Grivas Spotlights Advances With Immunotherapy-Based Approaches in Urothelial Cancer

Petros Grivas, MD, PhD

Efforts to deliver individualized care for patients with advanced urothelial cancer continue to explore and incorporate novel immunotherapy combinations into earlier lines of treatment, resulting in more options and improved outcomes in the frontline setting, according to Petros Grivas, MD, PhD.

“When I started my career evaluating and researching bladder cancer, it was such a challenge, because we did not have many options for our patients at that time,” Grivas said in an interview with OncLive^®. “Because of that, we always want to create more options and change the paradigm. Right now, we have many more options, which is exciting for patients.”

In a presentation delivered at the ​​Second Annual Miami Cancer Institute Precision Oncology Symposium, Grivas highlighted key advancements and paradigm-shifting research conducted in the realm of urothelial cancer. Specifically, he spotlighted findings from the phase 3 CheckMate 901 trial(NCT03036098) of nivolumab (Opdivo) plus gemcitabine/cisplatin and the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda). Together, these pivotal studies showed that the incorporation of immunotherapy into the frontline setting could extend survival outcomes beyond what has been seen with platinum-based chemotherapy alone, Grivas stated in the interview.

Although enfortumab vedotin plus pembrolizumab is generally favored as the standard of care (SOC) in the first line, Grivas emphasized that individual patient characteristics and tolerability should inform therapeutic decisions.

In an interview with OncLive, Grivas discussed the significance of pivotal trials propelling progress in urothelial cancer, underscored their subsequent impact on treatment selection in the first-line setting, and outlined remaining questions regarding the use and incorporation of these regimens into clinical practice for select patient subsets. Grivas is a physician at Seattle Cancer Care Allliance; an associate professor in the Department of Medicine, Division of Oncology, clinical director of the Genitourinary Cancers Program at the University of Washington School of Medicine; and an associate member, Clinical Research Division, Fred Hutchinson Cancer Center, in Seattle, Washington.

OncLive: How have precision medicine approaches evolved and expanded in advanced urothelial cancer in recent years?

Grivas: It’s great to have options for patients. Specifically, if we think about [paradigm shifts in] frontline treatment, [we have] the JAVELIN Bladder 100 trial [NCT02603432] the data of which were published in 2020. I was honored to be the senior author of The New England Journal of Medicine paper [of this trial]. In JAVELIN Bladder 100, we saw that switch maintenance immunotherapy with avelumab [Bavencio] in patients who had a response or [achieved] stable disease on platinum-based chemotherapy lived longer [than those who underwent] observation. There was a significant overall survival [OS] and progression-free survival [PFS] benefit with avelumab maintenance after no progression on prior chemotherapy in the frontline setting.

What did findings from the CheckMate 901 trial reveal about the efficacy of adding immunotherapy to standard, up-front chemotherapy in urothelial cancer?

CheckMate 901 asked a different question. What about concurrent administration of nivolumab, an anti–PD-1 inhibitor, together with gemcitabine/cisplatin followed by the continuation of maintenance nivolumab for up to 2 years vs chemotherapy alone? This [trial] was only for cisplatin-eligible patients and showed a significant OS and PFS survival benefit [with the nivolumab regimen]. The hazard ratio was 0.78 for OS with [nivolumab plus gemcitabine/cisplatin] vs gemcitabine/cisplatin alone. The median PFS was [similar between the arms,] at [7.9] months. However, there was a tail of the curve in the PFS data, and patients with [the triplet] had a higher tail of the curve, showing a significant improvement in the HR for PFS.

Notably, approximately 20% of patients in the chemotherapy-alone arm received maintenance avelumab, and approximately 40% received immunotherapy at some point in time during the treatment course. Some people may argue, “What about if this access to immunotherapy was higher? Would that potentially have led to a longer OS in the control arm and potentially resulted in a negative trial?” It is hard to say. There is a higher response rate seen with gemcitabine/cisplatin/nivolumab vs gemcitabine/cisplatin alone, and [21.7%] of patients achieved a complete response [CR] with [the triplet]. We lack biomarkers to predict who these patients are. [However, patients who] achieved a CR with gemcitabine/cisplatin/nivolumab [had a] median duration of CR of 37.1 months. [Accordingly,] if a patient achieves a CR, they have a good chance of maintaining it for a while. [Therefore, gemcitabine/cisplatin/nivolumab] represents a great option for these patients especially, outside of the United States where pembrolizumab plus enfortumab vedotin is not approved.

How did data reported from the EV-302 trial influence the current treatment paradigm in urothelial cancer?

In the United States, we have a third available option: enfortumab vedotin plus pembrolizumab. Pembrolizumab is an anti–PD-1 agent and enfortumab vedotin is an ADC against Nectin-4 [featuring] a chemotherapy payload that disrupts microtubules known as monomethyl auristatin E. That combination produced impressive, transformative data in the EV-302 trial, with a PFS benefit and HR of 0.45 vs gemcitabine plus cisplatin or carboplatin. The HR for OS was 0.47, showing an OS benefit with enfortumab vedotin plus pembrolizumab vs chemotherapy.

There are a couple of caveats. The proportion of patients who received maintenance avelumab in the chemotherapy arm was [approximately] 30% and approximately two-thirds of patients had access to immunotherapy at some point during their treatment course. The other question is, “How many patients on the chemotherapy arm had access to enfortumab vedotin upon progression?” This may have impacted the degree and magnitude of benefit [for a] few patients, especially with regard to OS. Having said that, pembrolizumab plus enfortumab vedotin is the preferred SOC first-line regimen in advanced, metastatic urothelial cancer or disease that is not amenable to curative-intent therapy in the absence of contraindication, because of the dramatic difference [in survival outcomes] between the 2 arms.

In what clinical scenarios might you not utilize enfortumab vedotin plus pembrolizumab? What factors are important to consider when selecting between this combination and other first-line regimens?

Because the data are so strong, the question becomes, “Is there any patient who should not receive enfortumab vedotin and pembrolizumab?” This [requires consideration] of the patient’s [individual factors, such as] grade 2 or higher neuropathy, uncontrolled diabetes with high hemoglobin A1C, significant liver cirrhosis and poor liver function, and active autoimmune disease. These are special populations with special considerations and nuances [for treatment selection.] They require informed, shared decision-making with the patient, because some of those [subsets] may not have been studied in the EV-302 trial. What do you do in those cases? Do you forgo pembrolizumab? Do you [administer] a lower dose of enfortumab vedotin? [How do you treat] patients with active autoimmune disease who are on steroids? These are discussions [that we need to have] on an individual basis. For the vast majority, however, pembrolizumab plus enfortumab vedotin is the preferred SOC regimen for advanced urothelial carcinoma in the United States.