ESMO 2018: ABACUS, A phase II Study Investigating the Safety and Efficacy of Neoadjuvant Atezolizumab in Muscle Invasive Bladder Cancer

Munich, Germany ( There is a high metastatic relapse rate for patients with muscle-invasive bladder cancer after cystectomy – neoadjuvant chemotherapy can decrease that risk. The standard of care neoadjuvant therapy for muscle-invasive bladder cancer typically involves a cisplatin-based regimen, the most common being MVAC (methotrexate, vinblastine, doxorubicin, cisplatin), GC (gemcitabine and cisplatin), or CMV (cisplatin, vinblastine, and methotrexate).  Compared with cystectomy alone, neoadjuvant chemotherapy can improve overall survival and decrease the risk of recurrence1,2 However, not all patients are chemotherapy candidates, depending on performance status and renal dysfunction. Thus, checkpoint inhibitors may represent a solution for this unmet need. Pembrolizumab has been studied in this setting, and data presented at ASCO 2018 showed that neoadjuvant pembrolizumab could result in a pathologic complete response in 17 of 43 patients (39.5%, 95%CI: 26.3-54.4)3. This is similar to MVAC, which resulted in a pathologic complete response in 38% of patients in the study by Grossman et al. 

This study describes the outcomes of another checkpoint inhibitor, atezolizumab, for neoadjuvant treatment of muscle-invasive bladder cancer. 
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In this study, patients with T2-T4aN0M0 urothelial carcinoma who were not candidates or declined cisplatin chemotherapy were enrolled and given atezolizumab at week 0 and week 3, with a maximum of 8 week delay until cystectomy. The primary clinical endpoint was a pathologic CR, with a goal of >20%.
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74 patients have been treated and 68 patients are evaluable at this time.
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The pathologic complete response rate was 29% (20/68, 95%CI: 19% to 42%) and 39% of patients were successfully downstaged to non-muscle invasive disease. During therapy, 28% of patients had a radiographic response to atezolizumab, whereas 17% of patients progressed during therapy. 

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7 patients did not receive radical cystectomy. 1 patient declined, 3 patients had clinical deterioration, 2 patients died (MI, pneumonia), and 1 patient had disease progression and received chemotherapy.

In terms of adverse events, very few people had grade 3-4 AEs. The most common AEs were fatigue, transaminitis, anorexia, rash, pyrexia, diarrhea, and pruritus.  

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This study adds to the growing body of evidence which suggests that neoadjuvant immune checkpoint inhibition may be a reasonable approach for patients who do not tolerate platinum-based chemotherapy. For patients who are eligible for both, tt is unknown at this time which approach is more efficacious with respect to disease-free survival and overall survival. Randomized trials will be necessary to better determine the best approach for patients with muscle-invasive disease. Biomarker work in both this study and the pembrolizumab study suggests that there may be biomarkers (PD-L1 CPS score, DNA Damage Response, TMB) which predict which patients may have a high rate of pathologic complete response but this is still a work in progress. 

Presented by: Daniel Castellano, MD, Medical Oncology Department, University Hospital, Madrid, Spain

1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. New England Journal of Medicine 2003;349:859-66.
2. Goodman A, Piccioni DE, Kato S, et al. Analysis of over 100,000 patients with cancer for CD274 (PD-L1) amplification: Implications for treatment with immune checkpoint blockade. Journal of Clinical Oncology 2018;36:47-.
3. Necchi A, Briganti A, Bianchi M, et al. Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study. American Society of Clinical Oncology; 2018

Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany