Bladder cancer: Current state and future directions in treatment

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Published: 15 Aug 2022
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Prof Jorge Garcia - GU Medical Oncology Program, UH Seidman Cancer Center, Case Western Reserve University, Cleveland, USA

Prof Jorge Garcia speaks to ecancer, following his talk at IGILUC 2022, about the current state of play and future directions in bladder cancer treatment.

He reviews the developments of bladder cancer treatment including the importance of a recently FDA approved adjuvant immunotherapy for high risk patients.

Prof Garcia also discusses the genomics aspects of bladder cancer treatments and the potential for a biomarker driven approach.

It was a great opportunity to review the changes in the landscape of bladder cancer in general. Our conversation during the meeting was simple, we talked a little bit about the importance of adjuvant immunotherapy now that it’s FDA approved for patients with high risk bladder cancer, that is for patients who have undergone local definitive curative treatment with surgery whose pathology demonstrates high risk features defined by a pathological T3, T4 or nodal disease in the absence of objective disease, meaning in the absence of metastatic disease defined by negative scans. Obviously nivolumab, which is a PD-1 inhibitor, is now an FDA approved agent for those patients, based upon the data that demonstrated that you can delay disease free survival. Although survival benefit is immature, it was quite interesting to see that you can actually drive an improvement in outcome for a selected group of patients.

The challenge of that data is that traditionally we continue to use perioperative chemotherapy with cisplatin-based therapy before surgery and certainly in the adjuvant space as well. That data, at least in the adjuvant space, although imperfect in many ways because it is all flawed to some extent, the meta-analysis of the adjuvant chemotherapy trials clearly demonstrate a survival benefit for those who get chemotherapy, specifically for those with high risk disease. So that’s the limitation of the nivolumab data – that we don’t have survival data yet.

Now, we also talked about the changes in the management of advanced bladder cancer, that is for those patients who are chemotherapy fit. There are two pockets of patients, one group of patients who actually are cisplatin fit for which the standard of care remains today cisplatin-based chemotherapy, 4-6 cycles, and the new wave of treatment is the addition of maintenance PD-L1-based approaches such as avelumab. So that is the JAVELIN 100 data demonstrates a survival benefit for those patients with metastatic disease who receive platinum-based therapy, a median of 4-6 cycles of chemotherapy, achieving a stable disease or best response as a stable, PR or CR moving forward with avelumab against placebo and, again, the arm receiving avelumab demonstrated survival benefit. So that’s the new standard of care for us in the United States. If you cannot get cisplatin-based therapy because of cisplatin unfitness, often defined by renal dysfunction, hearing loss, peripheral neuropathy and/or cardiovascular disease then it used to be that immunotherapy with single agent pembrolizumab was an attractive option for us. Now the setting with the JAVELIN data most of us probably feel more comfortable moving the patient to carboplatin-based approaches followed by maintenance avelumab. It’s fair to say that if you cannot get chemotherapy whatsoever, a single agent immunotherapy would be a reasonable choice as well.

Now, we also talked about what to do for patients who progress after chemotherapy and that really resides on two things. I think the standard of care right now in the United States after platinum-based therapy is to receive immunotherapy if you have not seen it, specifically pembrolizumab with the KEYNOTE data from many years ago. If you get immunotherapy in the maintenance space then that sequence changes and now for those patients likely it’s going to be enfortumab vedotin, which is an antibody drug conjugate that we now are using for that patient population. So that data actually demonstrates robust responses, RECIST defined, and also significant survival benefit on the phase III data.

Equally important is the genomics aspects of bladder cancer. When we talk about FGFR amplification or FGFR changes that allows our patients with bladder cancer the opportunity to receive an FGFR inhibitor known as erdafitinib, although that data has been published that data does not have survival benefit, it has response and progression data. But certainly a biomarker-driven approach for a small but selective group of patients and a viable option for those with FGFR mutational changes.

Also another antibody-drug conjugate also known as sacituzumab govitecan, again an antibody-drug conjugate similar to EV, or enfortumab vedotin, but with a different [inaudible] which is the chemotherapy that is the toxic aspect of the antibody-drug conjugate when it gets into the cell. That data also has shown a solid response rate in the third line setting, pretty much, and also some progression free improvement, although survival data is not there yet just by virtue of the clinical trial design.

So the sequence is chemo followed by immunotherapy followed by EV or Saci-G with survival benefit, probably EV before Saci-G in my opinion. Then a selected group of people will get erdafitinib, the EGFR inhibitor, if they have the mutational changes for it. For those who have seen chemo followed by maintenance then there is no role to do more immunotherapy when you progress so EV gets closer to that second line space and you still have those options of erdafitinib if you have the appropriate genomic profile and/or sacituzumab govitecan if you progress on EV. So that’s the sequence.

We also talk a little bit about biomarker-driven approaches and I think perhaps it’s the recognition that circulating tumour DNA may in fact become a very good biomarker for us to define who may be at risk to develop progression of disease after cystectomy. Certainly they may be perioperative chemotherapy and there are some elegant data from Dr Pals and his group demonstrating the importance of that, using Signatera which is a molecular profile that basically looks at circulating tumour DNA. So, for patients who actually still have the presence of circulating tumour DNA after therapy, they have a significant detriment in outcome compared to those who don’t have the presence
of circulating tumour DNA.

We are still pretty early in that biomarker development, certainly that was actually done on one of the atezolizumab adjuvant trials and certainly is something that a lot of people in our bladder cancer community are adopting as a way to stratify patients and define their risk as they move forward from perioperative treatments to surgery to advanced disease.

Certainly there are going to be many other clinical trials that are ongoing that are going to reshape how we manage patients in bladder cancer. There is a very unique trial that looks at the combination of pembrolizumab, the PD-1 inhibitor, plus enfortumab vedotin as an antibody-drug conjugate together. The published data that we have seen is quite impressive for response and also progression free so that data actually has been publically announced that the trial has met the primary endpoint and all of us in the community are anxious to see the full final report and how that combination moves forward in the management of our advanced bladder cancer patients.