Upcoming event

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial

  • Bernadett Szabados 1,
  • Alejo Rodriguez-Vida 2,
  • Ignacio Durán 3,
  • Simon J. Crabb 4,
  • Michiel S. Van Der Heijden 5,
  • Albert Font Pous 6,
  • Gwenaelle Gravis 7,
  • Urbano Anido Herranz 8,
  • Andrew Protheroe 9,
  • Alain Ravaud 10,
  • Denis Maillet 11,
  • Maria J. Mendez-Vidal 12,
  • Cristina Suárez 13,
  • Mark Linch 14,
  • Aaron Prendergast 1,
  • Charlotte Tyson 1,
  • Kelly Mousa 1,
  • Daniel Castellano 15,
  • Thomas Powles 1
1 Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK 2 Department of Medical Oncology, Hospital del Mar, Barcelona, Spain 3 Instituto de Biomedicina de Sevilla, IBiS, Hospital Universitario Virgen del Rocio, CSIC and Universidad de Sevilla, Seville, Spain 4 Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK 5 Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 6 Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B.ARGO)-IGTP, Hospital Universitari Germans Trias i Pujol, Badalona, Spain 7 Medical Oncology Department, Institut Paoli-Calmettes, Aix-Marseille Université, Inserm, CNRS, CRCM, Marseille, France 8 Department of Medical Oncology, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain 9 Maimonides Institute for Biomedical Research oh Cordoba (IMIBIC), Hospital Universitario Reina Sofia, Cordoba, Spain 10 Department of Medical Oncology, Hopital Saint-Andre, University of Bordeaux-CHU Bordeaux, Bordeaux, France 11 Department of Medical Oncology, Hospital Lyon Sud, Lyon, France 12 Department of Medical Oncology, Reina Sofia University Hospital, Cordoba, Spain 13 Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain 14 Department of Oncology, University College London Cancer Institute, London, UK 15 Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain

Publication: European Urology Oncology, February 2021

Background

There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).

Objective

To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.

Design, setting, and participants

ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.

Intervention

Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.

Outcome measurements and statistical analysis

Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.

Results and limitations

Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.

Conclusions

Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.

Commentary by Dr. Benjamin Pradere

While trials have recently reported early results of neoadjuvant checkpoint inhibitors, trials such as Pure-01 with pembrolizumab or ABACUS with atezolizumab, little is known regarding the impact of these treatments on surgical outcomes.

ABACUS (NCT02662309) is an open-label, multicentre, phase-II trial for patients with histologically confirmed (T2-T4aN0M0) muscle-invasive bladder cancer (MIBC) awaiting radical cystectomy (RC). Patients participating in the trial were either ineligible for or refused cisplatin-based neoadjuvant chemotherapy. Before surgery, patients received two cycles of atezolizumab (1200mg, given every 3 weeks), which contrasted with PURE-O1, where pembrolizumab was administered for 3 cycles. Postoperative complications related to surgery were graded according to the Clavien-Dindo classification system and were reported 28 days after surgery.

Between May 2016 and June 2018, 87 patients underwent RC with a median follow-up duration of 24.9 months. The mean age of the patients was 73 years old.  Before receiving atezolizumab, most of the patients had a cT2 disease (74%); 18% had cT3 and 8% cT4. Among the patients included, 79% (75/95) completed the planned two cycles of atezolizumab.

The authors of this article present a comprehensive safety analysis of the ABACUS trial. They report that atezolizumab-related grade 3–5 adverse events (AEs) occurred in 11% of the patients who received at least one cycle. Regarding the AEs and immune-mediated toxicity during the neoadjuvant period, they report that 71% of the patients experienced AEs (27% fatigue, 9% urinary tract infection [UTI], and 9% anaemia) and 16% of these AEs were grade 3 or more. 44% of the patients experienced immune-mediated toxicity: fatigue (20%), decreased appetite (6%), transaminitis (6%), pruritus (6%), diarrhoea (6%), and/or rash (4%). Severe event >3 occurred in only 9% of the patients. Of note, one patient died from a myocardial infarction and pulmonary embolism 4 weeks after the first treatment administration.

From the overall cohort of 95 patients, 87 (92%) successfully underwent RC. The median time between first administration of atezolizumab and RC was 5.6 weeks. Surgical complications occurred in 61%, with 43% of minor and 18% of major complications. The most frequent surgical complications were UTI (23%), anaemia requiring blood transfusion (13%), and constipation/paralytic ileus (9%). 14% (12/87) of the patients had atezolizumab-related toxicities occurring after RC, the most common being decreased appetite (5%), anaemia (2%), transaminitis (1%), adrenal insufficiency (1%), hypothyroidism (1%), and pruritus (1%). Late treatment-related side effects occurred up to 12 weeks after surgery; therefore, patients receiving neoadjuvant immune checkpoint inhibitors (ICIs) may require more frequent follow-ups, even after RC.

The authors underline the safety of single-agent neoadjuvant ICIs, with similar results observed in the PURE-01 trial. Nevertheless, the authors underlined there is a need for preoperative frailty assessment to predict complications after an oncological procedure, especially in the elderly. Moreover, regular assessment by physicians with experience in immune therapy is recommended to prevent and treat any AEs that might be related to ICIs as soon as possible, even after surgery. It is crucial that urologists who perform RC and administer ICIs in the neoadjuvant setting are aware of these complications and know how to manage them.

The authors, giving clear results and information for the daily practice, underline the safety of ICIs in the neoadjuvant setting. ICIs do not increase the surgical complications rates. The most important thing is to educate urologists to propose the RC-ICI treatment as often as possible (e.g. through inclusion in randomised controlled trials) and to teach them how to manage the AEs that may result from it. Collaboration between medical oncologists and urologists will be of the utmost importance to improve the management of this group of MIBC patients.