ASTRO 2022: INTACT (S/N1806): Phase III Randomized Trial of Concurrent Chemoradiotherapy with or without Atezolizumab in Localized Muscle Invasive Bladder Cancer—Toxicity Update on First 213 Patients

( The 2022 ASTRO annual meeting featured a session on bladder and kidney preservation, including a presentation by Dr. Sameer Jhavar discussing toxicity updated results from the INTACT trial assessing concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer. Trimodality therapy with maximal TURBT followed by chemoradiation is a category 1 bladder preservation treatment option for patients with non-metastatic muscle invasive bladder cancer. Additionally, previous work suggests that radiation therapy increases PD-L1 expression in bladder cancer. The INTACT trial is evaluating the activity of atezolizumab in muscle invasive bladder cancer in combination with trimodality therapy. Moreover, it was designed with pre-specified safety analyses of the first 80 patients (40 in each arm). The previous analyses did not show any significant increase in toxicity and DSMC recommended to proceed with further enrollment. Presented at ASTRO 2022, this is the updated safety report of 213 patients.

 INTACT is a randomized phase III trial testing atezolizumab every 3 weeks for 6 months given concurrently and adjuvantly with trimodality therapy versus trimodality therapy alone in 432 eligible patients with muscle invasive bladder cancer (T2-T4aN0M0) within 120 days prior to randomization. Patients with unilateral hydronephrosis are eligible if their kidney function permits enrollment in the study. Additionally, patients must have a Zubrod performance status of 0-2, a GFR > 25 ml/min, and hemoglobin > 9 gm/dL. Patients are stratified based on: performance status, T2 vs T3 or T4, choice of chemotherapy, and radiation field (bladder only vs small pelvis). Patients undergo biopsy 3 months after finishing chemoradiation to assess treatment response and are followed for 5 years for bladder intact event free survival. The trial schema of INTACT is as follows:


ASTRO 2022 Sameer G. Jhavar_0 


 The primary endpoint was bladder intact event free survival, with events composed of histologically proven presence of muscle invasive bladder cancer, clinical evidence of nodal or metastatic disease, radical cystectomy, or death due to any cause. Patients last known to be bladder intact event free survival event free are censored at the date of last cystoscopy, and those patients without disease assessment who are still alive will be censored at randomization. With regards to statistical analysis: Ho = 52% (at 3 years), Ha = 64% (at 3 years) translating to an HR of 1.46, with 85% power, 1 sided alpha = 0.025.

 Among the 213 patients, 100 were randomized to the trimodality therapy alone (control) arm and 113 patients to the trimodality therapy + atezolizumab arm. Patient characteristics for the atezolizumab vs control arm are as follows: median age (75 vs 72 years), T2 (82% vs 81%), chemotherapy regimen: cisplatin (48% vs 50%), 5-fluorouracil/mitomycin (15% vs 13%), gemcitabine (37% vs 37%), radiation field including small pelvis (57% vs 58%), bladder only (43% vs 42%), performance status 0-1 (96% vs 95%):


ASTRO 2022 Sameer G. Jhavar_1 


Two patients in each arm reported grade 3 diarrhea. Two patients had grade 3 cystitis in the atezolizumab arm as compared to 1 patient in the control arm. Only 1 patient had treatment related grade 3 radiation cystitis confirmed by cystoscopy and biopsy and continued atezolizumab without worsening of symptoms. Overall, 65 patients reported treatment related grade 3 or higher toxicity events in the atezolizumab arm vs 44 in control arm (58% vs 44%). Most common toxicity was hematological (43% vs 36%) which was considered non-immune related:


ASTRO 2022 Sameer G. Jhavar_2 


Other Grade 3 or higher known immune related adverse events of atezolizumab like pancreatitis (n = 1), rash (n = 1), acute kidney injury (n = 2), gastritis (n = 1), transaminitis (n = 1), and dyspnea (n = 1) were observed in the atezolizumab arm.


Dr. Jhavar concluded his presentation discussing toxicity updated results from the INTACT trial assessing concurrent chemoradiotherapy with or without atezolizumab in localized muscle invasive bladder cancer with the following take home messages:

  • Toxicities observed were numerically higher in the atezolizumab arm (58% versus 44%)
  • One reason could be that more eligible patient data were available from the atezolizumab arm (113 vs 100)
  • Most of them were hematological toxicities which did not require holding atezolizumab and were considered non-immune related by the treating provider
  • Known immune related adverse events were observed in the atezolizumab arm
  • No new safety signals were observed in the atezolizumab arm
  • The trial is expected to finish accrual in next two years and this update demonstrates no safety concerns


Presented by:  Sameer G. Jhavar, MD, PhD, Baylor Scott & White Health, Temple, TX

Co-Authors: P. Singh1, J. A. Efstathiou2, M. Plets3,  S. Delacroix Jr.5, A. Tripathi6, A. Gupta7, S. Sachdev8, A. Jani9, A. N. Kirschner10, C. Tangen3, R. Bangs11, M. Joshi12, B. A. Costello13, I. L. Thompson14, F. Y. Feng15, and S. Lerner161Mayo Clinic, Arizona, Phoenix, AZ, 2Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 3Fred Hutchinson Cancer Research Center, Seattle, WA, 45Gulf South MU-NCORP/East Jefferson General Hospital/Louisiana State University, New Orleans, LA, 6University of Oklahoma, Oklahoma City, OK, 7Cedars Sinai Medical Center, Los Angeles, CA, 8Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, 9Department of Radiation Oncology, Emory University, Atlanta, GA, 10Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, 11Bladder Cancer Advocacy Network, Pittsford, NY, 12Penn State Cancer Institute, Hershey, PA, 13Division of Medical Oncology, Mayo Clinic, Rochester, MN, 14Texas Urology Group, San Antonio, TX, 15Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 16Baylor College of Medicine, Houston, TX


Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Radiation Oncology (ASTRO) Annual Hybrid Meeting, San Antonio, TX, Sat, Oct 22 – Wed, Oct 26, 2022.

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