disease. There was a paper published by Steven Holley in patients with melanoma and other diseases that are much more — immunotherapy is much more frequently prescribed.

But, in fact, if you see that — the first thing in this gentleman, you don’t want to give immunotherapy in someone who’s receiving prednisone at a dose of more than 10 mg. The studies, and there is no prospective data, this is kind of from retrospective data, the assumption is that the dose of prednisone if required for a chronic disease need to be less than 10 mg, and this is what we did with this gentleman. So I taper down, finally we left him at 5 mg. And then, we discussed with him the risk-benefit of giving immunotherapy.

So, the answers here is like, continue prednisone and ASA and start pembrolizumab. This is not an option because you don’t want to give immunotherapy in a patient who is receiving 15 mg a day of prednisone. Consider erdafitinib, despite not finding FGFR genomic alterations. This is not option. You need to have this mutation or genomic alterations if you want to prescribe erdafitinib. Rechallenging again with platinum/gemcitabine. As mentioned, this guy recurred in a short period of time, so likely not responding to a platinum again.

Enfortumab vedotin, this could be option because as mentioned, enfortumab vedotin is approved in patients failing chemotherapy and immunotherapy. And if you cannot give immunotherapy to a patient, maybe you can use enfortumab vedotin. But the duration of responses with enfortumab vedotin are shorter than the responses that we see — the duration of responses that we see with immunotherapy. So, it's not a bad option, but I would first try to give the patient immunotherapy.

And docetaxel will be the standard of care that we have been using for a long time before having immunotherapy as an option.

So, that's the case that you need to adjust the medication that the patient is receiving, like checking that the autoimmune disease is not recurring, and then offering him the option of immunotherapy.

DR LOVE: So what happened?

DR BELLMUNT: Well, in fact, this gentleman, as mentioned, we tapered down to 5 mg of prednisone and we started immunotherapy because it was the best option. Unfortunately, this patient didn’t respond to immunotherapy, disease progresses, and then received enfortumab vedotin. But the decision for immunotherapy was a good option at that time.

DR LOVE: But no flare up of the ulcerative colitis?

DR BELLMUNT: No. But this patient didn’t have any — well, the fact, when going back to the ulcerative colitis, you need to consider how severe is this ulcerative colitis. He had only proctitis, or a bit of — so it was not a severe ulcerative colitis. His bouts of megacolon or megacolon. And so, he was on this dose of ASA and prednisone since some gastroenterologist prescribed this dose and he didn’t pay attention, and no one did follow carefully. And the PCP would say, okay, are you doing well? Okay, continue with that. And that's it. And he didn’t have bout since the last 5 years. And that's the point.

DR LOVE: That's a fantastic case. And it's interesting looking at the timing, comparing it to the prior patient who got started first-line chemo just as ASCO was starting. Your patient was treated in 2019, so the year before, so we didn’t have the data. And then, like most patients, he waited until he recurred, in this case only 6 months later. Now you're looking at another line of therapy. And I wonder would you, for example, have given avelumab or offered avelumab maintenance to him if the data had been available at that point?

DR BELLMUNT: Absolutely yes, because the patient had some partial response to platinum/gemcitabine. But, as it usually happens, in the follow up, you see the median duration of response to chemotherapy is only 4-1/2 months, or 5 months. So the majority of patients are progressing. There are these small percentage of patients that are in complete response that are long-term survivors, but this is like 10%, sometimes patients having lymph node-only disease, like tiny amounts of disease. This guy could have benefited for receiving avelumab maintenance.

DR LOVE: When you hear this discussed in other cancers, you see people’s reluctance to give IOs vary based on the autoimmune problem, for example, if you say the patient has multiple sclerosis and they’re onto a treatment, people want to like delay therapy until there’s no other option and their 6-month life expectancy and then maybe the patient will try it. I’ve heard cases like that. But, again, coming back to the first-line maintenance situation, you said you’d be okay putting a patient with this kind of history. For example, multiple sclerosis or Crohn’s disease, same thing? You’d use the maintenance? Or maybe wait until they run out — completely run out of options, enfortumab, etc?

DR BELLMUNT: So, I think that the data is what we have, so we have this retrospective reports. Each patient is completely different, so you need to like take the case and carefully pay attention on how severe is the autoimmune phenomena? What are the survival expectations for the patient? How much the patient is able to face side effects of having a recurring or reactivation of the autoimmune disease?

I was mentioning another patient, saying, well, if you develop a re-bout of your autoimmune phenomena, we will give you steroids, high dose. We are going to block the effects of immunotherapy. And then, obviously, there is a risk but then we will stop, and we will not give you more immunotherapy. And I have never had any patient having this severe, like autoimmune recurrence. As mentioned, in these patients, the first is the good medical history, like, when was the last time you had any episode of this autoimmune phenomena? Maybe we can taper down these steroids. And in this patient, did work. We didn’t completely stop steroids. We left him at a dose of 5m, just in case. But as mentioned, this works. Unfortunately, the patient in the end didn’t respond to immunotherapy. But at least he had the chance to try immunotherapy.

DR LOVE: This concludes our program. Special thanks to Dr Bellmunt, and thank you for listening. This is Dr Neil Love for Oncology Today.