Daniel Petrylak, MD and Donald Barry Boyd, MD, MS, examine real-world data presented in the recent publication, “Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.”
Daniel Petrylak, MD: Hello, I’m Dr. Daniel Petrylak, professor of medicine and urology at the Smilow Cancer Center at Yale School of Medicine in New Haven, Connecticut. I’m joined by my friend and colleague, Dr. Barry Boyd, who is a professor of medicine at the Yale School of Medicine, and practices at Greenwich Hospital, part of the Smilow Cancer Center in New Haven, Connecticut. Our topic for discussion today is, “[Avelumab] first-line maintenance [therapy] for locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.”
Bladder cancer treatment has evolved over the last 30 years. Cisplatin-based chemotherapy, either the MVAC [methotrexate, vinblastine, doxorubicin, and cisplatin] combination, which was invented by my mentor, Alan Yagota, [MD,] or gemcitabine and cisplatin really follows the rule of thirds. About a third of patients will have a complete response, a third of patients will have a partial response, and another third of patients will have no response or progress. When we look at the long-term survival data with MVAC or gemcitabine and cisplatin, we see that only about 5% to 10% of patients are alive with that disease at 5 years. So certainly there is a need for second-line treatments, as well as treatments that may prolong the responses that are seen with either MVAC or gemcitabine and cisplatin. Immune therapy is approved by the FDA in 3 clinical settings, the first of which is second-line therapy that was initially approved in 2016, I believe, when pembrolizumab and atezoluzimab were approved as second-line agents. Then pembrolizumab and atezoluzimab are also approved as first-line agents for patients who are platinum ineligible. Then finally, avelumab is FDA approved for those patients who have responded or have stable disease with platinum-based chemotherapy for metastatic urothelial carcinoma. So we have several different areas in which we may be able to employ checkpoint inhibitors. Switch maintenance is one of the more intriguing areas that has developed in the treatment of urothelial carcinoma. We’re going to be talking today about how the strategy can be used in clinical practice.
This slide basically reports the attrition between first line and latter lines of therapy for metastatic urothelial carcinoma. As we can see, there’s a fairly big drop off in those patients who receive therapy in the first line and second line and then third line. It’s only about 10% for third line. It’s about a third of patients who eventually do receive second-line therapy. I think it would be interesting to find out, perhaps Barry can also talk about his experience, why patients may drop off from first-line therapy. My experience is most patients will go, at our institution, on to second-line therapy. Barry, what’s your experience with second-line therapy in our patients?
Donald Barry Boyd, MD, MS: This is probably speaking not just in our institution, but elsewhere. I think we know that when patients progress, they may actually be on first-line therapy and be into their progression, and then their repeat scans show worsening disease. The other part of this is the age, the typical age of community-related populations, who are often over 65, their performance status is not as good. By the time they progress, they have increasing tumor burden and worse, they have worsening symptom burden. And they may be deemed ineligible by their oncologist for second-line therapy. So we lose those patients to mortality, really. Then we go on to supportive care, etc.
Daniel Petrylak, MD: Yes, I would agree with that. I think that these are patients who are older, they tend to have multiple medical problems. As we know, bladder cancer is a tobacco-related tumor, so along with tobacco goes hypertension, heart disease, then of course, patients who may have other medical problems such, as diabetes or obesity. That will affect, of course, how we treat our patients and their performance statuses. But I think also, we’ve really been remiss in getting the message out that there are treatments available for our patients. We all believe firmly that patients should be molecularly profiled when a patient comes on to second-line therapy, or after avelumab. I like to call it line 1.5 because avelumab was actually part of the original regimen. We need to molecularly phenotype our patients to determine whether they should go on an FGFR3 inhibitor, or whether they potentially could be eligible for some clinical trial. Now we have third-line therapy with enfortumab vedotin as well as beyond with sacituzumab. Again, I would like to see what these numbers are showing us now that we have options that are more viable for the treatment of patients with metastatic urothelial carcinoma. But it’s important for both the physicians and the patients to know that there are options that are out there, and then to determine whether the performance status degradation is due to their baseline medical problems, or whether it’s due to disease burden, and the consequences thereof.
One way in which we may be able to expand that pool of patients who benefit from chemotherapy is to give maintenance therapy to these patients. I like to think of this in terms of, you are inducing cellular damage, as we see on the left side, with chemotherapy. Tumor neoantigens may be released, these are taken up by antigen-presenting cells. Then by giving checkpoint inhibition agents in this clinical setting, within the time that these patients are having the response, you may actually receive more of a benefit from a checkpoint treatment. We know that, at least in the preliminary studies with pembrolizumab and atezolizumab, there doesn’t seem to be a survival benefit for combining chemotherapy with immune therapy. Nonetheless, as we’ll see in the data in a few moments, combining checkpoint therapy, or at least giving maintenance therapy, may be a better way of administering immune therapy to our patients who are responding to treatment. Barry, what’s been your experience?
Donald Barry Boyd, MD, MS: Yes, I agree Dan, and I think one of the keys about chemotherapy is, how do we unlock the immune response in patients? Now again, bladder is very similar to lung and skin, or melanoma, because they are all fairly enriched in tumor and tumor neoantigens, making them theoretically more sensitive to the immune response. I think the other advantage of chemotherapy, and Dr. Petrylak was alluding to the damage to the tumor cell, releasing antigens and enhancing the expression of PD-L1 on the tumor cell, which will then make it more sensitive. But the other thing that chemotherapy does is it can downregulate the cellular immune suppressive network, which includes the T-regs [T regulatory cells], but also myeloid suppressor cells, which actually turned out to be pretty sensitive to gemcitabine. So maybe the regimens we’re giving are downregulating numerous components of the checkpoints that block the immune response. Then you come in with avelumab, and you now have enhanced the sensitivity to the immune response.
Daniel Petrylak, MD: In fact, I think that in the adjuvant avelumab data, in patients who’ve undergone radical cystectomy, there does seem to be a difference in those patients who have received neoadjuvant chemotherapy vs those who have not. And that may be a way of changing the tumor microenvironment or affecting the tumor cells that circulate that maymake them more susceptible to the immune system. So there’s a lot of very good rationale for doing this particular approach. I had the pleasure of being involved in this trial, I was one of the authors on the New England Journal of Medicine paper on the JAVELIN Bladder 100 study. This is a trial that looked at those patients who received platinum-based chemotherapy. In the trial it was either cisplatin/gemcitabine or carboplatin/gemcitabine. The FDA approval is for all platinum-based therapy, including MVAC. So it doesn’t have to be the double combinations with cisplatin/gemcitabine or carboplatin/gemcitabine. But for the study purposes, they did receive cisplatin or carboplatin, combined with gemcitabine. Patients were then administered 4 to 6 cycles of treatment, and their response was assessed. Those patients who had a complete response, partial response, or stable disease, they went on to be randomized to receive avelumab at 10 mg/kg every other week combined with best supportive care vs best supportive care alone.
These are the safety elements of the JAVELIN trial. This is really what you see with immune checkpoint therapy. Those with any treatment-related adverse events was 77%, 16% had grade 3 or higher. Pruritus, hypothyroidism, diarrhea, infusion reactions, asthenia, all these are seen with avelumab. As one would expect, there’s a higher rate of fusion reactions with avelumab compared to observation. So again, I think that we’re seeing immune-related events that occur. Serious treatment-related events were 27.9%, and only 1.2% of those lead to death.
This is the crucial slide from the study, overall survival for the entire population. There was a 7-month difference in the median, a hazard ratio of 0.69 in favor of maintenance avelumab. If we look at the plots in terms of the different clinical characteristics, patients with visceral disease were a little closer to a hazard ratio of 1 compared to nonvisceral, but nonetheless, on the right side, favoring avelumab. It didn’t matter what the primary chemotherapy was, it didn’t matter what the race of the patient was. There did seem to be a little better survival in the PD-L1 positives versus the PD-L1 negatives, not surprisingly. Barry, what are some of your thoughts on these data?
Donald Barry Boyd, MD, MS: What’s fascinating too, is there even seemed to be a bit of an improvement in outcomes in terms of overall survival in the older patients, which is crucial. So this really challenges many of the beliefs we have that gemcitabine/cisplatin is better than gemcitabine/carboplatin here. Once you get through that, you actually do see a very good immune response and maintenance of overall survival in both groups, and also older age patients, the people we think of as being at a higher risk. The fact that even in the PD-L1–negative patients, we’re still coming to grips with the idea that some patients who are PD-L1 negative may still have an immune response. It may be the timing of when we measure PD-L1 and maybe the staining properties and which assay we use, but you still can get a benefit in the PD-L1–negative population.
Daniel Petrylak, MD: Absolutely. But I think the important point also is, it doesn’t matter how you get to that response, as long as you respond. I’m a very anticarboplatin person, so to speak. I’m not a big fan of carboplatin. But these data don’t justify the difference between gemcitabine/cisplatin or gemcitabine/carboplatin as frontline treatment. They justify the fact that you need to give checkpoint maintenance therapy, irrespective of what your initial treatment was.
I think that when you put a bunch of experts into a room and try to define, at least what the criteria are for administering cisplatin, you get a lot of different answers from people. I think the more important issue is once you get there, and this is going to be coming into play more and more as we see some of our newer agents moving up earlier in the course of disease, such as enfortumab. When you get there, maintenance therapy is something we want to think about.
Donald Barry Boyd, MD, MS: Dan, I have one question for you because we’re not privy to those data. But this presumed 4 to 6 cycles of either gemcitabine/cisplatin, gemcitabine/carboplatin, or those regimens based on the reasons why that’s given, was there a difference in those who made it into this study based on that? Do you know that from the original population?
Daniel Petrylak, MD: I’m sorry, difference in what?
Donald Barry Boyd, MD, MS: In the patients who were eligible and had not progressed. In other words, we tend to think that it may be up front that there may be a better response rate to gemcitabine/cisplatin than gemcitabine/carboplatin when given, and those people are more likely to get into this study because they were started on this after having a response. They had fewer progressions, for instance.
Daniel Petrylak, MD: Actually, a subsequent paper basically demonstrated there was no difference in the outcome, whether you had a complete or partial response. Obviously the complete responses did better, but they all benefited from receiving avelumab pretty much at the same level.
Transcript edited for clarity.