Outcomes and the impact of genomic characteristics on patients with metastatic urothelial carcinoma enrolled in early phase trials.

5029 Background: With the recent approvals of checkpoint inhibitors (CPIs), a fibroblast growth factor receptor (FGFR) inhibitor, and an antibody-drug conjugate, patients with platinum-refractory metastatic urothelial carcinoma (mUC) have several treatment options available. However, many patients with platinum-refractory mUC need novel therapies after progressing on current therapies. We assessed the role of early phase trials in treatment of mUC and the impact of genomic alterations on their outcomes. Methods: We retrospectively analyzed medical records of patients with mUC who received an investigational therapy at the phase 1 clinic and had CLIA-certified clinical next generation sequencing. Clinical parameters and mutations were abstracted. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Among the 57 pts enrolled in 41 unique phase 1 trials between 2015 and 2019, 16% (9/57) had variant histology: neuroendocrine carcinoma (n = 3) and urachal carcinoma (n = 6). Median age was 64. Majority were males (72%). 97% received prior platinum therapy and 60% had received prior CPI therapy. Across the pure urothelial carcinoma cohort (n = 48), median PFS was 4.2 months (m), median OS was 9.8 m, and the overall response rate (ORR) was 19%. TP53, FGFR, TERT, and ARID1A alterations (alt) were detected in 54%, 41%, 21% and 17% of UC patients, respectively. Patients harboring a TP53 alt, compared to no alt, had a shorter median PFS of 3.2m vs 9.6 m (HR = 2.738 [1.247 - 6.011], p = 0.0121). On the contrary, median PFS was longer in FGFR alt, compared to no alt, 6.3m vs 3.2m (HR = 0.4662 [0.224 - 0.971], p = 0.0415). Of note, 64% of FGFR alt patients were treated under an early phase FGFR targeting trial. Median OS was numerically longer in FGFR alt and shorter in TP53 alt but did not reach statistical significance (table). Conclusions: Patients with mUC may derive clinical benefit from enrollment in phase I clinical trials. Patients with TP53 alterations had numerically worse outcomes. Patients with mUC should be considered for an FGFR targeting therapy in the setting of an FGFR alteration. [Table: see text]

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Nivolumab demonstrates benefit over nomogram-predicted 12-month survival as salvage therapy for metastatic urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.451 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 451-451 ◽

Cited By ~ 1

Author(s):

Gregory Russell Pond ◽

Guru Sonpavde ◽

Matt D. Galsky ◽

Padmanee Sharma ◽

Jonathan E. Rosenberg ◽

...

Keyword(s):

Prognostic Factors ◽

Urothelial Carcinoma ◽

Salvage Therapy ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Statistical Significance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Progression Free Survival ◽

Metastatic Urothelial Carcinoma

451 Background: Intermediate endpoints of benefit in metastatic urothelial carcinoma (mUC) nonrandomized trials are necessary to identify promising drugs, particularly for checkpoint inhibitors, where response and progression-free survival remain suboptimal. We previously reported a nomogram (Pond GR et al, 2017 GU Cancers Symposium) using 5 prognostic factors (hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group performance status ≥1, presence of liver metastasis, time from last treatment ≤3 months, and albumin < lower limit of normal) from phase 2 trials of historical agents (eg, taxanes) to estimate 12-month overall survival (OS), against which observed survival could be compared. Nivolumab was granted approval as salvage therapy for patients with mUC, based on the CheckMate (CM) 275 trial; it is thus of interest to compare the nivolumab observed survival versus nomogram-predicted survival results. Methods: Data were obtained from CM 275, including survival and all 5 prognostic factors. Nomogram points were calculated and the expected 12-month OS was estimated. Bootstrap analyses based on 2000 replications were used to estimate 95% confidence intervals (CIs) for the median expected, observed, and difference between the expected and observed 12-month OS values. All tests were 2-sided, with statistical significance defined as P≤0.05. Results: Data were available from 270 patients from CM 275. Fifteen patients did not have albumin recorded and were excluded. Among the 255 evaluable patients, 46 (18.0%) patients had 0 adverse prognostic factors, 85 (33.3%) had 1, and 124 (48.6%) had 2 or more. The observed nivolumab 12-month OS from CM 275 (43.3% [95% CI, 37.0%-50.5%]) was 19.8% higher (95% CI, 13.6%-26.4%) when compared with the nomogram-predicted 12-month OS (23.5%; [95% CI, 22.5%-25.5%]) if patients received historical chemotherapy. Across all 2000 bootstrap samples, the observed nivolumab 12-month OS exceeded the nomogram-predicted 12-month OS. Conclusions: Nivolumab was associated with a significantly improved 12-month OS compared with historical chemotherapy based on the value predicted by the validated nomogram incorporating baseline prognostic factors. Clinical trial information: NCT02387996.

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Overcoming the impact of the COVID‐19 pandemic on oncology early phase trials and drug development in Asia—Experiences and perspectives of the Asian Oncology Early Phase 1 Consortium

Asia-Pacific Journal of Clinical Oncology ◽

10.1111/ajco.13510 ◽

2021 ◽

Author(s):

Toshio Shimizu ◽

Dong‐Wan Kim ◽

Herbert H. Loong ◽

Chia‐Chi Lin ◽

Matthew CH Ng ◽

...

Keyword(s):

Drug Development ◽

Early Phase ◽

Phase 1 ◽

Early Phase Trials ◽

The Impact

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Impact of concurrent medications on outcomes with PD1/PD-L1 inhibitors for metastatic urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.435 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 435-435 ◽

Cited By ~ 3

Author(s):

Archana Agarwal ◽

Gregory Russell Pond ◽

Catherine Curran ◽

Amin Nassar ◽

Pier Vitale Nuzzo ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Median Survival ◽

Cox Regression ◽

Statistical Significance ◽

Lower Probability ◽

Cox Regression Analysis ◽

Prior Therapy ◽

Metastatic Urothelial Carcinoma ◽

The Impact ◽

Concurrent Medication

435 Background: The impact of concurrent medications (meds) on outcomes with PD1/PD-L1 inhibitors in metastatic urothelial carcinoma (mUC) is unclear. We investigated whether candidate concurrent meds (NSAIDS [N], metformin [M], antibiotics [A], statins [S] and corticosteroids [C]) have an association with outcomes in mUC patients (pts) receiving a PD1/PD-L1 inhibitor. We hypothesized that A and C compromise outcomes, while N, M and S improve outcomes. Methods: Data from mUC pts who received PD1/PD-L1 inhibitors at the Dana-Farber Cancer Institute (DFCI) was obtained. The concurrent medication was required to be administered within 1 month before starting to anytime during PD1/PD-L1 inhibitor therapy. A Cox regression analysis was done to study the association of variables with response and survival. Results: Data was available for 101 pts with mUC who received atezolizumab [n = 52], pembrolizumab [n = 39], nivolumab [n = 9] and durvalumab [n = 1]. Prior platinum had been administered in 74 pts (73.2%), 25 were chemonaive (24.8%) and prior therapy status was unknown in 2 pts (2%). The concurrent meds were N (n = 30), M (n = 7), A (n = 26), S (n = 33) and C (n = 12). The median survival was 57.9 weeks. Response was seen in 26 pts [25.7%]. A was associated with a lower probability of response (11.5%) than those not on A (30.7%), and worse survival (HR = 1.93, 95% CI 1.93 – 3.42, P = 0.024). Pts who received neither A nor C, one of them or both had a response rate (RR) of 30.6%, 20% and 0%, and median survival of 65.3, 53.1 and 14.9 weeks, respectively (HR = 3.02, 95% CI = 1.34-6.83, p = 0.027). Pts who did not receive N, M and S (n = 52) exhibited a median OS of 39.6 weeks, while those who received ≥1 of these meds (n = 49) exhibited a median survival of 160.3 weeks (p = NS). The study is limited by the retrospective design and modest sample size. Conclusions: In this hypothesis-generating study, concurrent antibiotics or corticosteroids compromised outcomes in mUC pts receiving a PD1/PD-L1 inhibitor and receiving both further compromised outcomes. The numerically higher survival with concurrent N, M or S did not attain statistical significance, but requires further study in larger datasets.

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Faculty Opinions recommendation of Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726265741.793526241 ◽

2016 ◽

Author(s):

Ashish Kamat

Keyword(s):

Urothelial Carcinoma ◽

Platinum Refractory ◽

Metastatic Urothelial Carcinoma

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Atezolizumab-induced myositis and myocarditis in a patient with metastatic urothelial carcinoma

BMJ Case Reports ◽

10.1136/bcr-2020-236357 ◽

2020 ◽

Vol 13 (12) ◽

pp. e236357

Author(s):

Mary Sessums ◽

Siva Yarrarapu ◽

Pramod K Guru ◽

Devang K Sanghavi

Keyword(s):

Urothelial Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Basic Knowledge ◽

Malignant Neoplasms ◽

Diverse Range ◽

History Of ◽

Metastatic Urothelial Carcinoma ◽

Acute Hypercapnic Respiratory Failure

Immune checkpoint inhibitors have revolutionised cancer therapy in the past decade. Although they have been indicated to treat a diverse range of malignant neoplasms, they are also associated with various immune-related adverse effects. We report the case of a 74-year-old man with a history of urothelial carcinoma who had atezolizumab-induced myocarditis and myositis resulting in acute hypercapnic respiratory failure, despite the discontinuation of atezolizumab and aggressive treatment with corticosteroids. This case highlights the importance of a multidisciplinary approach for early diagnosis and treatment of immune-related adverse events. Physicians must be aware of the risks associated with immune checkpoint inhibitors and have a basic knowledge regarding their management.

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Urothelial carcinoma in the era of immune checkpoint inhibitors

Immunotherapy ◽

10.2217/imt-2021-0042 ◽

2021 ◽

Author(s):

Nadine Khalife ◽

Claude Chahine ◽

Manal Kordahi ◽

Tony Felefly ◽

Hampig Raphael Kourie ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Invasive Disease ◽

Line Treatment ◽

First Line ◽

Metastatic Urothelial Carcinoma ◽

Muscle Invasive

Bladder cancer is the seventh most frequent cancer worldwide. The majority of patients present with nonmuscle invasive disease, while 20% of the patients are diagnosed with muscle-invasive bladder cancer. The treatment of nonmuscle invasive disease is endoscopic resection followed by intravesical adjuvant treatment for high risk patients. The standard treatment of localized muscle-invasive disease is neoadjuvant chemotherapy followed by radical cystectomy. Platinum-based chemotherapy is the first-line treatment in locally advanced or metastatic urothelial carcinoma. Immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma as second-line treatment or first-line in platinum-ineligible patients. Recently, pembrolizumab have been approved in BCG-refractory nonmuscle invasive bladder cancer. This review summarizes the current evidence concerning immunotherapy in the treatment of urothelial carcinoma.

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Impact of clinicopathological features on survival in patients treated with immune-based combinations for metastatic urothelial carcinoma: A meta-analysis of randomized clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16534 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16534-e16534

Author(s):

Veronica Mollica ◽

Alessandro Rizzo ◽

Matteo Santoni ◽

Andrea Marchetti ◽

Matteo Rosellini ◽

...

Keyword(s):

Clinical Trials ◽

Liver Metastases ◽

Urothelial Carcinoma ◽

Meta Analysis ◽

Clinicopathological Features ◽

Cochrane Library ◽

Risk Of Death ◽

Metastatic Urothelial Carcinoma ◽

Ecog Ps ◽

The Impact

e16534 Background: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma (mUC). Nonetheless, little is known regarding the impact of clinicopathological features in this setting. We performed a meta-analysis aiming to evaluate the predictive value of ECOG-PS, age, gender, liver metastases, and histology in randomized controlled trials (RCTs) comparing ICI-based combinations versus chemotherapy in mUC patients. Methods: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs comparing ICI-based combinations versus chemotherapy alone in mUC patients. The primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI). All statistical analyses were performed using R studio software. Results: Overall, 1032 mUC patients were included in the analysis. Compared with chemotherapy, ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including no liver metastases (HR, 0.84; 95% CI, 0.74-0.95) and ECOG-PS 0 patients (HR, 0.84; 95% CI, 0.72-0.97). Similarly, ICI-based combinations were associated with prolonged OS in mUC patients who were < 65 years old (HR, 0.82; 95% CI, 0.72-0.95), as well as in male (HR, 0.90; 95% CI, 0.82-0.99) and female patients (HR, 0.81; 95% CI, 0.68-0.97). Conversely, a non-statistically significant benefit was observed for chemotherapy alone in mUC patients with liver metastases (HR, 1.06; 95% CI, 0.86-1.31). Conclusions: According to our results, the magnitude of benefit of ICI-based combinations over chemotherapy in mUC was consistent across a number of clinicopathological subgroups, while a proportion of patients could respond to chemotherapy alone.Despite several limitations affect our analysis, we believe these results could guide in everyday treatment decision-making, also assisting in the design and interpretation of future clinical trials on ICIs in mUC.

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Current Strategies and Novel Therapeutic Approaches for Metastatic Urothelial Carcinoma

Cancers ◽

10.3390/cancers12061449 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1449 ◽

Cited By ~ 4

Author(s):

Veronica Mollica ◽

Alessandro Rizzo ◽

Rodolfo Montironi ◽

Liang Cheng ◽

Francesca Giunchi ◽

...

Keyword(s):

Medical Treatment ◽

Urothelial Carcinoma ◽

Checkpoint Inhibitors ◽

Cancer Control ◽

Parp Inhibitors ◽

Published Data ◽

Drug Conjugates ◽

Platinum Based Chemotherapy ◽

Metastatic Urothelial Carcinoma

Urothelial carcinoma (UC) is a frequent cause of cancer-related deaths worldwide. Metastatic UC has been historically associated with poor prognosis, with a median overall survival of approximately 15 months and a 5-year survival rate of 18%. Although platinum-based chemotherapy remains the mainstay of medical treatment for patients with metastatic UC, chemotherapy clinical trials produced modest benefit with short-lived, disappointing responses. In recent years, the better understanding of the role of immune system in cancer control has led to the development and approval of several immunotherapeutic approaches in UC therapy, where immune checkpoint inhibitors have been revolutionizing the treatment of metastatic UC. Because of a better tumor molecular profiling, FGFR inhibitors, PARP inhibitors, anti-HER2 agents, and antibody drug conjugates targeting Nectin-4 are also emerging as new therapeutic options. Moreover, a wide number of trials is ongoing with the aim to evaluate several other alterations and pathways as new potential targets in metastatic UC. In this review, we will discuss the recent advances and highlight future directions of the medical treatment of UC, with a particular focus on recently published data and ongoing active and recruiting trials.

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