Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303

Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). Clinical trial registration: NCT03924856 & NCT03924895 (ClinicalTrials.gov)

Download Full-text

Systematic Review and Meta-Analysis of Cisplatin Based Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer

Bladder Cancer ◽

10.3233/blc-201511 ◽

2021 ◽

pp. 1-13

Author(s):

Raed Benkhadra ◽

Tarek Nayfeh ◽

Sai Krishna Patibandla ◽

Chelsea Peterson ◽

Larry Prokop ◽

...

Keyword(s):

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Meta Analysis ◽

Nausea And Vomiting ◽

Phase Iii ◽

Invasive Bladder Cancer ◽

Efficacy And Safety ◽

Muscle Invasive Bladder Cancer ◽

Increased Risk ◽

Muscle Invasive

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC). OBJECTIVE: To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). METHODS: We searched MEDLINE, Embase, Scopus and other sources. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. RESULTS: We identified 24 studies. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15–1.82) and all-cause mortality at longest follow-up (OR 0.63; 95%CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95%CI 0.13–0.80), anemia (OR 0.32; 95%CI 0.18–0.54), nausea and vomiting (OR 0.27; 95%CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95%CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95%CI 0.01–0.31). Certainty in the estimates was very low for most outcomes. CONCLUSIONS: Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.

Download Full-text

Methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) versus gemcitabine, and cisplatin (GC) as neoadjuvant chemotherapy in muscle-invasive bladder cancer, a systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16522 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16522-e16522

Author(s):

Raed Benkhadra ◽

Tarek Nayfeh ◽

Naga Sai Krishna Patibandla ◽

Chelsea Peterson ◽

Larry Prokop ◽

...

Keyword(s):

Systematic Review ◽

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Meta Analysis ◽

Nausea And Vomiting ◽

Phase Iii ◽

Invasive Bladder Cancer ◽

Efficacy And Safety ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

e16522 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC) in cisplatin-eligible patients. This systematic review and meta-analysis provide an updated efficacy and safety comparison between the two most commonly used cisplatin-based regimens; dose-dense (dd) or conventional MVAC versus GC. Methods: We searched different databases for studies comparing MVAC versus GC in the neoadjuvant setting. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. Results: We identified 24 studies from inception to March 2020; among them 17 were peer reviewed and 7 were only reported as abstracts in national or international meetings, including a phase 3, randomized-controlled clinical trial. Among peer-reviewed published studies, efficacy outcomes such as OS, downstaging and pCR were comparable between conventional MVAC and GC for MIBC. If including non-peer-reviewed studies, dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95% CI 1.15–1.82), and OS at longest follow-up (OR 0.63; 95% CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95% CI 0.13–0.80), anemia (OR 0.32; 95% CI 0.18–0.54), nausea and vomiting (OR 0.27; 95% CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95% CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95% CI 0.01-0.31). Certainty in the estimates was very low for most outcomes. Conclusions: Among peer-reviewed published studies, efficacy and safety outcomes were comparable between conventional MVAC and GC for MIBC. However, If including non-peer-reviewed studies, this analysis showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice

Download Full-text

INTACT (S/N1806) phase III randomized trial of concurrent chemoradiotherapy with or without atezolizumab in localized muscle-invasive bladder cancer: Safety update on first 73 patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.428 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 428-428

Author(s):

Parminder Singh ◽

Jason A. Efstathiou ◽

Catherine Tangen ◽

Sameer G. Jhavar ◽

Noah M. Hahn ◽

...

Keyword(s):

Bladder Cancer ◽

Standard Of Care ◽

Phase Iii ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Trimodality Therapy ◽

Radiation Cystitis ◽

Study Team ◽

Grade 3 ◽

Muscle Invasive

428 Background: Trimodality therapy (TMT) with maximal TURBT followed by chemoradiation(CRT) is a standard of care for select patients with muscle invasive bladder cancer (MIBC). This trial evaluates the activity of atezolizumab (atezo) in MIBC in combination with TMT. This trial was designed with pre-specified safety analyses of the first 80 patients (40 in each arm). At the time of SWOG fall 2020 DSMC report deadline we had enrolled 84 patients but data on only 73 patients were available. The same data are being submitted to ASCO GU meeting. Methods: This trial is testing atezo every 3 weeks for 6 months given concurrently and adjuvantly with CRT vs. CRT alone in 475 patients with MIBC T2-T4aN0M0 disease. Patients are stratified based on PS; T2 vs T3 or T4; choice of chemotherapy; and radiation field (bladder only vs small pelvis). Patients undergo biopsy 3 months after finishing CRT to assess treatment response. Patients are followed for 5 years for recurrence or survival. This trial was not preceded by a phase I study but was designed with a safety run in of 80 patients. Study team agreed on the study design based on available data from other tumor types and initial experience from investigators running smaller similar trials. It was pre-specified that if we observe more than 25% patients having grade 3-5 colitis or cystitis in the atezo arm or any other toxicity which is deemed clinically significant and related to atezo, the trial investigators and DSMC would consider stopping further enrollment. Results: 36 patients were enrolled on the TMT alone arm and 37 patients on the TMT + atezo arm. No grade 3 or higher colitis was reported in the atezo arm. Only one patient had treatment related grade 3 radiation cystitis which was diagnosed after finishing atezo treatment. No steroids were given. Overall 23 grade 3 or higher toxicity events were reported in the atezo arm vs 11 in non- atezo arm. Most common toxicity was hematological which was considered non-immune related. None of the grade 3 or higher toxicities were considered to be immune related by the treating investigator. Conclusions: There is no evidence of increased immune related grade 3-5 AEs.DSMC has recommended to continue enrollment. Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed Clinical trial information: NCT03775265 . [Table: see text]

Download Full-text

Re: International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial

European Urology ◽

10.1016/j.eururo.2011.07.032 ◽

2011 ◽

Vol 60 (4) ◽

pp. 870-871

Author(s):

Damien Pouessel ◽

Stéphane Culine ◽

Pierre Mongiat-Artus

Keyword(s):

Bladder Cancer ◽

Phase Iii ◽

Long Term Results ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Phase Iii Trial ◽

Muscle Invasive

Download Full-text

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

Tumori Journal ◽

10.1177/03008916211061604 ◽

2021 ◽

pp. 030089162110616

Author(s):

Fausto Petrelli ◽

Gianluca Perego ◽

Ivano Vavassori ◽

Andrea Luciani

Keyword(s):

Bladder Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Urothelial Cancer ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Cancer Of The Bladder ◽

Muscle Invasive

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

Download Full-text