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CPD

Exploring Key Progress With Targeted Therapies for Urothelial Carcinoma: A Quickfire Expert Exchange

  • Authors: Thomas Powles, MBBS, MRCP, MD; Cora N. Sternberg, MD
  • CPD Released: 3/24/2022
  • Valid for credit through: 3/24/2023
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  • Credits Available

    Non-US Physicians - maximum of 0.25 CPD

    You Are Eligible For

    • Letter of Completion

Target Audience and Goal Statement

This educational activity is intended for an international audience of non-US hematology and oncology specialists, urologists, and pathologists.

The goal of this activity is to provide an informative snapshot of where we are to date with targeted therapies for advanced/metastatic urothelial carcinoma from a clinical perspective.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Available evidence for targeted therapies for locally advanced/metastatic urothelial carcinoma 
  • Demonstrate greater confidence in their ability to
    • Identify which patients with locally advanced/metastatic urothelial carcinoma could benefit from treatment with targeted therapies 


Disclosures

WebMD Global requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships with ineligible companies.


Faculty

  • Thomas Powles, MBBS, MRCP, MD

    Professor of Genitourinary Oncology
    Barts Cancer Institute
    Queen Mary University of London
    London, United Kingdom

    Disclosures

    Disclosure: Thomas Powles, MBBS, MRCP, MD, has the following relevant financial relationships:
    Advisor or consultant for: Astellas; AstraZeneca; Bristol Myers Squibb; Eisai; Exelixis; Incyte; Ipsen; Johnson & Johnson; Merck; Merck Serono; Merck Sharpe & Dohme; Novartis; Pfizer; Roche; Seagen Inc., formerly Seattle Genetics, Inc.
    Grants for clinical research from: Astellas; AstraZeneca; Bristol Myers Squibb; Eisai; Exelixis; Ipsen; Johnson & Johnson; Merck; Merck Sharpe & Dohme; Merck Serono; Novartis; Pfizer; Roche; Seagen Inc., formerly Seattle Genetics, Inc.
    Other: Travel: AstraZeneca; Ipsen; Merck Sharpe & Dohme; Pfizer; Roche

  • Cora N. Sternberg, MD

    Clinical Director
    Englander Institute for Precision Medicine
    Professor of Medicine
    Sandra and Edward Meyer Cancer Center
    Weill Cornell Medicine
    New York-Presbyterian
    New York, New York, USA

    Disclosures

    Disclosure: Cora N. Sternberg, MD, has the following relevant financial relationships:
    Advisor or consultant for: Astellas; AstraZeneca; Bayer; Bristol Myers Squibb; Foundation Medicine; Gilead; Immunomedics; Incyte; Janssen; Merck; Merck Sharpe & Dohme; Pfizer; Roche-Genentech; Sanofi-Genzyme

Editor

  • Megan Cannon, PhD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Disclosure: Megan Cannon, PhD, has disclosed no relevant financial relationships.

Compliance Reviewer

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance

    Disclosures

    Disclosure: Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.


Accreditation Statements

    For Physicians

  • The Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom (FPM) has reviewed and approved the content of this educational activity and allocated it 0.25 continuing professional development credits (CPD).

    Contact WebMD Global

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information about your eligibility to claim credit, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent participating in the activity. To successfully earn credit, participants must complete the activity online during the credit eligibility period that is noted on the title page.

Follow these steps to claim a credit certificate for completing this activity:

  1. Read the information provided on the title page regarding the target audience, learning objectives, and author disclosures, read and study the activity content and then complete the post-test questions. If you earn a passing score on the post-test and we have determined based on your registration profile that you may be eligible to claim CPD credit for completing this activity, we will issue you a CPD credit certificate.
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CPD

Exploring Key Progress With Targeted Therapies for Urothelial Carcinoma: A Quickfire Expert Exchange

Authors: Thomas Powles, MBBS, MRCP, MD; Cora N. Sternberg, MDFaculty and Disclosures

CPD Released: 3/24/2022

Valid for credit through: 3/24/2023

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Activity Transcript

Thomas Powles, MBBS, MRCP, MD: Hello. I'm Tom Powles from Barts Cancer Centre in London, the United Kingdom. Welcome to this program entitled Exploring Key Progress with Targeted Therapies for Urothelial Carcinoma: A Quickfire Expert Exchange. The expert I'm with today is Cora Sternberg. Cora is from the Weill Cornell Medicine, New York Presbyterian in New York. Welcome, Cora.

Cora Sternberg, MD: Thank you. Happy to be here.

Dr Powles: Cora and I are going to have 90 seconds to answer some questions together. I'm going to give a very quick overview, if I may, and then I'm going to ask Cora the first question.

The overview for targeted therapies in locally advanced/metastatic disease is going to include the antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. We're also going to include the FGFR inhibitor, erdafitinib. This has been a big change in the way we treat urothelial cancer. Indeed, all three of these are approved by the FDA.

The antibody-drug conjugates are essentially agents that have a targeted antibody to a specific molecule, nectin-4, for example, with enfortumab vedotin; a linker molecule; and then a payload such as MMAE, again, for enfortumab vedotin. Sacituzumab govitecan has different antibody and payload.

The FGFR inhibitor, the tyrosine kinase inhibitors, they're mainly targeting FGFR2 and FGFR3. There is some debate about the biomarker, which I think Cora and I will have today.

That was my quickfire 90 seconds. Let's start and go over.

Cora, what are the main findings of the EV-301 trial for enfortumab vedotin vs chemotherapy in patients whose cancer had previously progressed on both chemotherapy and immune therapy?

Dr Sternberg: Thank you, Tom. This is a study in which patients with advanced urothelial cancer, including those with squamous differentiation and had radiographic progression after PD-L1 and a prior platinum regimen, were randomized between enfortumab vedotin and investigator's choice of chemotherapy. The primary endpoint was overall survival. In fact, overall survival was improved by 30% with enfortumab vedotin vs chemotherapy in this trial. The progression-free survival was also improved. The overall response rate was 40.6% with EV vs chemotherapy, 17.9%.

So FDA has approved enfortumab vedotin for adult patients with locally advanced or metastatic urothelial cancer, who have previously received a PD-L1 inhibitor and platinum-containing chemotherapy, who are ineligible for a cisplatin-containing chemotherapy, and have previously received one or more prior lines of therapy. I've been fortunate enough to be able to use this very efficacious drug. Thank you.

Tom, what are the key findings from the TROPHY-U-01 trial with sacituzumab govitecan?

Dr Powles: Cora, thank you. You did spectacularly well to keep in your 90 seconds. I'm going to do my best with this section, but I've already wasted 10. Sacituzumab govitecan is also an antibody-drug conjugate. Its payload is SN38, which is like irinotecan. It has a different side effect profile from MMAE, for example. It obviously has a linker molecule and attached to that is trop-2, which is what the antibody targets. There are different cohorts to this trial. We're going to focus on cohort 1, which is those individuals whose cancer has progressed after both platinum-based chemotherapy and immune checkpoint inhibitors. Actually, quite similar to the 301 population, although cross-trial comparisons should be largely avoided.

Here, you can see 113 patients were recruited to this part of the trial. The progression-free survival at about 5 months and overall survival of 10 months are in line with expectations. Response rates, PR of 22%, CR of 5% are also promising. Now cross-trial comparisons should of course be avoided, but this drug looks to have significant efficacy. In my opinion, this efficacy looks better than we've seen for standard chemotherapy in the past. Therefore, this drug has also received the form of FDA approval.

Cora, in terms of safety, what are the key aspects we need to consider with these antibody-drug conjugates?

Dr Sternberg: Well, these two antibody-drug conjugates are different and they have different payloads, as you've mentioned. In the enfortumab vedotin, it's highly efficacious, but there were treatment-related adverse events.

In this study, the dose was reduced in 32% of patients. There was an interruption of treatment in 51% and withdrawal of treatment in 13.5%. I find this to be an extremely efficacious drug. I find the biggest problem to be peripheral neuropathy. In fact, in this study, 50% of patients had peripheral neuropathy, which were mostly sensory events. Rash also occurs in 48% and hyperglycemia in 11% of patients.

Sacituzumab govitecan is different. The side effects are different. There is no rash. There is no peripheral neuropathy, but there are hematologic toxicities. I see neutropenia. I see anemia and even febrile neutropenia. The GI side effects of diarrhea and nausea are there as well. It has a completely different safety profile, a different payload, and one can be used after the other as well.

Tom, are there particular factors you consider in choosing one ADC over the other?

Dr Powles: Cora, it's a good question and no one really knows the answer. I think that the obvious question is: Are there subgroups of patients or biomarkers to deliver these therapies? The EV-301 trial showed the agent working across broad subgroups of patients in the forest plot analysis. The biomarker, nectin-4, is overexpressed in the vast majority, well over 90% of patients with urothelial cancer. That's probably not going to turn out to be a great biomarker. Therefore, perhaps we need to look at other factors. We haven't seen any data along those lines. Certainly, PD-L1 is not a logical biomarker to use and we have to explore perhaps other biomarkers. We know less about biomarkers for sacituzumab govitecan. It's only 100 patients in a phase 2 trial. Again, we're not using trop-2 as a biomarker because it's overexpressed in the vast majority of cancers.

That takes us to clinical factors. I guess if patients had a history of diarrhea or problems with diarrhea, or neutropenia or other issues with chemotherapy, those factors are more common with sacituzumab govitecan. I think significant ongoing peripheral neuropathy, you might say, well, that is perhaps something where one would consider using enfortumab vedotin more sparingly and one might want to choose other agents. I think at the moment, the baseline clinical factors are probably more relevant in driving treatment choice and that's particularly around adverse event profile. It's also worthwhile saying that as it currently stands, enfortumab vedotin has a response rate of 40% and positive randomized phase 3 data with level 1A evidence. Sacituzumab doesn't yet have that. That's important when we consider choosing these agents for our patients. Cora is absolutely right that sequencing these agents may be attractive. We'd look into that in the future.

Of course, erdafitinib has a role to play in this sequencing issue.

Cora, perhaps you could describe the key findings from BLC2001 for erdafitinib.

Dr Sternberg: Oh. I'm very happy to and I agree with everything you've said. I find EV to be very efficacious, but I often have to lower the dose and I have to beg my patients to stop the treatment when the peripheral neuropathy is a real problem.

Erdafitinib is also FDA approved for patients with FGFR2 and FGFR3 gene alterations. This comes from the BLC2001 phase 2 trial where patients who have had pre-specified FGFR alterations, were randomized between an intermittent schedule and a continuous schedule of erdafitinib.

At the interim analysis, they understood that the 8 mg/day continuous schedule was perhaps pharmacodynamically the best dose. The primary endpoint was overall response rate.

In this trial, 99 patients with FGFR3 mutations or FGFR2/3 fusions were placed. In all patients, the overall response rate was 40% and in those who had prior immunotherapy, it was 59%; 43% of the patients received at least 2 prior courses of treatment; 79 had visceral metastases; and 53% had a creatinine clearance of less than 60. Now erdafitinib is approved for patients with advanced and metastatic urothelial cancer with selected FGFR2 and FGFR3 gene alterations, and progression during or after chemo or within 12 months after neoadjuvant or adjuvant platinum-based chemotherapy.

The long-term outcomes have been also presented. The median PFS being 5.5 months and the median OS is 11.3 months with a median follow-up of 24 months.

Dr Powles: Cora, perhaps you can also talk to us briefly about the THOR Study, which I think is a really important study.

Dr Sternberg: Now we have an ongoing interesting trial called the THOR phase 3 trial. In this trial, patients have received 1 line of prior systemic treatment with cisplatin-based or carboplatin-based chemotherapy. They have the FGFR2/3 alterations. The cohort 1 are those patients who have had an anti-PD-1 or anti-PD-L1 therapy, randomized between erdafitinib and chemotherapy. In cohort 2, we have patients who have had no prior immunotherapy checkpoint inhibitors, randomized between erdafitinib and pembrolizumab. The primary endpoint is overall survival. I think this trial should be very, very interesting.

Dr Powles: Thanks, Cora. I agree with you. My experience of erdafitinib is it causes genuine tumor shrinkage in quite a high proportion of patients that we've used the drug on. I've been impressed with it, even in those patients who have progressed on other treatments. I think it has a real role to play and I think that THOR randomized trial is going to be really important for approval of this drug in Europe.

Dr Sternberg: Tom, in terms of safety, which are the key aspects we need to consider with erdafitinib?

Dr Powles: Of course, the drug has an adverse event profile. Hyperphosphatemia, which is thought to be an on-target effect and indeed you can dose escalate in the absence of hyperphosphatemia, is an important adverse event that requires monitoring. Skin adverse events, including hand-foot syndrome, are very important. It's the nail adverse events that really stands this drug out. We've seen that patients’ nails can get into a lot of trouble and they require quite a lot of attention. I've seen patients’ nails actually bleeding from this drug. Obviously, we'd like to dose reduce before that occurs. Central serous retinopathy is an important adverse event that requires investigation and indeed monitoring if it was to occur with stopping the drug.

The whole picture shows actually broad-spectrum adverse events from skin to metabolic to gastrointestinal with diarrhea and hepatic changes. Of course, this eye toxicity, which I mentioned before. Careful monitoring is required. But actually, it's fair to say that all three of these drugs we described today, sacituzumab govitecan, enfortumab vedotin, and the FGFR inhibitor, erdafitinib, all have slightly different adverse events profiling. We're going to have to learn how to use these drugs well.

Cora, we've seen some data combining these therapies with immune therapy. Could you give an overview of that for us?

Dr Sternberg: Certainly, I'd be happy to. But one thing that we know is if you combine pembrolizumab and enfortumab vedotin in the EV-103 trial, which was for cisplatin-ineligible patients, there was a 93% response rate. If you look at the EV-302 trial, this is a trial in which EV and pembrolizumab are being compared to gemcitabine and cisplatin or carboplatin. We're moving EV up earlier because the combination with EV and pembro is so very efficacious.

There's also a trial with pembro and sacituzumab govitecan. This is cohort 3 of the TROPHY-U-01 trial that you've just discussed.

We have two phase 2 trials, the NORSE trial and the FORT-2 trial in first-line for cisplatin-eligible patients that harbor FGFR alterations. In the NORSE trial with erdafitinib vs erda and cetrelimab, the overall response rate was 68% compared to 33%. The CR rate was 21% compared to 6%. In the FORT-2 trial with rogaratinib and atezolizumab the overall response rate was 58% and the CR rate, 13%. These combinations are very, very interesting as far as I'm concerned.

Dr Powles: I agree with you, Cora. I just feel that particularly the EV/pembro data looks better from the back of the room than we've seen with chemotherapy. Also, the progression-free and overall survival were both much longer than I was expecting. We've seen the chemotherapy combinations with immune therapies haven't been that successful, but it may be that the immunogenic effects of enfortumab vedotin and potentially sacituzumab govitecan are different from that with gemcitabine and cisplatin chemotherapy. Well, we hope the EV-302 trial, obviously, will supersede and become a new standard of care. We haven't yet heard about where NORSE will go next and whether that would also lead to a randomized phase 3 study. But it is incredible that we have managed to develop two novel therapies and stick them into the frontline setting, look at their individual parts, combine them together, and potentially replace chemotherapy in urothelial cancer in a relatively short period of time.

If I may, I'm going to conclude. I'm going to start by saying that this is an incredibly exciting area. We have seen the first chapter of development of new drugs with immune therapies with modest results. What we've shown is the immune checkpoint inhibitors work in subsets of patients, about 20% of patients. We haven't had a lot of luck with the biomarker, but this second chapter with targeted therapies looks really promising as well, perhaps with higher response rates, perhaps less durability. We've discussed the tolerability, but the key is we may be able to improve that durability, as Cora has just described, by combining them with immune therapy together and perhaps change practice in the long-term. I've said we've struggled with biomarkers in immune therapy many times. We haven't yet seen this chapter with antibody-drug conjugates. We know, of course, the FGFR inhibitor is biomarker-driven by its nature.

I'd like to thank you for your attention today. I'd like particularly to thank Cora for her spectacular performance by keeping in this 90-second time limit, which I find quite difficult because I like to gabble. Cora, thank you very much indeed.

Dr Sternberg: My pleasure. It's been fun.

Dr Powles: Thanks for your participation. Please continue to answer the questions and complete the evaluation form. Many thanks for your attention.

This is a verbatim transcript and has not been copyedited.

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