Treatment Related Adverse Events in Urothelial Carcinoma: Non-Physician
Faculty: Peter H. O’Donnell & Shilpa Gupta, MD Educational Grant Support: Seagen and Merck
Joint Providers: Medical Education Resources and Enquiring Minds, LLC
Release: September 30, 2022 Expires on: December 31, 2023 Media Type: internet Completion Time: 1 hour
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Melvin is a 72-year-old male who presents with 5 months of intermittent hematuria.
Melvin
Christine is a 66-year-old female who presents with gross hematuria. She has hypertension, type 2 diabetes, and chronic renal insufficiency (CrCl, 45 mL/min) but otherwise has been in relatively good health.
Christine
Catherine
Catherine, a 71-year-old woman, presents with metastatic urothelial carcinoma approximately 9 months after cystectomy for muscle-invasive bladder cancer.
Clyde
Clyde is a 65-year-old man with a history of active Crohn’s disease who presents with metastatic urothelial carcinoma after multiple transurethral resections (TURs) due to recurrence and progression of non-muscle–invasive bladder cancer.
NILE
There are several phase 3 trials that are evaluating novel first-line combination treatments in patients with previously untreated advanced urothelial carcinoma.1,2
Durvalumab is a PD-L1 inhibitor, and tremelimumab is a CTLA-4 inhibitor. In NILE, patients with previously untreated advanced or metastatic urothelial carcinoma will be randomly assigned to receive durvalumab with standard-of-care chemotherapy, durvalumab plus tremelimumab with standard-of-care chemotherapy, or chemotherapy alone.1 Although durvalumab plus tremelimumab failed to improve overall survival (OS) over chemotherapy in previously untreated urothelial carcinoma in the phase 3 DANUBE trial, there was nonetheless evidence of antitumor activity, particularly for patients with high PD-L1 expression levels (hazard ratio, 0.74; 95% CI, 0.59-0.93).3 As such, the NILE trial design has been modified to focus on patients with high levels of PD-L1 expression.1
1. Galsky MD, Necchi A, Sridhar SS, et al. A phase III, randomized, open-label, multicenter, global study of first-line durvalumab plus standard of care (SoC) chemotherapy and durvalumab plus tremelimumab, and SoC chemotherapy versus SoC chemotherapy alone in unresectable locally advanced or metastatic urothelial cancer (NILE). J Clin Oncol. 2021/02/20 2021;39(6_suppl):TPS504-TPS504.
2. Van Der Heijden MS, Gupta S, Galsky MD, et al. Study EV-302: A two-arm, open-label, randomized controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated advanced urothelial carcinoma (aUC) (trial in progress). J Clin Oncol. 2022/02/20 2022;40(6_suppl):TPS589-TPS589.
3. Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588.
ctDNA
According to recent data, circulating tumor DNA (ctDNA) levels in the plasma may be useful for considering the relative benefit of adjuvant therapy for bladder cancer. ctDNA is believed to be released into the bloodstream when cancer cells undergo apoptosis and necrosis and can be detected by next-generation sequencing. It has been suggested that the presence of ctDNA may be indicative of molecular residual disease (MRD) and thus may be used as a predictor of relapse for patients who have undergone treatment for early cancer.1-3
Recent evidence for the utility of ctDNA in post-cystectomy adjuvant therapy decision making comes from an analysis of data from the phase 3 IMvigor010 trial, which showed that adjuvant atezolizumab did not improve outcomes over observation in patients with operable urothelial carcinoma.4 However, among the 214 patients (37%) who were positive for ctDNA postsurgery, atezolizumab improved disease-free survival (DFS) by 42% and overall survival (OS) by 41% compared with observation alone. In contrast, DFS and OS were not significantly different between trial arms among those patients who were negative for ctDNA.1
Further supporting the correlation between ctDNA and residual disease, the proportion of patients with ctDNA clearance at 6 weeks was significantly higher for those treated with atezolizumab compared with observation (18% vs 4%; P = .0204). Additionally, in an analysis of the ABACUS trial, which was a separate phase 2 study of neoadjuvant atezolizumab for muscle-invasive bladder cancer, atezolizumab was associated with reduced ctDNA levels among patients who responded to neoadjuvant therapy.1
1. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. Jul 2021;595(7867):432-437.
2. Hasenleithner SO, Speicher MR. A clinician’s handbook for using ctDNA throughout the patient journey. Mol Cancer. 2022/03/21 2022;21(1):81.
3. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019/06/20 2019;37(18):1547-1557.
4. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(4):525-537.
EV-302
There are several phase 3 trials that are evaluating novel first-line combination treatments in patients with previously untreated advanced urothelial carcinoma.1,2
EV-302 is comparing chemotherapy with the immune checkpoint inhibitor pembrolizumab in combination with the Nectin-4–directed antibody-drug conjugate, enfortumab vedotin, among patients with previously untreated advanced urothelial carcinoma.2 The EV-302 trial is supported by results from the phase 1/2 EV-103 trial (also known as KEYNOTE-869), which evaluated enfortumab vedotin plus pembrolizumab versus enfortumab vedotin alone in a cohort of patients with previously untreated advanced urothelial carcinoma. After median follow-up of about 15 months, enfortumab vedotin plus pembrolizumab was associated with an overall response rate (ORR) of 64.5% and a complete response rate of 10.5%, while enfortumab vedotin monotherapy was associated with an ORR of 45.2% (complete response rate, 4.1%).3 In EV-302, this promising combination therapy will be compared with standard-of-care chemotherapy.
1. Galsky MD, Necchi A, Sridhar SS, et al. A phase III, randomized, open-label, multicenter, global study of first-line durvalumab plus standard of care (SoC) chemotherapy and durvalumab plus tremelimumab, and SoC chemotherapy versus SoC chemotherapy alone in unresectable locally advanced or metastatic urothelial cancer (NILE). J Clin Oncol. 2021/02/20 2021;39(6_suppl):TPS504-TPS504.
2. Van Der Heijden MS, Gupta S, Galsky MD, et al. Study EV-302: A two-arm, open-label, randomized controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated advanced urothelial carcinoma (aUC) (trial in progress). J Clin Oncol. 2022/02/20 2022;40(6_suppl):TPS589-TPS589.
3. Rosenberg J, Milowsky MI, Ramamurthy C, et al. LBA73 - Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Accessed September 13, 2022, oncologypro.esmo.org/meeting-resources/esmo-congress/study-ev-103-cohort-k-antitumor-activity-of-enfortumab-vedotin-ev-monotherapy-or-in-combination-with-pembrolizumab-p-in-previously-untreated-
JAVELIN Bladder 100
In JAVELIN Bladder 100, 700 patients with advanced urothelial carcinoma who did not progress on 4 to 6 cycles of gemcitabine with carboplatin or cisplatin were randomly assigned to receive best supportive care with avelumab or placebo. After a median follow-up of more than 19 months, avelumab maintenance was associated with 31% longer median overall survival (OS) than placebo (21.4 vs 14.3 months; P =.001).1 In long-term follow up of more than 38 months, OS benefit with avelumab was maintained (23.8 vs 15.0 months; P = .0036). Furthermore, among patients with PD-L1–positive tumors, OS was 30.9 months with avelumab compared with 18.5 months for placebo.2
1. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020/09/24 2020;383(13):1218-1230.
2. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Long-term follow-up results from the JAVELIN Bladder 100 trial. J Clin Oncol. 2022/02/20 2022;40(6_suppl):487-487.