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Key Studies in Urothelial, Prostate, and Kidney Cancer: CCO Independent Conference Highlights of the 2021 Genitourinary Cancers Symposium

Robert Motzer, MD
Daniel P. Petrylak, MD
Released: March 26, 2021

Urothelial Cancers

CheckMate 274: Adjuvant Nivolumab vs Placebo After Radical Surgery ± Neoadjuvant CT in High-Risk MIUC

Daniel P. Petrylak, MD:
I would like to start by discussing adjuvant therapy for bladder cancer. Currently, for patients with high-risk urothelial carcinoma who have had neoadjuvant chemotherapy prior to surgery, there is no standard of care for those with residual muscle-invasive disease after surgery.

CheckMate 274 is a phase III trial that asked the question whether immune checkpoint inhibition after surgery improves disease-free survival (DFS) in 709 patients with high-risk muscle-invasive urothelial carcinoma (MIUC).1 There were 2 different groups of patients enrolled on this trial: For those who received neoadjuvant cisplatin chemotherapy, they had to have ypT2-ypT4a or ypN+; for those who did not receive neoadjuvant cisplatin chemotherapy and were ineligible for or refused adjuvant cisplatin chemotherapy, they had to be of a higher stage, pT3-pT4a or pN. Patients had undergone radical surgery within 120 days of study entry, and they had to be disease free within 4 weeks of study dosing. Patients were randomized to receive either adjuvant nivolumab 240 mg every 2 weeks or placebo for up to 1 year. The primary endpoints were DFS in the ITT population and in all randomized patients with PD-L1 expression ≥1%. Secondary endpoints were nonurothelial tract recurrence-free survival, disease-specific survival, and OS. Exploratory endpoints included distant metastasis-free survival, safety, and health-related quality of life (HRQoL).

CheckMate 274: Efficacy Outcomes

Daniel P. Petrylak, MD:
In the ITT population, there was a 10‑month improvement in median DFS with nivolumab compared with placebo (21.0 vs 10.9 months; HR: 0.70; P <.001). The DFS benefit with nivolumab was more pronounced in patients with PD-L1 expression ≥1% and was not reached vs 10.8 months with placebo (HR: 0.53; P <.001). The study met the primary endpoint of DFS, and most patient subgroups had a DFS improvement, except in patients who had initial origin of the tumor in the renal pelvis (HR: 1.16) and ureter (HR: 1.55). An interesting endpoint of this study was nonurothelial tract recurrence-free survival—in other words, any recurrence outside of the urinary tract. Here again, the HR for patients who received nivolumab vs placebo was 0.72 in the ITT population and 0.54 in all randomized patients with PD-L1 expression ≥1%. Similarly, the median distant metastasis–free survival was improved at 35.0 months vs 29.0 months (HR: 0.74) in the ITT population and median was not reached vs 21.2 months (HR: 0.60) in patients with PD-L1 ≥1%.

CheckMate 274: Safety and HRQoL

Daniel P. Petrylak, MD:
When we look at the safety data from CheckMate 274, there were no unexpected signals. Typical immune‑related AEs that one would expect with any immune checkpoint inhibitor were observed. Nothing seems to be more prominent compared with other studies with immune checkpoint inhibitors in metastatic disease. Any-grade pruritus (23.1%), fatigue (17.4%), diarrhea (16.8%), and rash (15.1%) were the most common treatment-related AEs (TRAEs) with nivolumab, and the most common grade ≥3 TRAEs were diarrhea, colitis, and pneumonitis (all 0.9%). With placebo, the most common grade ≥3 TRAEs were colitis (0.6%), diarrhea, gamma-glutamyl transferase elevation, and hepatitis (all 0.3%). Also, there was no degradation in HRQoL with nivolumab vs placebo.

 

CheckMate 274: Conclusions

Daniel P. Petrylak, MD:
In summary, adjuvant nivolumab significantly prolonged DFS in high-risk MIUC vs placebo in CheckMate 274 with no HRQoL deterioration observed.1

EV-301: Enfortumab Vedotin vs Chemotherapy in LA or Metastatic UC After Platinum and Anti–PD-(L)1 Therapy

Daniel P. Petrylak, MD:
The phase III EV 301 trial evaluated enfortumab vedotin in a difficult-to-treat patient population of 608 patients with locally advanced or metastatic UC after platinum and checkpoint inhibitor therapy.2 Enfortumab vedotin is an antibody–drug conjugate targeting Nectin‑4, which is almost ubiquitously expressed in UC specimens. Patients must have been treated with both platinum‑containing chemotherapy and a PD-1/PD-L1 inhibitor, followed by radiographic progression or relapse, and have an Eastern Cooperative Oncology Group performance status of 1 or better. Patients were randomized 1:1 to receive either enfortumab vedotin at 1.25 mg/kg on Days 1, 8, and 15 of 28‑day cycles or investigator’s choice chemotherapy, which could be standard docetaxel or paclitaxel in the United States and vinflunine in Europe. The primary endpoint was OS and secondary endpoints were investigator‑assessed PFS, disease-control rate (DCR), ORR, and safety.

EV-301: Efficacy Outcomes

Daniel P. Petrylak, MD:
OS was significantly longer in the enfortumab vedotin arm vs the chemotherapy arm, with an approximately 4‑month improvement (median: 12.88 vs 8.97 months; HR: 0.70; P = .00142). In addition, PFS was significantly improved as well, with a median of 5.5 months with enfortumab vedotin vs 3.71 months with chemotherapy. If we look at responses, confirmed ORR was 40.6% in the enfortumab vedotin arm vs 17.9% in the control arm (P <.001) with a 4.9% complete response (CR) rate and a 35.8% partial response (PR) rate. The DCR was 71.9% with enfortumab vedotin vs 53.4% with chemotherapy. What is remarkable about enfortumab vedotin is the fact that there is a consistent ORR of 40% from phase I to phase III trials, including patients with liver metastases. So, in my mind, enfortumab vedotin is a very exciting drug.

This was an interim analysis that met its primary endpoint of significantly improved OS and the OS benefit was seen in all subgroups except women. It is important to note that this trend was not seen in the response rate in women, which was similar to the overall population. The number of women entered in this trial was small, reflecting the  the fact that bladder cancer is a disease with a 3:1 ratio of men vs women. Additionally, the survival of women treated in the control arm was higher than the overall population while the survival in the Enfortumab arm was similar to the overall population.

EV-301: Treatment-Related AEs

Daniel P. Petrylak, MD:
TRAEs with enfortumab vedotin were similar to what we had seen in phase I and phase II trials. Grade ≥ 3 rash maculopapular occurred in 7% of patients receiving enfortumab vedotin vs none in the chemotherapy arm, which was generally treated with topical steroids. Compared with the chemotherapy arm, rates of grade ≥ 3 neutrophil count decreases, white blood cell decreases, and febrile neutropenia were much lower in enfortumab vedotin arm. Comparable rates of any-grade serious AEs (23% vs 23%) and any-grade TRAEs leading to treatment discontinuation (14% vs 11%) were seen with enfortumab vedotin vs chemotherapy. Overall, enfortumab vedotin was very well tolerated and there was really no safety signal that was different from what was observed in the phase I and phase II trials. With enfortumab vedotin you have  for peripheral neuropathy, which occurred in 34% of patients (grade ≥ 3, 3%) in this study. This sometimes requires dose reduction or holding of doses to prevent it from progressing further.

EV-301: AEs of Special Interest

Daniel P. Petrylak, MD:
As mentioned previously, some of the grade ≥3 AEs of special interest reported with enfortumab vedotin were rash (15%), severe cutaneous adverse reactions (5%), and peripheral neuropathy (5%). The other thing you have to be cognizant of with enfortumab vedotin is that hyperglycemia can occur and no patients with a glucose level higher than 250 mg/dL were permitted to be enrolled on this trial, and patients’ diabetes had to be under control at the time of study entry.

EV-201 Cohort 2: Enfortumab Vedotin in Cisplatin-Ineligible Patients With UC and Prior PD-(L)1 Inhibitor

Daniel P. Petrylak, MD:
Enfortumab vedotin has been granted accelerated approval by the FDA at this point and we hope that results from the EV‑301 trial will support its full approval. The pivotal trial that led to the accelerated approval of enfortumab vedotin in patients who have had previous platinum chemotherapy and immunotherapy was the EV‑201 trial, which was divided into 2 different cohorts: cohort 1, consisting of patients who had previous PD-(L)1 inhibitor and platinum-based chemotherapy; and cohort 2, consisting of patients who had previous PD-(L)1 inhibitor, were cisplatin ineligible, and/or had no previous platinum-based chemotherapy. Results from cohort 2 were reported at ASCO GU 2021.4 Patients received enfortumab vedotin at 1.25 mg/kg on Days 1, 8, and 15 of 28-day cycles. The primary endpoint was confirmed ORR per blinded independent central review, and secondary endpoints included DoR, PFS, OS, and safety.

EV-201 Cohort 2: Response

Daniel P. Petrylak, MD:
The confirmed ORR was somewhat better than what was expected based on other previous data, but still within the confidence limits. Overall, 52% of patients had a confirmed objective response, with 20% of patients having a CR and 31% having a PR. Again, as we have seen in other studies, responses were seen across all patient subgroups: 61% in patients who had urothelial carcinoma of the upper tract, 48% in those with liver metastases, and 48% in patients who did not respond to previous PD-(L)1 therapy. These similar response rates are reflective of the mechanism of delivering monomethyl auristatin E to Nectin‑positive tumor cells. A high ORR of 64% was observed in those patients who responded to previous PD-(L)1 treatment.

EV-201 Cohort 2: Change in Tumor Measurements (BICR)

Daniel P. Petrylak, MD:
The waterfall plot represents the change in the tumor measurements by blinded independent central review. Overall, 88% of assessable patients had some decrease in tumor measurements from baseline.

EV-201 Cohort 2: Duration of Response

Daniel P. Petrylak, MD:
Among 46 responders, the median DoR was almost 11 months, which I think is pretty good for a single agent in this disease setting. It’s probably the best response duration from a single agent that I have seen at this point.

EV-201 Cohort 2: PFS and OS

Daniel P. Petrylak, MD:
Although phase II data can be related to patient selection, a median OS of 14.7 months and a median PFS of 5.8 months were consistent with what we have seen from other enfortumab vedotin studies.

EV-201 Cohort 2: TRAEs

Daniel P. Petrylak, MD:
Rates of TRAEs including rash, alopecia, peripheral neuropathy, and hyperglycemia were similar. There were 4 deaths that were considered treatment-related, 1 each for acute kidney injury, metabolic acidosis, multiple organ dysfunction, as well as pneumonitis. Three of the 4 deaths were within 30 days of their first dose and all 3 patients had high body mass index, suggesting that the deaths may be related to some form of glucose resistance. All 4 deaths occurred in patients at least 75 years of age with comorbidities. TRAEs necessitated discontinuation in 16% of patients, with the most common being peripheral sensory neuropathy in 4% of patients.

EV-201 Cohort 2: TRAEs of Special Interest

Daniel P. Petrylak, MD:
Regarding TRAEs of special interest, there were no grade 5 skin reactions and only 1 grade 4 event was reported. Thirteen patients had severe cutaneous adverse reactions, but these were mostly low grade with no grade 4/5 events reported. Grade 3 events included 1 each of stomatitis, skin exfoliation, dermatitis bullous, and dermatitis exfoliative generalized. Severe cutaneous adverse reactions led to 1 discontinuation. Peripheral neuropathy rates were similar in patients with or without preexisting peripheral neuropathy. Hyperglycemia was more common in patients with preexisting hyperglycemia and those with high body mass index.

EV-301 and EV-201 Cohort 2: Conclusions and Takeaways

Daniel P. Petrylak, MD:
In EV-301, enfortumab vedotin significantly improved OS, PFS, and ORR vs chemotherapy in previously treated patients with advanced UC.2 In cisplatin-ineligible patients with locally advanced or metastatic UC previously treated with a PD-(L)1 inhibitor, enfortumab vedotin yields an ORR between 48% and 61%.4

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