ASCO 2020: IMvigor010: Primary Analysis from a Phase III Randomized Study of Adjuvant Atezolizumab versus Observation in High-Risk Muscle-Invasive Urothelial Carcinoma

(UroToday.com) The current standard of care for patients with localized muscle-invasive bladder cancer involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. Unfortunately, even with chemotherapy and surgery, cancer recurrence is common, with a 5 year survival rate of 50—60%1. Thus, additional strategies are necessary to help patients achieve long term survival. The approach tested here is the addition of immune checkpoint inhibitor atezolizumab as adjuvant immunotherapy following cystectomy. Checkpoint inhibitors such as Atezolizumab and Pembrolizumab has demonstrated efficacy in the metastatic setting (IMvigor210, KEYNOTE-052) and thus would be reasonable to try in the adjuvant setting.

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The study design is shown above. Patients with high-risk disease, defined as pathologic ≥T2 disease, or ≥T3 muscle-invasive disease without neoadjuvant chemotherapy, or any patient with node-positive disease were included in the study. Patients were stratified by many risk factors, including number of lymph nodes resected, tumor stage, receipt of neoadjuvant chemotherapy, and PD-L1 status. Atezolizumab was given every 3 weeks for 1 year in the treatment arm, and patients were assessed with scans every 12 weeks for the first three years, and every 24 weeks for years 4-5.
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809 patients were randomized to treatment or observation. About 31% of patients discontinued treatment due to adverse events. The majority of patients discontinued either atezolizumab or observation due to disease progression. 
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In terms of baseline characteristics, 52% of patients in each arm were node positive.  Half of the patients had neoadjuvant chemotherapy, which is typical of this population as many patients are not cisplatin eligible due to underlying comorbidities (renal disease, hearing loss, neuropathy). 

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In terms of the primary endpoint, this study did not meet its endpoint as there was no significant difference in disease-free survival (DFS) between atezolizumab and observation. The median DFS for atezolizumab was 19.4 months, compared with 16.6 months with observation, HR 0.89, P=0.2446.
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Patients who had PD-L1 IC2/3 appeared to do better overall regardless of atezolizumab or observation compared with those with PD-L1 IC0/1. Subgroup analysis also did not show any benefit for adjuvant atezolizumab in any subgroup. Overall survival data is currently immature as median OS has not yet been reached. Currently 18-month OS was 79% for atezolizumab and 73% for observation (HR 0.85).
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In terms of safety, no new safety signals were seen with atezolizumab. The standard immune-related side effects were noted, including rash, hepatitis, colitis, pneumonitis, and nephritis. Most adverse events were grade 1/2. 33% of patients discontinued atezolizumab due to adverse events.

Adjuvant atezolizumab in patients with high-risk muscle-invasive bladder cancer does not improve disease-free survival. Atezolizumab is relatively well tolerated, however, 1/3 of patients did discontinue therapy due to adverse events. Two other large studies are evaluating immune checkpoint inhibitors in the adjuvant setting, Checkmate 274 (Nivolumab) and AMBASSADOR (Pembrolizumab) which will hopefully provide further guidance for this patient population.

Presented by: Maha Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, Deputy Director, Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Evanston, IL

Written by: Jason Zhu, MD, Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.

References:

  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.
Clinical Trial Information: NCT02450331 - A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection
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