TY - JOUR
T1 - Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder
AU - Szabados, Bernadett
AU - Kockx, Mark
AU - Assaf, Zoe June
AU - van Dam, Pieter-Jan
AU - Rodriguez-Vida, Alejo
AU - Duran, Ignacio
AU - Crabb, Simon J.
AU - van der Heijden, Michiel S.
AU - Pous, Albert Font
AU - Gravis, Gwenaelle
AU - Herranz, Urbano Anido
AU - Protheroe, Andrew
AU - Ravaud, Alain
AU - Maillet, Denis
AU - Mendez, Maria Jose
AU - Suarez, Cristina
AU - Linch, Mark
AU - Prendergast, Aaron
AU - Tyson, Charlotte
AU - Stanoeva, Diana
AU - Daelemans, Sofie
AU - Rombouts, Miche
AU - Mariathasan, Sanjeev
AU - Tea, Joy S.
AU - Mousa, Kelly
AU - Sharma, Shruti
AU - Aleshin, Alexey
AU - Banchereau, Romain
AU - Castellano, Daniel
AU - Powles, Thomas
N1 - Funding Information: Financial disclosures: Thomas Powles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Bernadett Szabados—research funding from MSD and Roche; honoraria from Roche, MSD, and BMS. Mark Kockx—employee of CellCarta. Zoe June Assaf—employee of Roche. Pieter-Jan van Dam—employee of CellCarta. Alejo Rodriguez-Vida—research funding and honoraria from Roche, BMS, and Pfizer; research funding from Novartis and Astellas. Ignacio Duran—research funding and honoraria from Roche, BMS, Pfizer, and Johnson & Johnson; research funding from Astellas. Simon J. Crabb—research funding and honoraria from Roche, MSD, Pfizer, Exelixis, and Clovis. Michiel S. Van Der Heijden—research funding and honoraria from BMS, AstraZeneca, MSD, Novartis, Pfizer, MSD, and Seattle Genetics. Albert Font Pous—research funding and honoraria from MSD, Pfizer, and Astellas. Gwenaelle Gravis—research funding and honoraria from Roche, AstraZeneca, Pfizer, and Astellas. Urbano Anido Herranz—research funding and honoraria from Roche, MSD, Exelixis, and Astellas. Andrew Prothoroe—research funding and honoraria from Astellas, Pfizer, Novartis, and BMS. Alain Ravaud—research funding and honoraria from MSD, Roche, BMS, and Pfizer. Denis Maillet—research funding and honoraria from MSD and Roche. Maria Jose Mendez—research funding and honoraria from Roche and Pfizer. Cristina Suarez—research funding and honoraria from Pfizer, BMS, Roche, AstraZeneca, and Astellas. Mark Linch—research funding and honoraria from BMS, Roche, Pfizer, Astellas, and AstraZeneca. Aaron Prendergast and Charlotte Tyson—no conflicts. Diana Stanoeva, Sofie Daelemans, and Miche Rombouts— employee of CellCarta. Sanjeev Mariathasan—employee of Genentech. Joy S. Tea—employee of Roche. Kelly Mousa—no conflicts. Romain Banchereau—employee of Genentech. Daniel Castellano—research funding and honoraria from Astellas, BMS, Roche, and AstraZeneca. Thomas Powles—honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; research funding from AstraZeneca, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; travel/accommodation/expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. Funding Information: Funding/Support and role of the sponsor: Queen Mary University of London was the Sponsor of the study. Roche granted QMUL funding for the study and supplied the study drug. J. Bull and M. Jacobson also provided financial support for aspects of the biomarker analysis. We acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network, and La Roche-Hoffmann for funding. Publisher Copyright: © 2022 European Association of Urology
PY - 2022/8
Y1 - 2022/8
N2 - Background: Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC). Objective: To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial. Design, setting, and participants: ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. Intervention: Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected. Outcome measurements and statistical analysis: The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements. Results and limitations: The median follow-up time was 25 mo (95% confidence interval [CI] 25–26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21–41). Two-year DFS and OS were 68% (95% CI 58–76) and 77% (95% CI 68–85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65–94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24–1.5], p = 0.26, and 0.72 [95% CI 0.31–1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09–0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3–13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work. Conclusions: Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future. Patient summary: We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
AB - Background: Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC). Objective: To report on 2-yr disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumor DNA (ctDNA) in the ABACUS trial. Design, setting, and participants: ABACUS was a multicenter, single-arm, neoadjuvant, phase 2 trial, including patients with MIBC (T2-4aN0M0) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. Intervention: Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected. Outcome measurements and statistical analysis: The primary endpoints of pathological complete response (pCR) rate and dynamic changes to T-cell biomarkers were published previously. Secondary outcomes were 2-yr DFS and OS. A biomarker analysis correlated with relapse-free survival (RFS) was performed, which includes FOXP3, major histocompatibility complex class I, CD8/CD39, and sequential ctDNA measurements. Results and limitations: The median follow-up time was 25 mo (95% confidence interval [CI] 25–26). Ninety-five patients received at least one cycle of atezolizumab. Eight patients did not undergo cystectomy (only one due to disease progression). The pCR rate was 31% (27/88; 95% CI 21–41). Two-year DFS and OS were 68% (95% CI 58–76) and 77% (95% CI 68–85), respectively. Two-year DFS in patients achieving a pCR was 85% (95% CI 65–94). Baseline PD-L1 and tumor mutational burden did not correlate with RFS (hazard ratio [HR] 0.60 [95% CI 0.24–1.5], p = 0.26, and 0.72 [95% CI 0.31–1.7], p = 0.46, respectively). RFS correlated with high baseline stromal CD8+ (HR 0.25 [95% CI 0.09–0.68], p = 0.007) and high post-treatment fibroblast activation protein (HR 4.1 [95% CI 1.3–13], p = 0.01). Circulating tumor DNA positivity values at baseline, after neoadjuvant therapy, and after surgery were 63% (25/40), 47% (14/30), and 14% (five/36), respectively. The ctDNA status was highly prognostic at all time points. No relapses were observed in ctDNA-negative patients at baseline and after neoadjuvant therapy. The lack of randomization and exploratory nature of the biomarker analysis are limitations of this work. Conclusions: Neoadjuvant atezolizumab in MIBC is associated with clinical responses and high DFS. CD8+ expression and serial ctDNA levels correlated with outcomes, and may contribute to personalized therapy in the future. Patient summary: We showed that bladder cancer patients receiving immunotherapy followed by cystectomy have good long-term outcomes. Furthermore, we found that certain biological features can predict patients who might have particular benefit from this therapy.
KW - CD8
KW - Circulating tumor DNA
KW - Disease-free survival
KW - Muscle-invasive bladder cancer
KW - Neoadjuvant immunotherapy
KW - Overall survival
UR - http://www.scopus.com/inward/record.url?scp=85130375188&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.eururo.2022.04.013
DO - https://doi.org/10.1016/j.eururo.2022.04.013
M3 - Article
C2 - 35577646
SN - 0302-2838
VL - 82
SP - 212
EP - 222
JO - European Urology
JF - European Urology
IS - 2
ER -