Benjamin P. Saylor is associate editor of Urology Times, an Advanstar Communications publication.

Benjamin P. Saylor

The FDA has granted a priority review designation to supplemental Biologics License Applications (sBLAs) for the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for the frontline treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

The combination of pembrolizumab and enfortumab vedotin was previously granted an FDA breakthrough therapy designation.

The sBLAs are supported by findings from cohorts A and K from the phase 1b/2 EV-103 trial (KEYNOTE-869; NCT03288545). Under the Prescription Drug User Fee Act, the FDA is scheduled to make a final decision on the sBLAs by April 21, 2023.

“Despite advancements in treatment options, approximately half of advanced bladder cancer patients in the United Sates are ineligible for cisplatin-based chemotherapy, and these patients need new options. We are encouraged by the investigational results of the combination of Padcev and Keytruda for this patient population and are fully committed to work to bring this new approach forward to patients,” Eliav Barr, MD, senior vice president, head of Global Clinical Development and chief medical officer, Merck Research Laboratories, the developer of pembrolizumab, stated in a press release.1

Overall, the multicohort, open-label, multicenter EV-103 trial evaluated the antibody-drug conjugate enfortumab vedotin alone and with different combinations of anticancer therapies as a first- and second-line treatment for patients with locally advanced or metastatic urothelial cancer.

The dose-escalation and dose-expansion cohort A of the trialenrolled 45 patients with locally advanced or metastatic urothelial cancer who were not eligible for cisplatin-based chemotherapy.

 All patients received enfortumab vedotin plus the immune checkpoint inhibitor pembrolizumab.

The median patient age was 69 years. Men accounted for 80% (n = 36) of the study population and the primary tumor location was lower tract in 69% (n = 31) of patients. Sites of metastasis included lymph nodes only in 4 patients and visceral disease in the remaining 41 patients, including liver metastases in 15 patients. PD-L1 expression status by combined composite score was less than 10 in 19 patients, 10 or higher in 13 patients, and was not evaluable/available in 13 patients.

Results from this cohort showed that the combination led to an objective response rate (ORR) of 73.3% (n = 33), comprising a 15.6% complete response rate and a 57.8% partial response rate. The median duration of response was 25.6 months and the median overall survival was 26.1 months.

In cohort K of EV-103, patients were randomized to either monotherapy with enfortumab vedotin or combination therapy with enfortumab vedotin plus pembrolizumab.

 There were 149 patients in cohort K, 76 of whom were treated with enfortumab vedotin plus pembrolizumab and 73 who were treated with enfortumab vedotin alone.

The patient population was predominantly male, and approximately 60% had impaired performance status. Visceral disease was presented more than 80% of patients, and approximately 40% were PD-L1 high; a proportion of patients were not evaluable because they did not have tumor to be submitted.

The confirmed ORR (for enfortumab vedotin plus pembrolizumab was 64.5%, and median DOR was not reached. The confirmed ORR for enfortumab vedotin alone was 45.2%, with a median DOR of 13.2 months.

Regarding adverse events (AEs), 15.6% of patients receiving enfortumab vedotin plus pembrolizumab stopped treatment due to an AE, and 24.3% of patients receiving enfortumab vedotin alone stopped treatment due to an AE. The most common AEs seen in patients receiving enfortumab vedotin plus pembrolizumab included fatigue, peripheral sensory neuropathy, alopecia, and maculo-papular rash.

Eighteen (23.7%) serious treatment-related adverse events (TRAEs) were seen in the combination therapy group and 11 (15.1%) were seen in the monotherapy group. Three TRAEs leading to death (3.9%) were seen in the combination group and 2 (2.7%) were seen in the monotherapy group. Rosenberg reported that skin reactions were more frequent with patients receiving enfortumab vedotin plus pembrolizumab, although none were serious.

The combination of pembrolizumab and enfortumab vedotin was previously granted an FDA breakthrough therapy designation based on the results of cohort A. Also of note, the ongoing phase 3 EV-302 trial is comparing the combination with chemotherapy in the frontline setting for patients with locally advanced or metastatic urothelial cancer (NCT04223856).

“Urothelial cancer, the most common type of bladder cancer, is associated with poor survival in the advanced stage,” Marjorie Green, MD, senior vice president and head of Late-Stage Development at Seagen, which co-develops enfortumab vedotin with Astellas, stated in the press release.1 “The investigational results from our clinical development program support the combination of Padcev and Keytruda as a potential treatment for this patient population.”

1. Astellas, Seagen and Merck Announce FDA Acceptance of Supplemental Biologics License Applications for PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) for the First-Line Treatment of Certain Patients With Locally Advanced or Metastatic Urothelial Cancer. Published online and accessed December 20, 2022. https://prn.to/3FJNpLf

2. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer [published online ahead of print August 30, 2022]. J 

3. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). 

. 2022;33(suppl 7):LBA73. doi:10.1016/annonc/annonc1089

Articles

The FDA will be evaluating findings from cohorts A and K from the phase 1b/2 EV-103 trial.

FDA grants priority review to frontline pembrolizumab/enfortumab vedotin for urothelial cancer

Triplet therapy incorporating an alpha prostate-specific membrane antigen-targeted radionuclide therapy (PSMA-TRT, 

Ac-J591), an androgen receptor (AR) signaling inhibitor, and pembrolizumab (Keytruda) showed early signs of efficacy in the treatment of chemo-naïve metastatic castration-resistant prostate cancer (mCRPC), investigators reported.

Based on the findings of the phase 1 portion, the investigators selected the 80 KBq/kg dose of 225Ac-J591 for the phase 2 portion of the study.

The preliminary phase 1 findings of a phase 1/2 study were presented at the Society of Urologic Oncology Annual Meeting in San Diego, California, by Michael Sun, MD, a hematology-oncology fellow at Weill Cornell Medicine in New York City, New York.

“Immunotherapy generally results in modest responses for prostate cancer. Radiation, though, may increase the proportion of patients that respond to immunotherapy,” Sun explained. In addition, PSMA-TRT is able to radiate multiple sites of disease simultaneously, and AR signaling inhibitors upregulate PSMA expression, may lead to increased PD-L1 expression, and can also radiosensitize prostate cancer.

“We hypothesize that triple therapy with [PSMA-TRT], pembrolizumab, and an [AR signaling inhibitor] will have a synergistic effect and lead to better responses and outcomes relative to immunotherapy plus [AR signaling inhibitor] alone,” Sun said.

The study enrolled patients with progressive mCRPC as defined by Prostate Cancer Working Group 3 criteria (at least 1 AR pathway inhibitor and no chemotherapy in the mCRPC setting). During the phase 1 portion of the study, patient received physician’s choice of AR signaling inhibitor along with pembrolizumab (400 mg every 6 weeks) along with a single infusion of 225Ac-J591 in 2 different cohorts of 6 patients (65 KBq/kg or 80 KBq/kg). The phase 1 portion’s primary end point was the determination of 225Ac-J591 dose for the phase 2 portion of the study.

Median patient age was 66.5 years, and median prostate-specific antigen level was 7.75 ng/mL. Six patients (50%) had Cancer and Leukemia Group B intermediate-risk disease, 4 (33%) had low-risk disease, and 11 patients (92%) had bone metastases. All patients had received at least 1 prior AR pathway inhibitor. Five patients (42%) had received prior sipuleucel-T (Provenge), 1 (8%) had received prior radium-223 (Xofigo), 6 (50%) had received prior enzalutamide (Xtandi), 7 had received prior abiraterone acetate (Zytiga), and 2 (17%) had received prior PSMA-TRT.

AR signaling inhibitors used in the study included enzalutamide in 7 patients (58%), apalutamide (Erleada) in 3 patients (25%) and darolutamide (Nubeqa) in 2 patients (17%).

All of the patients experienced PSA decline, and half the cohort experienced a PSA decline greater than 50%. At more than 6 months’ follow-up, 4 patients (all from the 80 KBq/kg cohort) are still progression free and on study.

Regarding adverse events (AEs), “7 patients (58%) developed an unexpected inflammatory syndrome 7-14 days following treatment (C1D1) characterized by morbilliform rash, fever higher than 101°F, and low blood counts,” wrote the authors in their poster. All-grade AEs included thrombocytopenia in 9 patients (75%), neutropenia in 7 patients (58%), nausea in 6 patients (50%), fatigue in 8 patients (67%), xerostomia in 9 patients (75%), and AST increase in 8 patients (67%).

Based on the findings of the phase 1 portion, the investigators selected the 80 KBq/kg dose of 

Ac-J591 for the phase 2 portion of the study, Sun reported at the meeting. That phase of the study is currently under way.

“Phase 2 is multicenter. Patients are randomized to triplet vs doublet [therapy]. The stratification criteria is based on presence or absence of visceral metastases, PSMA-PET imaging intensity, and [circulating blood cell (CBC)] count at baseline,” Sun said.

“The primary end point is response…which is a composite of radiographic response by RECIST criteria, conversion of unfavorable CBC counts to favorable, or PSA 50,” he added.

1. Sun M, Nauseef J, Huicochea Castellanos S, et al. Phase I results of a phase I/II trial of pembrolizumab and AR signaling inhibitor (ARSI) +/- 225Ac-J591 for chemo-naïve metastatic castration-resistant prostate cancer (mCRPC). Presented at: Society for Urologic Oncology (SUO) 23rd Annual Meeting; November 30-December 2, 2022; San Diego, California. Poster 76. https://suo-abstracts.secure-platform.com/a/gallery/rounds/15/details/2687

The regimen consists of an alpha prostate-specific membrane antigen-targeted radionuclide therapy (225Ac-J591), an androgen receptor signaling inhibitor, and pembrolizumab.

Triplet therapy incorporating novel PSMA-TRT 225Ac-J591 shows efficacy in mCRPC

Independent urology continues to face issues including reimbursement cuts and staffing. In this interview, LUGPA President 

 discusses goals for his term and also summarizes a session on prostate-specific membrane antigen-positron emission tomography (PSMA-PET) that he led at the 2022 LUGPA Annual Meeting in Chicago, Illinois. Goldfischer is the director of the Research Department at Premier Medical Group in Poughkeepsie, New York.

What health policy wins and losses occurred in 2022?

The legislative calendar is not over yet; we're obviously striving to get rid of that 4.4% reimbursement cut. We've also made great progress with extending telehealth to make it permanent. I think we were successful in getting rid of the [ambulatory surgical center] cuts as a result of the Supreme Court ruling this year. We continue to make progress with [Merit-based Incentive Payments system], [Medicare Access and CHIP Reauthorization Act of 2015], and [alternative payment model] reforms and to really build our relationships with the congressmen and congresswomen and with the senators, so that we're going to be even more successful in 2023 and 2024.

Could you talk a little bit about LUGPA's legislative and advocacy goals for 2023?

As you know, Congress somehow every year seems to decrease our reimbursement. If you look back over the past 20 years, hospitals have done reasonably well with reimbursement. I think the Medicare conversion factor about 20 years ago was about $31, which would be about $56 in today's dollars. We're at $33, so we've gone backwards. We have to do better there. We definitely want to make telehealth permanent. We think that's an important part of the practice of medicine now. There's also site payment neutrality. The fact that the same procedure can be done in 2 different places - an ambulatory surgery center/office and a hospital - and have completely different reimbursement rates, makes no sense.

What are the biggest challenges facing independent urology practices?

There's just a lot of financial pressure on us to survive financially, given the reimbursement cuts. In addition, labor shortages face all of us, but particularly in independent urology, we're trying to always maintain a really high-quality staff. There are just not enough people out there. I think just about every urology practice is looking. We want to encourage residents to go into independent urology, but now they're obviously being courted for employed opportunities by academic practices. We want to make sure that independent urology continues to thrive by recruiting new people to independent urology. That's what we're going to try and do.

Could you discuss your goals as LUGPA president?

Obviously, number one is health policy. We've got to be on the Hill, and we've got to do more with state legislatures. That's going to be priority number 1. Number 2 is programming for our independent groups. We have our annual meeting. We have 3 regional meetings. We have Prostate Cancer Academy, we have Bladder Cancer Academy, and we have a Urology Resident Summit coming up in March, just to name a few of the programs that are coming up. Programming is going to be big.

[Another goal is] getting our younger members involved. We have more younger members here at the annual meeting than we've ever had before. We want to make that a priority. We have a group specifically dedicated to younger members called LUGPA Forward. We have a leadership program, which is a formal training program that takes about a year for members to participate in that's completely paid for by LUGPA. So, another goal is membership expansion and engagement of our younger colleagues.

You chaired a discussion on PSMA-PET at this meeting. Could you summarize the key takeaways from this discussion and talk about the value of PSMA-PET to physicians and patients?

Every once in a while, something comes out that's a game-changer. PSMA scanning is definitely a game-changer with regard to imaging and advanced prostate cancer in urology. People are still getting their hands around this new technology because we've only had it since March. Because of the nature of the isotope and how it's made, it's still not available to everybody. Now we're trying to understand what it means when you find these micrometastases in terms of the treatment algorithm. Are you still a candidate for radical prostatectomy? Are you still a candidate for radiation therapy? Or at that point, when you have micrometastases, does it mean hormonal therapy and advanced oncolytics? We're still getting our hands around that, but 1 thing is if you talk to people in the room, the consensus was PSMA scanning is definitely a game-changer for us.

"We want to make sure that independent urology continues to thrive by recruiting new people to independent urology. That's what we're going to try and do," said Evan R. Goldfischer, MD.

LUGPA President Dr. Goldfischer discusses the challenges facing independent urology

 shares advice on optimizing advanced prostate cancer clinics, recaps the biggest advances in urologic cancer treatment in 2022, and discusses how his use of mitomycin-containing reverse thermal gel (Jelmyto) has evolved over time. Hafron, who spoke with 

, is a partner at the Michigan Institute of Urology, PC; an associate professor of Urology at the William Beaumont School of Medicine, Oakland University; and the director of Robotic Surgery at Beaumont Hospital Royal Oak in Michigan.

Nurse navigators, in-house pharmacies, and data analytics are some of the ideal components every advanced prostate cancer clinic should have, according to Jason Hafron, MD.

 At the LUGPA Annual Meeting, you participated in a discussion titled, "APCC Optimization.” What are your thoughts on best practices for APCCs?

 It's really exciting, because in 2011, here at LUGPA, we launched mCRPC management and this APCC concept. So it's been over 10 years that we've been having these CME events revolving around advanced prostate cancer clinics and how to manage these patients appropriately. As things evolve, and as we've gained a lot of experience, I think [we've learned] that there's no one-size-fits-all method to this. There are some key components that every advanced prostate cancer clinic should have. One is a nurse navigator. Having your own pharmacy in house is very helpful. And I think what's really critical as we are seeing more patients and patients are becoming more complex, is the utilization of data analytics to identify these patients and to make sure they are being followed appropriately, according to guidelines.

What have been the biggest advances in urologic cancer treatment in 2022? What advances are you anticipating in 2023?

One of the things that drives me to be a part of advanced prostate cancer care is that literally every 6 months, we are having major trials read out guideline-based changes in care. 2022 was a phenomenal year. We saw lutetium read out in the early part of the year, which raises a whole new disease therapeutic: theranostics. We're just at the tip of the iceberg with that, from the results of the VISION trial [NCT03511664]. I think the biggest thing this year is triplet therapy. The ARASENS trial [NCT02799602] read out, which is a combination of [androgen deprivation therapy], darolutamide [Nubeqa], as well as docetaxel. Then there was the PEACE-1 trial [NCT01957436], which was led in Europe [and looked at] the combination of ADT, docetaxel, and abiraterone [Zytiga]. Those are really significant trials; they led to changes in the National Comprehensive Cancer Network guidelines. I think the most inspiring thing about the results of these trials is these are the first trials we've seen in advanced prostate cancer that have extended survival beyond 5 years. We're making a difference; the combination of therapies are really extending men's lives, and hopefully—maybe I'm being a little presumptuous—getting us closer to a potential cure in this space.

What key research has had a hand in revolutionizing sequencing strategies?

Sequencing is always a challenge. It's hard to do sequencing trials, and it's hard to identify best practices. Where I focused a lot of my work recently is in real-world evidence, looking at claims data, and just looking at how patients are being treated in large volumes across the United States. I think that, really, when you tie that to overall survival, and which combinations in which sequencing, I think it gives you a really good clue. I don't know if it's the best way to look at it, but I think it gives you a good idea, or at least some direction on what's ultimately best practice and best sequencing.

How do you hope to see the field progress in the future in terms of sequencing strategies?

We have to keep doing trials and asking questions. As we keep accumulating new therapies every 6 to 12 months, we need to find out their role and what position they should be in. As we have seen over this 10-year journey of advanced prostate cancer, we always start with the sickest patients. We keep seeing these trials move earlier in the disease spectrum, and when you're doing that, it changes the sequencing of when to use these and how to use these. It's a challenge that we're going to face for many years, but it's an exciting challenge because the therapies are very manageable. That's why, as a urologist, I'm very comfortable using these therapies. Ultimately, they lead to improved progression-free survival. Patients just do better, and that's what keeps me going.

Jelmyto was approved in April 2020 for the treatment of low-grade upper tract urothelial carcinoma. How has your use of this treatment evolved since its approval?

That's a great question. If you look at the original trial, the OLYMPUS trial [NCT02793128], most of the treatments were retrograde through a ureteral catheter. In our practice in Michigan, we've evolved to an antegrade percutaneous approach. We've taken this therapy, and we placed percutaneous nephrostomy tubes in these patients, and we delivered Jelmyto in the office. We're seeing that it's beneficial to the patient—it's easier, they don't require a general anesthetic, and we don't have to bring them to the hospital. Also, we don't have the data yet, but I think we're going to have a lower ureteral stenosis rate because we are going antegrade. That has been a significant change, and a change for the better. It's better for the patient, better for our practice, and hopefully will minimize that ureteral stenosis rate.

In an interview during the 2022 LUGPA Annual Meeting, Jason M. Hafron, MD, shared advice on optimizing advanced prostate cancer clinics, recapped the biggest advances in urologic cancer treatment in 2022, and discussed how Jelmyto treatment for UTUC has evolved over time.

Benjamin P. Saylor

Articles

FDA grants priority review to frontline pembrolizumab/enfortumab vedotin for urothelial cancer

Triplet therapy incorporating novel PSMA-TRT 225Ac-J591 shows efficacy in mCRPC

LUGPA President Dr. Goldfischer discusses the challenges facing independent urology

Tips for optimizing an advanced prostate cancer clinic