Does Immuno-Oncology Therapy Have a Larger Role in the Urology Clinic?

Adam C. Reese, MDe

Adam C. Reese, MD

The FDA approved indications in urologic cancers for 6 immune checkpoint inhibitors since 2015. That is unquestionably a good thing for patients, but the rise of these agents means that the role of the urologist in cancer care is changing. Some urologists are still on the fence about these agents, some prefer to leave immuno-oncology (I/O) in the hands of the medical oncologist, and others have fully embraced I/O agents and advocate that urologists start prescribing them.

Whether to move I/O treatment squarely into the urology clinic has been a hot topic at recent conferences. “The reason this has been getting a lot of attention is that urologists over the past decade have been very successful in treating metastatic castrate-resistant prostate cancer [CRPC],” said Raoul S. Concepcion, MD, FACS, editor-in-chief of Urologists in Cancer Care (UCC) and director of The Comprehensive Prostate Center in Nashville, Tennessee. Concepcion firmly believes that I/O administration can be managed by urology clinics.

On the other side of the argument is Adam C. Reese, MD, associate professor of urology at the Lewis Katz School of Medicine and chief of urologic oncology at Temple University Hospital, both in Philadelphia, Pennsylvania, who does not prescribe I/O in his practice. The use of I/O, as well as chemotherapy, is not part of the standard training for urologists, and Reese does not feel sufficiently knowledgeable about or comfortable prescribing these agents.

“I’m totally in favor of the new immunotherapies when indicated,” Reese said. “I just prefer to send patients to somebody who prescribes a lot of these therapies, is comfortable with [I/O], and has a greater understanding of the indications and the potential AEs [adverse effects] and how to manage them.”

In the prostate cancer setting, urologists have already faced a changing paradigm. In research findings reported at the 2016 Genitourinary Cancers Symposium, investigators from Fox Chase Cancer Center in Philadelphia, Pennsylvania, noted that urologists are familiar with prescribing androgen deprivation therapy to patients with recurrent or advanced disease. However, they typically would send those who develop CRPC to medical oncologists.¹

Investigators surveyed members of the Society of Urologic Oncology to determine their comfort level in prescribing the growing options for men with CRPC, which at that time comprised 5 new agents, including the immunotherapy sipuleucel-T (Provenge), that the FDA approved from 2010 to 2016.

Overall, 85.8% of 84 respondents (out of 697 surveyed) definitely or somewhat agreed that prescribing therapy for CRPC falls within the domain of urologists; 51.2% said they had personally prescribed new agents. The most significant obstacle to administering medical therapy for CRPC was identified as managing AEs by 22.7% of those who responded to this question (N = 185).

To be sure, urologists have long been familiar with some forms of immunotherapy, starting with use of intravesical bacille Calmette-Guérin (BCG) for nonmuscle invasive urothelial cancer (Timeline).

Sipuleucel-T won FDA approval for the treatment of patients with asymptomatic or minimally symptomatic metastatic CRPC in 2010. It is currently the only immunotherapy agent approved for use in prostate cancer.

Checkpoint inhibitors have represented a revolution in treatment of urologic cancers. These agents “take the brakes off ” inhibitory signals that prevent the patient’s immune system from fighting tumor cells.

In 2015, the FDA approved nivolumab (Opdivo), which inhibits the PD-1 immune checkpoint, as a treatment for patients with metastatic renal cell carcinoma (RCC) following prior antiangiogenic therapy. Since then, the agency has approved 4 drugs that target the PD-1/ PD-L1 pathway and ipilimumab (Yervoy), which blocks CTLA-4.

A Necessary Adjustment Period

Although urologists have adapted to novel agents, such as enzalutamide (Xtandi), abiraterone acetate (Zytiga), and radium 223 (Xofigo), they will need time and clinical evidence before they become as comfortable with I/O, Concepcion said.

Neal D. Shore, MD, director of the Carolina Urologic Research Center and a practitioner with Atlantic Urology Clinics in Myrtle Beach, South Carolina, noted there were periods of adjustment when sipuleucel-T, novel agents for CRPC, radiopharmaceuticals, and taxane-based therapy were introduced. He said urologists now are appropriately learning the administration and the AE management for checkpoint inhibitors. “Indications for the checkpoint inhibitor immuno-oncologic drugs that essentially work on the PD receptor axis are in patients who have metastatic bladder cancer. These patients have traditionally been managed in the medical oncology clinic, so these are the patients who have received typically neoadjuvant or adjuvant chemotherapy.”

Shore added that data from ongoing trials could make I/O more prominent in bladder cancer. “That will necessitate that urologists who are dedicated to diagnosing and managing these patients will absolutely be interested in adopting [I/O] therapy for bladder cancer,” he said.

Some of the concern over using I/O agents in this space stems from the lack of data. Results from some early studies, such as PIVOT-02 exploring the combination of the novel IL-2 agent bempegaldesleukin (NKTR-214) plus nivolumab for metastatic urothelial cancer (UC), are promising.^2-4 However, Géraldine Pignot, MD, of the Institut Paoli-Calmettes in Marseille, France, and colleagues have concluded that “little evidence exists on the oncological impact of immunotherapy on the local treatment of genitourinary malignancies.”⁵

Study data do show potential value for I/O in bladder cancer, but they are not as strong as they need to be, said Eila Skinner, MD, the Thomas A. Stamey Research Professor in Urology and chair of the Department of Urology at Stanford University and a member of the Stanford Cancer Institute. She cited initial results from KEYNOTE-057, a phase II trial of pembrolizumab in patients with highrisk, BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC), as promising but said patients had only a “modest” response. She said that the patient population was small and that the findings are not strong enough to support the use of pembrolizumab in these patients.

Three-month interim data from KEYNOTE-057 showed a complete response rate of 38.8% (n = 40 of 103; 95% CI, 29.4-48.9) in patients with carcinoma in situ (CIS) or CIS plus papillary disease.⁶

Stronger clinical evidence may make urologists more comfortable prescribing these agents, and investigators are consistently producing new findings that suggest a role for I/O in genitourinary cancers (GU). For instance, results from the phase III KEYNOTE-045 trial presented at the 2018 Genitourinary Cancers Symposium showed a sustained improvement in overall survival (OS) at 2 years for patients with locally advanced or recurrent UC treated with pembrolizumab. After a median follow-up of 27.7 months, the median OS for patients who received pembrolizumab was 10.3 months compared with 7.3 months for those treated with chemotherapy (HR, 0.70; P = .00017).⁷

Shore noted that “very robust” recent data have shown positive results for patients with intermediate- and poor-risk metastatic RCC treated with anti—PD-1/PD-L1 and anti–CTLA-4 agents. Investigators are also analyzing checkpoint inhibitors in combination with oral tyrosine kinase inhibitors.

Based on data from the phase III KEYNOTE-426 trial, the FDA approved the combination of pembrolizumab plus axitinib (Inlyta) as frontline therapy for patients with advanced RCC. The combination improved OS compared with sunitinib (Sutent). In findings presented at the 2019 Genitourinary Cancers Symposium, the combination reduced the risk for death versus sunitinib by 47% (HR, 0.53; 95% CI, 0.38-0.74; P <.0001).⁸

In May, the FDA approved the combination of avelumab (Bavencio) plus axitinib for the first-line treatment of advanced RCC based on data from the JAVELIN Renal 101 trial showing that the regimen reduced the risk of disease progression or death by 31% compared with sunitinib (HR, 0.69; 95% CI, 0.56-0.84; P = .0002).⁹

I/O in Practice

The academic urologists who spoke to UCC, admittedly a small sample, do not prescribe immunotherapy and instead refer their patients to medical oncologists. Reese said that he does not feel knowledgeable about managing potential AEs and that referring patients to a medical oncologist is “more efficient.”

Reese added that “at our institution, we have a very close relationship with our medical oncology team, so we feel more comfortable sending patients who need those kinds of therapies to our medical oncologists who prescribe these agents more frequently and who are more comfortable with the potential AEs and how to manage them. We’re busy enough with the things that are in our standard urological practice.”

For her part, Skinner does not see any particular reason for urologists to prescribe these agents. “I personally don’t think it’s necessarily good for the patients,” she said. “In the academic setting, we have a very close relationship with our medical oncologists who are urology specialists. That may not reflect the rest of the world. Certainly, if someone in my family had metastatic prostate cancer, I would not have them getting all their treatments from a urologist. I would get a medical oncologist involved. The real expert medical oncologists do a fabulous job.

“I’m not going to prescribe it,” she added. "I’m going to work with my medical oncologists who know how to treat [these patients].”

In contrast, the private practitioners interviewed for this article said they are more likely to do their own prescribing. Private practitioners, especially in rural or underserved areas, may not have access to or strong relationships with medical oncologists. Plus, the economics of medicine mean that a clinic that can offer more services can make more money.

“I am a firm believer that the urology practice, if they are so motivated and if they have physician—champions who are interested in doing this, should look at a model to deliver these therapies,” Concepcion said. “The question is whether the urologist does this or they develop a business model partnering with a medical oncologist to deliver care.”

Concepcion added that patients with GU cancers comprise only a small fraction of patients at a medical oncologist’s office, so their expertise with I/O is not necessarily any greater than a urologist’s. The reluctance to prescribe these drugs centers on managing AEs, not managing drugs or disease. Concepcion said the same will be true for PARP inhibitors and tyrosine kinase inhibitors when they become more common in urology. “I live and die in this world,” he said. “I know about the drugs; I know about the indications. [The medical oncologist’s] expertise is the management of the AE profiles.”

That said, a urologist can certainly learn how to manage those AEs. “There’s nothing magical about the training of the medical oncologist or the systems they’ve created that can’t be reproduced by a urologist,” said Bryan A. Mehlhaff, MD, medical director of research and managing partner with the Oregon Urology Institute. “What did medical oncologists know about immuno-oncology before immuno-oncology became a thing?”

A Practice-Wide Commitment to Administering I/O

Prescribing immunotherapy or chemotherapy can be a complicated endeavor for urologists, who typically train as surgeons. In an interview at the 2018 Large Urology Group Practice Association Annual Meeting in December, Noah M. Hahn, MD, director of the medical oncology bladder program at Johns Hopkins University School of Medicine, said the use of I/O agents will require a major education component for urologists. He added that urology practices will have to think about infusion center and toxicity management infrastructure, their relationships with practitioners in other specialties, and the willingness to make an in-house commitment to this treatment modality.

“It’s one thing to have a champion who wants to do it and is going to take on doing it for their patients, but who’s going to take the call on Friday at 4:30 pm when you’re out on vacation and your partner is covering?” Hahn said. “Those things need to be talked about.”

Concepcion said that a practice must make a philosophic decision to administer I/O and create a wellthought-out business model that demonstrates that I/O makes financial sense for the clinic, develops processes for managing AEs, and “palliates” partners who might not want to manage those AEs.

“It’s not a dalliance,” Shore said. “It’s a dedication.”

Mehlhaff, who helped to introduce I/O at his clinic, said that making the decision to administer I/O takes both a champion and a practice-wide commitment. “Nothing is going to get started in a doctor’s office without the doctor saying, ‘I want to look into this,’” he said. Further, it takes a champion to convince his or her partners that the new thing—be it a treatment modality, a medical device, or even a billing system&mdash;is a better option. “It would be pointless for me to set something up for me and my patients,” Mehlhaff added. “If you’re going to do this, you want it for the entire practice’s patients.”

Shore said that urologists can and should prescribe immunotherapy when appropriate. However, any conflict about whether urologists or oncologists should prescribe I/O is pointless. The goal is to get the right care to the right patient at the right time.

“This concept of internecine specialty warfare is passé,” Shore said. “Anyone who is dedicated to learning how to administer these agents appropriately and with diligence because they have many of these types of patients in their clinic is fine from my standpoint. We have a personpower shortage among medical oncologists and urologists, so my feeling is, as long as there’s someone dedicated to administering new therapies in a skilled and timely way… that’s the true north that we all need to follow.”

References

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