Ramucirumab (RAM) exposure-response (ER) relationship in RANGE, a randomized phase III trial of docetaxel (DOC) with or without RAM in advanced urothelial carcinoma (UC) patients (pts) who progressed on or after platinum therapy.

PURPOSE A previously reported randomized intergroup trial demonstrated that combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was superior to single-agent cisplatin in patients with advanced urothelial carcinoma. We conducted a long-term analysis of patients included in the intergroup trial to examine factors associated with long-term survival. PATIENTS AND METHODS Two-hundred fifty-five assessable patients with urothelial carcinoma were randomized to receive either single-agent cisplatin (70 mg/m2 on day 1) or combination chemotherapy with methotrexate (30 mg/m2 on days 1, 15, and 22), vinblastine (3 mg/m2 on days 2, 15, and 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2 on day 2). Courses were repeated every 28 days. The association between patient characteristics and survival was assessed using Cox proportional hazards models. RESULTS With long-term follow-up evaluation, survival in the M-VAC arm continues to be superior to cisplatin (P = .00015, log-rank test). Predictors of survival include performance status, histology, and the presence of liver or bone metastasis. Only 3.7% of the patients randomized to M-VAC are alive and continuously disease-free at 6 years. CONCLUSION Long-term follow-up evaluation of the intergroup trial confirms that M-VAC is superior to single-agent cisplatin in patients with advanced urothelial carcinoma; however, durable progression-free survival is rare. Patients with non-transitional-cell histology, poor performance status, and/or bone or visceral involvement fare poorly and are unlikely to benefit significantly from M-VAC chemotherapy.

Download Full-text

EV-301: A phase III trial in progress evaluating enfortumab vedotin versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma

Annals of Oncology ◽

10.1093/annonc/mdz425.014 ◽

2019 ◽

Vol 30 ◽

pp. ix75-ix76 ◽

Cited By ~ 1

Author(s):

D.P. Petrylak ◽

J.E. Rosenberg ◽

J. Lee ◽

J. Yonese ◽

I. Duran ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Locally Advanced ◽

Phase Iii ◽

Phase Iii Trial ◽

Metastatic Urothelial Carcinoma

Download Full-text

Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4503 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4503-4503 ◽

Cited By ~ 39

Author(s):

David C. Smith ◽

Thomas Gajewski ◽

Omid Hamid ◽

Jeffrey S. Wasser ◽

Anthony J. Olszanski ◽

...

Keyword(s):

Phase I ◽

Urothelial Carcinoma ◽

Phase Ii ◽

Advanced Disease ◽

Alternative Therapy ◽

Phase Iii ◽

Open Label ◽

Advanced Urothelial Carcinoma ◽

Grade 3 ◽

Line Of Therapy

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.

Download Full-text

Analysis of PFS2 by subsequent therapy in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as 1L therapy for advanced urothelial carcinoma (UC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.448 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 448-448

Author(s):

Mustafa Ozguroglu ◽

Ajjai Shivaram Alva ◽

Tibor Csőszi ◽

Nobuaki Matsubara ◽

Lajos Geczi ◽

...

Keyword(s):

Clinical Trial ◽

Urothelial Carcinoma ◽

Progressive Disease ◽

Exploratory Analysis ◽

Phase Iii ◽

Treatment Sequence ◽

Advanced Urothelial Carcinoma ◽

To Receive ◽

Clinical Trial Information

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, >90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]

Download Full-text

Immunotherapy in urothelial cancer: recent data and perspectives

Cancer Urology ◽

10.17650/1726-9776-2017-13-4-16-24 ◽

2018 ◽

Vol 13 (4) ◽

pp. 16-24 ◽

Cited By ~ 2

Author(s):

M. I. Volkova ◽

Ya. V. Gridneva ◽

A. S. Ol’shanskaya

Keyword(s):

Urothelial Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Phase Iii ◽

Significant Survival ◽

Programmed Death ◽

Programmed Death 1 ◽

Advanced Urothelial Carcinoma

Immune-checkpoint inhibitors blocking the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) have shown a prominent anti-tumor activity with long-term responses and an acceptable toxicity profile in clinical trials. Pembrolizumab, atezolizumab, nivolumab, avelumab, and durvalumab are anti-PD-1/PD-L1 agents that redefine the standard of care for advanced urothelial carcinoma. CTLA-4 inhibitors are also under investigation in this setting. Phase III trial KEYNOTE-045 has demonstrated significant survival benefit in patients treated with pembrolizumab comparing with the standard second-line chemotherapy. Atezolizumab, nivolumab, avelumab, and durvalumab were also recommended for platinum-pretreated urothelial carcinoma patients based on phase II data. Following investigations of biomarkers such as PD-L1 expression are needed to determine high-responders to immunotherapy. This review article describes the advances in immunotherapy with immune-checkpoint inhibitors.

Download Full-text

Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835918788310 ◽

2018 ◽

Vol 10 ◽

pp. 175883591878831 ◽

Cited By ~ 28

Author(s):

Pooja Ghatalia ◽

Matthew Zibelman ◽

Daniel M. Geynisman ◽

Elizabeth Plimack

Keyword(s):

Urothelial Carcinoma ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Platinum Based Chemotherapy ◽

United States Food ◽

Phase Iii Trials ◽

Metastatic Urothelial Carcinoma ◽

States Food ◽

Advanced Urothelial Carcinoma ◽

Line Setting

The treatment of advanced metastatic urothelial carcinoma has recently evolved with the approval of five checkpoint inhibitors. In the second-line setting, in patients who have progressed on cisplatin-based chemotherapy, pembrolizumab, atezolizumab, durvalumab, nivolumab and avelumab are United States Food and Drug Administration (FDA) approved. In cisplatin-ineligible patients, atezolizumab and pembrolizumab are the FDA-approved checkpoint inhibitors. Here we describe the updated clinical efficacy of these checkpoint inhibitors in the treatment of advanced urothelial carcinoma and then suggest how they can be sequenced in the context of available chemotherapeutic options. For cisplatin-eligible patients, platinum-based chemotherapy remains the standard first-line treatment. For patients progressing on platinum-based therapy, phase III trials have been performed comparing pembrolizumab and atezolizumab separately with standard chemotherapy, and results favor the use of pembrolizumab.

Download Full-text