Investigators Set Their Sights on Optimizing Sequencing With Novel Therapies in GU Cancers

Ulka Nitin Vaishampayan, MBBS

Following significant clinical progress, treatment selection and sequencing in genitourinary (GU) cancers, such as metastatic bladder cancer and metastatic renal cell carcinoma (mRCC), have become more complicated and require nuanced decision making, according to a panel of experts from the University of Michigan that presented during an OncLive^® Institutional Perspectives in Cancer webinar on GU cancer.

During the meeting, faculty weighed in on approaches for first-, second-, and later-line treatment in metastatic urothelial cancer and mRCC, as well as surgical challenges in advanced RCC.

Notably, the chair of the event, Ulka Nitin Vaishampayan, MBBS, a professor of internal medicine and director of the Phase I program at the Rogel Cancer Center of the University of Michigan, underscored that with novel therapeutic options available in the second- and later-line settings of metastatic bladder cancer and mRCC, research efforts regarding sequencing, combination strategies, and novel therapies to address resistance mechanisms are under way.

Vaishampayan was joined by fellow faculty from the University of Michigan:

• Sarah Elizabeth Yentz, MD, clinical assistant professor
• Phillip Lee Palmbos, MD, PhD, assistant professor
• Khaled Samir Hafez, MD, PhD, the Valassis Professor of Urologic Oncology, a professor of urology, and associate chair for education in urology

During the meeting, the panelists discussed key considerations regarding treatment selection across the paradigms of metastatic bladder cancer and mRCC, as well as key aspects of surgical care that can optimize outcomes for patients with RCC.

Frontline Metastatic Bladder Cancer

Palmbos: The good news is that over the past several years, we have really made a lot of progress for patients with bladder cancer. We have multiple new effective agents, including checkpoint inhibitors and antibody-drug conjugates. For my patients with metastatic bladder cancer, especially in the first-line setting, I would recommend all eligible patients still receive cisplatin-based chemotherapy. However, now based on JAVELIN Bladder 100 [NCT02603432], these patients should also move directly on to maintenance [avelumab (Bavencio)].

We also now have space to discuss adjuvant immunotherapy for appropriate patients who have high-risk features after cystectomy, especially those who are not candidates for adjuvant chemotherapy. Those are both positive developments that are directly applicable to oncologists in the community.

Second- and Later-Line Metastatic Bladder Cancer

Vaishampayan: The treatment paradigm of advanced bladder cancer has rapidly evolved amid the development of several novel classes of agents that are non–cross- resistant. Therefore, optimizing combination regimens, as well as sequencing with available therapies in metastatic disease, requires additional evaluation.

It is possible that perioperative utilization of therapies used in the later-line setting could dramatically shift outcomes for patients with this aggressive malignancy.

Frontline mRCC

Yentz: For somebody [in the community] who doesn’t see RCC that frequently but is trying to sift through the different regimens, it is important to think about the 2 extremes [in terms of patient presentation]. If I have a relatively young, asymptomatic patient with no contraindications to immunotherapy, I give dual-agent ipilimumab [Yervoy] and nivolumab [Opdivo] as my frontline regimen. That is vs the opposite extreme of a symptomatic patient who needs an immediate response. In those cases, I would give immunotherapy plus a tyrosine kinase inhibitor [TKI].

Also, it is important to remember the prognostic index in RCC because not all patients with RCC are the same. We have 3 groups of patients: favorable risk, intermediate risk, and poor risk. The groups behave differently; therefore, prognosticating patients so that we can apply the data most directly to the patient who is in front of us is key.

Second- and Later-Line mRCC

Vaishampayan: A patient’s response and tolerability to prior therapy significantly affects decisions regarding second- and later-line treatment selection in mRCC; however, TKIs remain the mainstay treatment in this space.

Novel agents with unique mechanisms of action, such as HIF-2α inhibitors, are currently being evaluated for use in metastatic disease. Additionally, novel immunotherapies, such as LAG-3 inhibitors, IL-27–directed antibodies, and macrophage checkpoint inhibitors, are in clinical development.

Because rechallenging with checkpoint inhibitors in the second-line setting yields modest efficacy benefit and significant toxicity, local therapies like stereotactic body radiotherapy and surgical resection could be considered for localized, slowly progressing disease.

Finally, if a patient harbors a TSC1 mutation, treatment with a single-agent mTOR inhibitor could be considered.

Surgical Considerations in RCC

Hafez: Optimization of surgical intervention requires careful patient evaluation with scoring of performance status and disease distribution, as well as multidisciplinary decision-making. A multidisciplinary approach should also be utilized to plan the surgical approach, including anesthesia considerations and liver and cardiac surgery needs. Additionally, a plan should be put in place to optimize postoperative recovery and adjuvant therapy.

Ultimately, surgery for patients with RCC requires caseby-case considerations by an entire team. In the high-risk disease setting, personalized treatment is critical.