Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial

Galsky, Matthew D.; Arija, José Ángel Arranz; Bamias, Aristotelis; Davis, Ian D.; Santis, Maria De; Kikuchi, Eiji; García‐del‐Muro, Xavier; Giorgi, Ugo De; Mencinger, Marina; Izumi, Kouji; Panni, Stefano; Gümüş, Mahmut; Özgüroǧlu, Mustafa; Kalebasty, Arash Rezazadeh; Park, Se Hoon; Alekseev, Boris; Schütz, Fábio Augusto Barros; Li, Jian Ri; Ye, Dingwei; Vogelzang, Nicholas J.; Bernhard, S.; Tayama, Darren; Mariathasan, Sanjeev; Mecke, Almut; Thåström, Ann Christine; Grande, Enrique

doi:10.1016/s0140-6736(20)30230-0

Cited by 571 publications

(455 citation statements)

References 26 publications

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“…This randomized trial enrolled 1213 patients with locally advanced or metastatic bladder cancer who were newly diagnosed or had received neoadjuvant or adjuvant chemotherapy more than 12 months prior to commencement of atezolizumab treatment [ 25 ]. The goal was to determine the therapeutic effectiveness of atezolizumab alone or in combination with chemotherapy versus chemotherapy alone.…”

Section: Up-to-date Clinical Benefit Of the Current Ici Paradigmmentioning

confidence: 99%

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Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Bednova

Leyton

2020

IJMS

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The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on ‘targeting’ for affecting clinical practice for metastatic bladder cancer treatment.

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Section: Up-to-date Clinical Benefit Of the Current Ici Paradigmmentioning

confidence: 99%

“…The most up-to-date results of the trial as reported by Galsky et al, did not statistically show that atezolizumab improved OS in all intention-to-treat patients [ 25 ]. The proportions (53–58%) of cisplatin-ineligible patients were similar among the three groups.…”

Section: Up-to-date Clinical Benefit Of the Current Ici Paradigmmentioning

confidence: 99%

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Bednova

Leyton

2020

IJMS

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“…In addition, a clinical trial is evaluating first-line pembrolizumab in combination with lenvatinib versus pembrolizumab plus placebo in cisplatin-ineligible patients with CPS ≥ 10 or platinum-ineligible patients (LEAP-011 trial, NCT03898180). Among these trials, the final PFS and interim OS results of the IMvigor130 trial have been published [69]. After a median follow-up of 11.8 months, the mPFS was sig-…”

Section: Ongoing First-line Combination Ici Trialsmentioning

confidence: 99%

“…GCb has been the most widely used regimen [32]. Considering longer survival in atezolizumab and pembrolizumab arms among cisplatin-ineligible patients compared to the historical control in IMvigor210 and KEYNOTE-052 trials [65,66], and numerically longer survival of atezolizumab monotherapy arm compared to the chemotherapy arm in interim results of the IMvigor130 trial [69], ICIs can also be used in only PD-L1 high patients [68]. When platinum cannot be used (platinum-ineligible), ICIs can be used regardless of PD-L1 expression, even though the criteria for "platinum-ineligibility" are not yet well defined [140].…”

Section: First-line Treatment For Patients With Mucmentioning

confidence: 99%

Systemic treatment for advanced urothelial cancer: an update on recent clinical trials and current treatment options

Park

Lee

2020

Korean J Intern Med

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After cisplatin-based chemotherapy became the standard treatment for metastatic urothelial cancer (mUC), very little progress has been made in the treatment landscape of this condition until recently. With increased knowledge about the molecular biology of mUC and advances in the field of cancer immunobiology, there has been an explosion in the number of clinical trials for mUC, and systemic treatment of mUC is rapidly changing. Despite the availability of several novel therapeutic agents, cisplatin-based cytotoxic chemotherapy remains the standard, first-line treatment option. Immune checkpoint inhibitors (ICIs), including programmed death-1 and programmed death ligand-1 inhibitors, are preferred second-line treatment options that are also used in first-line cisplatin-ineligible settings. For patients with actionable fibroblast growth factor receptor 2 (FGFR2) or FGFR3 genomic alterations, erdafitinib can be considered after platinum-based treatment. Enfortumab vedotin, a monoclonal antibody targeting nectin-4 conjugated to monomethyl auristatin E, has been approved for patients who do not respond to both cytotoxic chemotherapy and ICIs. In this review, we address the clinical trial data that have established the current standard treatments and ongoing clinical trials of various agents with different mechanisms as well as provide a brief overview of current practice guidelines and recommendations in patients with mUC.

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“…Whereas first interim analyses confirmed that the KEYNOTE-361 and DANUBE trial did not meet their primary endpoints of improving PFS and OS versus chemotherapy alone [ 18 , 19 ], IMvigor130 is the first immune checkpoint inhibitor study demonstrating improvement in PFS over chemotherapy alone. Nevertheless, interim OS data did not cross the pre-specified interim efficacy boundary for statistical significance [ 20 ]. Exploratory biomarker analyses from IMvigor130 provide the first evidence that specific subgroups (IC2/3, TMB high , APOBEC mutagenesis high , IC2/3 + TMB high ) possibly benefit from atezolizumab monotherapy [ 21 ].…”

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confidence: 99%

Immune Checkpoint Inhibitors in Uro-Oncology: Urgent Call for Biomarkers

Pichler

2020

Cancers

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Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial

Cited by 571 publications

References 26 publications

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

Systemic treatment for advanced urothelial cancer: an update on recent clinical trials and current treatment options

Immune Checkpoint Inhibitors in Uro-Oncology: Urgent Call for Biomarkers

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