TY - JOUR
T1 - A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer
T2 - The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study
AU - Hahn, Noah M.
AU - O'Donnell, Michael A.
AU - Efstathiou, Jason A.
AU - Zahurak, Marianna
AU - Rosner, Gary L.
AU - Smith, Jeff
AU - Kates, Max R.
AU - Bivalacqua, Trinity J.
AU - Tran, Phuoc T.
AU - Song, Daniel Y.
AU - Baras, Alex S.
AU - Matoso, Andres
AU - Choi, Woonyoung
AU - Smith, Kellie N.
AU - Pardoll, Drew M.
AU - Marchionni, Luigi
AU - McGuire, Bridget
AU - Grace Phelan, Mary
AU - Johnson, Burles A.
AU - O'Neal, Tanya
AU - McConkey, David J.
AU - Rose, Tracy L.
AU - Bjurlin, Marc
AU - Lim, Emerson A.
AU - Drake, Charles G.
AU - McKiernan, James M.
AU - Deutsch, Israel
AU - Anderson, Christopher B.
AU - Lamm, Donald L.
AU - Geynisman, Daniel M.
AU - Plimack, Elizabeth R.
AU - Hallman, Mark A.
AU - Horwitz, Eric M.
AU - Al-Saleem, Essel
AU - Chen, David Y.T.
AU - Greenberg, Richard E.
AU - Kutikov, Alexander
AU - Guo, Gordon
AU - Masterson, Timothy A.
AU - Adra, Nabil
AU - Kaimakliotis, Hristos Z.
N1 - Funding Information:
Funding/Support and role of the sponsor: This work was supported by grant funding from investigator-initiated funds from AstraZeneca (Cambridge, UK), Hoosier Cancer Research Network, NCI Cancer Center Support grant funding (P30CA006973), UM1 grant funding (UM1CA186691), K08 grant funding (K08CA248967), and R01 grant funding (R01CA235681).
Publisher Copyright:
© 2023 European Association of Urology
PY - 2023/6
Y1 - 2023/6
N2 - Background: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. Objective: To evaluate the safety and preliminary efficacy of anti–PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). Design, setting, and participants: A multicenter phase 1 trial was conducted at community and academic sites. Intervention: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). Outcome measurements and statistical analysis: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 –mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. Results and limitations: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. Conclusions: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. Patient summary: Durvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates.
AB - Background: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. Objective: To evaluate the safety and preliminary efficacy of anti–PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). Design, setting, and participants: A multicenter phase 1 trial was conducted at community and academic sites. Intervention: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). Outcome measurements and statistical analysis: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 –mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. Results and limitations: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. Conclusions: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. Patient summary: Durvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates.
KW - Bacillus Calmette-Guerin
KW - Bacillus Calmette-Guerin unresponsive
KW - Bladder cancer
KW - Clinical trial
KW - Durvalumab
KW - Non–muscle invasive
KW - PD-L1
KW - Radiation
KW - Urothelial carcinoma
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UR - http://www.scopus.com/inward/citedby.url?scp=85147230119&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2023.01.017
DO - 10.1016/j.eururo.2023.01.017
M3 - Article
C2 - 36717286
AN - SCOPUS:85147230119
SN - 0302-2838
VL - 83
SP - 486
EP - 494
JO - European Urology
JF - European Urology
IS - 6
ER -