Applying ASCO GU 2024 Data to Clinical Practice in Bladder, RCC Care

The 2024 ASCO Genitourinary Cancers Symposium (ASCO GU 2024), held January 25 to 27, wrapped up in San Francisco with many informative presentations and discussions. One of the major themes from the meeting was the role of adjuvant immunotherapy. For example, the presented findings from the phase 3 AMBASSADOR study (A031501; NCT03244384) in urothelial carcinoma, as well as both the phase 3 CheckMate 914 (NCT03138512) and KEYNOTE-564 (NCT03142334) studies in clear cell renal cell carcinoma potentially impact clinical practice.

Urothelial Cancer

Bladder cancer has an estimated 63,070 new cases in men and 20,120 cases in women in the United States.1Globally, it is the tenth most commonly diagnosed cancer, with approximately 573,000 new cases and 213,000 deaths.² Urothelial carcinoma is the most common histologic subtype of bladder cancer.³ Standard of care for muscle-invasive urothelial carcinoma (MIUC) includes radical cystectomy preceded by neoadjuvant cisplatin-based chemotherapy if deemed cisplatin-eligible.⁴ Recurrence-free survival (RFS) at 5 years and 10 years with radical cystectomy alone varies based on T and N stage but can range from 89% and 87%, respectively, for T2N0 disease to as low as 35% and 34%, respectively, for N+ disease.⁵

The addition of neoadjuvant cisplatin-based chemotherapy (NAC) provides an estimated 5% absolute improvement in 5-year overall survival (OS) compared with radical cystectomy alone.⁶ Adjuvant cisplatin-based chemotherapy has not demonstrated an OS benefit to date and is difficult to sufficiently administer.⁷ Many patients will be cisplatin-ineligible or demonstrate persistent muscle-invasive pathologic features following NAC with a high rate of metastatic recurrence prompting interest in studying immune checkpoint inhibitors (ICI) in the adjuvant setting.

At ASCO GU 2024, the second interim analysis of the AMBASSADOR trial was presented.⁸ This phase 3 randomized clinical trial evaluated pembrolizumab (Keytruda) as adjuvant therapy in patients with high-risk MIUC. Pembrolizumab administered every 3 weeks for up to 1 year was compared with observation in patients with predominantly urothelial carcinoma of the bladder, urethra, renal pelvis, or ureter that had persistent muscle-invasive disease after NAC (ypT2 or higher) and/or node-positive disease and/or positive surgical margins. Patients who refused or were ineligible for NAC were required to have pathologic stage T3 or higher and/or node-positive disease and/or positive surgical margins.

Lead AMBASSADOR author, Andrea Apolo, MD, head of the Bladder Cancer Section of the Genitourinary Malignancies Branch, and director of the Bladder Cancer and Genitourinary Tumors Multidisciplinary Clinic Center for Cancer Research of the National Cancer Institute, presented disease-free survival (DFS) and OS data. These were dual primary end points in a hierarchical study design and were analyzed in the intention-to-treat population, as well as stratified based on PD-L1 status. Approximately 50% of enrolled patients had node-positive disease, similar with other adjuvant trials in urothelial carcinoma. It had a higher percentage of patients who received neoadjuvant chemotherapy at approximately 64%. While the inclusion of positive surgical margins was a unique feature of the study, only approximately 2% of patients made up this subgroup in each arm.

The study met its DFS end point at 29.0 months (95% CI, 21.8-not reached) with pembrolizumab vs 14.0 months (95% CI, 9.7-20.2) with observation (HR, 0.69; 95% CI, 0.54-0.87; P =.001). The OS data remained immature at a median follow-up of 36.9 months (HR, 0.98; 95% CI, 0.76-1.26; P =.884). PD-L1 status did not predict for benefit with pembrolizumab though it did appear to be prognostic as patients with PD-L1 combined positive score of 10% or higher had better DFS and OS outcomes overall.

It is important to interpret the presented data from the AMBASSADOR study in the context of 2 additional adjuvant ICI studies in urothelial carcinoma. The trial was stopped early with 96% accrual following FDA approval of adjuvant nivolumab (Opdivo) for MIUC based on data from the phase 3 CheckMate 274 (NCT02632409), which also met its DFS end point.⁹ This led to significant censoring for DFS at 58.5% in the pembrolizumab arm and 50.6% in the observation arm. Many of these patients withdrew consent, which will likely impact OS assessment. This is significant as adjuvant ICI has not yet demonstrated an OS benefit in urothelial carcinoma.

The phase 3 IMvigor010 study (NCT02450331) of adjuvant atezolizumab (Tecentriq) vs observation was unable to meet its DFS and OS end points and the final OS data from the CheckMate 274 study of adjuvant nivolumab vs placebo have yet to be reported.^9,10

Another important point to consider when discussing adjuvant ICI with patients is its role in upper tract urothelial carcinoma (UTUC). The AMBASSADOR study, though it did not cap enrollment of UTUC, only had 24% of patients with UTUC on each arm, resulting in an unclear DFS benefit due to wide confidence intervals (HR, 1.05; 95% CI, 0.61-1.82). Wide confidence intervals were also reported for patients with UTUC in the CheckMate 274 study, which limited UTUC enrollment to 20% of patients.

A particular challenge for oncologists when discussing adjuvant therapy with patients is that a significant number of patients are effectively cured of their disease, even with radical cystectomy alone. In these patients, introduction of adjuvant systemic treatment presents no potential benefit while carrying a risk for harm.

In the AMBASSADOR study, 48.4% of patients in the pembrolizumab arm had grade 3 or higher adverse effects. Some high-grade immune-related events can have drastic consequences on quality of life or even result in death. Therefore, the value of a DFS benefit should be weighed with the risk of harm in the absence of a reported OS benefit. Predicting the benefit of adjuvant ICI for the patient is further complicated by the recent approval of frontline combination enfortumab vedotin-ejfv (Padcev) plus pembrolizumab for advanced and metastatic urothelial carcinoma, which demonstrated durable responses and a significant OS benefit compared with platinum-based chemotherapy.¹¹ Those patients who do not receive adjuvant immunotherapy and recur after surgery may be effectively salvaged with frontline systemic therapy, which may be associated with superior outcomes compared with traditional platinum-based chemotherapy.

While the PD-L1 biomarker was predictive of benefit from adjuvant nivolumab on CheckMate 274, this finding was not seen on the IMvigor010 or AMBASSADOR studies. This calls into question the reliability of PD-L1 testing as a reliable biomarker for determining adjuvant ICI use. The AMBASSADOR study has circulating tumor DNA (ctDNA) analysis planned using two separate commercial platforms. This analysis, in addition to the efforts being undertaken with the ongoing phase 3 IMvigor011 (NCT04660344) and MODERN (NCT05987241) studies, could inform a more reliable and effective biomarker for patient selection, optimizing the use of adjuvant ICI for those patients who are most likely to benefit.

In addition to the reported efficacy and remaining questions surrounding adjuvant ICI use, the treatment paradigm of NAC and radical cystectomy followed by adjuvant ICI may be altered altogether. The role of bladder preservation strategies has garnered interest after early-phase data appear promising. In a phase 2 trial (NCT03451331) the combination of gemcitabine, cisplatin, and nivolumab achieved a clinical complete response rate in 43% (95% CI, 32%-55%) of patients, most of whom (n = 32/33) were able to forego immediate cystectomy.¹² The results of the phase 3 KEYNOTE-909/EV-303 (NCT03924895) and KEYNOTE-B15/EV-304 (NCT04700124) studies assessing the efficacy of perioperative enfortumab vedotin plus pembrolizumab in MIUC are also eagerly awaited.

Renal Cancer

Kidney and renal pelvis cancers are the sixth and ninth most common cancers diagnosed in men and women, respectively, with an estimated 52,380 new cases in men and 29,230 cases in women in the United States.1 Clear cell is the most common histologic subtype of kidney cancer representing 75% to 85% of renal cell carcinomas (RCC).^13,14

Surveillance following partial or radical nephrectomy had been the standard of care following several adjuvant studies of VEGF-targeting tyrosine kinase inhibitors (TKIs) and mTOR inhibitors that were unable to demonstrate a significant survival benefit.^15-20 Notably, approximately 50% of post-nephrectomy patients with high-risk features will eventually recur.²¹ As ICIs have become established as a standard of care for advanced disease, there has been significant interest in exploring their efficacy as part of perioperative management of clear cell RCC.

At ASCO GU 2024, Robert Motzer, MD, section head, Kidney Cancer, Genitourinary Oncology Service, Jack and Dorothy Byrne Chair in Clinical Oncology, of Memorial Sloan Kettering Cancer Center, first presented the final analysis of part B from the CheckMate 914 study.²² This was a phase 3 randomized trial that compared adjuvant nivolumab 240 mg every 2 weeks for up to 6 months with placebo in patients with clear cell RCC with high risk of relapse: stage pT2a with grade 3 to 4, pT2b-T4 with any grade, or node-positive disease. Approximately 82% of patients had pT3 disease and 8% had sarcomatoid histology. At a median follow-up of 27 months, the study did not find a significant improvement in DFS (HR, 0.87; 95% CI, 0.62-1.21; P =.3962). Based on the study design, a final OS analysis will not be performed in the setting of a negative DFS end point.

Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, then presented the OS analysis from the phase 3 KEYNOTE-564 study.²³ This was a phase 3 randomized trial comparing adjuvant pembrolizumab 200 mg every 3 weeks for up to 17 cycles, or approximately 1 year, with placebo in patients with clear cell RCC with intermediate-high risk of relapse (pT2 grade 4 or pT3 any grade) as well as patients with high risk for relapse (pT4 any grade or node-positive disease). The study also enrolled patients with stage M1 rendered no evidence of disease with resection within 1 year of nephrectomy. The study previously met its primary end point of DFS (HR, 0.68; 95% CI, 0.53-0.87; P =.001) leading to FDA approval.²⁴ The updated DFS remains significant (HR, 0.72; 95% CI, 0.59-0.87) and consistent across all subgroups. At a median follow-up of 57.2 months, the study also met its OS end point, demonstrating a 38% reduction in the risk of death with adjuvant pembrolizumab vs placebo (HR, 0.62; 95% CI, 0.44-0.87; P =.002). The OS benefit also persisted in all subgroups analyzed. In regard to toxicity, pembrolizumab demonstrated similar tolerability to adjuvant nivolumab from part B of CheckMate 914 with grade 3/4 toxicities at 18.6% and 17.0%, discontinuation rates of 21.1% and 20.0%, and high-dose corticosteroid use 7.6% and 6.0%, respectively.

The KEYNOTE-564 study was the first to demonstrate an OS benefit with adjuvant therapy in RCC. This has led many to question why other perioperative ICI studies in RCC have not generated similar findings. The phase 3 IMmotion010 study (NCT03024996) randomly assigned patients with clear cell RCC to adjuvant atezolizumab vs placebo and did not meet its DFS end point (HR, 0.93; 95% CI, 0.75-1.15; P =.50) at a median follow-up of 44.7 months.²⁵ However, one might suggest that anti–PD-L1 therapy might have less activity in RCC, which is supported by the lack of significant OS benefit with these agents in the metastatic setting to date.^26,27

Part A of the phase 3 CheckMate 914 study compared adjuvant nivolumab at 240 mg every 2 weeks for 12 doses plus ipilimumab (Yervoy) at 1 mg/kg every 6 weeks for 4 doses with placebo. The primary DFS end point was not met (HR, 0.92; 95% CI, 0.71-1.19; P =.53) at a median follow-up of 37.0 months.²⁸ Notably, median duration of treatment with ipilimumab plus nivolumab in part A and nivolumab monotherapy in part B was 5.1 of the intended 6 months. The KEYNOTE-564 study had a median duration of 11.1 of the intended 12 months while still meeting its DFS and OS end points, suggesting that perhaps 6 months of intended therapy is too short to attain efficacy. The results of the ongoing phase 3 RAMPART study (NCT03288532) of adjuvant durvalumab (Imfinzi), durvalumab plus tremelimumab-actl (Imjudo), or active monitoring may provide additional clarity as it incorporates anti–CTLA-4 therapy into regimens given up to 1 year.

The phase 3 PROSPER study (NCT03055013) randomly assigned patients to perioperative nivolumab vs surgery alone. Notably, 1 dose of neoadjuvant nivolumab was administered followed by 9 doses of adjuvant nivolumab at 480 mg every 4 weeks. The trial was halted due to futility for RFS (HR, 0.97; 95% CI, 0.74-1.28; P =.43) and OS remained immature (HR, 1.48; 95% CI, 0.89-2.48; P =.93).²⁹ The different dosing strategy of the ICI could explain the lack of significant benefit observed.

Importantly, up to 50% of patients will be cured with nephrectomy alone. Despite enriching for patients at higher risk for relapse, the median DFS on the placebo arm was 50.7 months (95% CI, 48.1-not estimable) on the CheckMate 914 study at a median follow-up 37.0 months and not reached on the KEYNOTE-564 study at median follow-up 57.2 months. It is notable that KEYNOTE-564 enrolled the highest number of sarcomatoid histology at 10.5% of patients, which has been associated with favorable outcomes in ICI treatment.³⁰

In addition, DFS benefit was pronounced in those with M1 no evidence of disease and M0 high-risk disease, suggesting those at higher risk in the enrolled population derive the most benefit from adjuvant ICI use. Therefore, patient selection is important, and reliable predictive biomarkers remain an unmet need.

Discussion following the presentations focused on the subsequent therapy received in the KEYNOTE-564 study. While approximately 80% of patients who progressed in both arms went on to receive subsequent therapy, only 69.7% of those who received systemic therapy on the placebo arm received an ICI. With ICI representing the appropriate standard of care for most patients with advanced or metastatic RCC, a concern was raised that patients not receiving ICI in the placebo arm could have contributed to the OS benefit observed in the pembrolizumab arm. However, it was also suggested that patients who relapse with favorable-risk disease may undergo metastasis-directed therapy or TKI monotherapy per standard of care. It is also difficult to determine if patients went on to receive salvage ICI as later lines in these instances. Additional data regarding the pattern of relapse based on subsequent therapy received could be informative.

Another issue regarding subsequent therapy is the role of ICI in the treatment of patients with recurrent disease following adjuvant pembrolizumab. As many as 41.2% of patients who received subsequent systemic therapy at recurrence in the pembrolizumab arm received an ICI. However, the phase 3 CONTACT-03 study (NCT04338269) demonstrated a lack of benefit from continuing an ICI-based regimen after progression on previous ICI.³¹ Time to recurrence following completion of adjuvant pembrolizumab is likely to be an important factor for treatment decision-making and warrants further study.

Lastly, the treatment of localized clear cell RCC at high risk of relapse may undergo further paradigm shifts pending results of other ongoing studies, such as the phase 3 study of adjuvant pembrolizumab plus the HIF-2α inhibitor belzutifan (Welireg) vs pembrolizumab alone (NCT05239728). It is also important to remember that the findings of KEYNOTE-564 were specific to those with clear cell histology and that further studies of patients with various non-clear cell variants in the absence of sarcomatoid histology are needed.

Paul V. Viscuse, MD, is a genitourinary oncologist at the University of Virginia.

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