Circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA.
Thomas Powles, Michiel Simon Van Der Heijden, Ying Wang, James W.F. Catto, Joshua J. Meeks, Hikmat Al‐Ahmadie, Hiroyuki Nishiyama, Agrin Moeini Mortazavi, Toan Quang Vu, Lorenzo Antonuzzo, Tae‐Hwan Kim, Vagif Atduev, Hiroaki Kikukawa, Bernhard J. Eigl, Yousef Zakharia, Kazuo Nishimura, Svetlana Ho, Wenjing Xin, Yashaswi Shrestha, Matthew D. Galsky
Abstract
4503 Background: In the phase 3 NIAGARA trial (NCT03732677) of patients (pts) with cisplatin-eligible MIBC, addition of perioperative D to neoadjuvant chemotherapy (NAC) demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) and overall survival compared with NAC alone, and a 10% higher pathological complete response (pCR) rate, with a manageable safety profile and no impact on the feasibility of surgery. Here, we report a planned exploratory analysis of ctDNA and association with clinical outcomes from NIAGARA. Methods: NIAGARA enrolled cisplatin-eligible pts with MIBC (cT2-T4aN0/1M0) planned for radical cystectomy (RC). Pts were randomized 1:1 to receive either neoadjuvant D (1500 mg IV Q3W) and NAC (cisplatin + gemcitabine IV Q3W) for 4 cycles followed by RC, then adjuvant D monotherapy (1500 mg IV Q4W) for 8 cycles (D arm), or NAC followed by RC alone (comparator [C] arm). Dual primary endpoints were pCR and EFS. Disease-free survival (DFS) was a secondary endpoint. Plasma ctDNA was assessed using the Signatera personalized, tumor-informed molecular residual disease (MRD) assay (Natera, Inc, Austin, TX, USA). ctDNA was assessed at baseline (screening or neoadjuvant C1D1, n = 460), after neoadjuvant treatment prior to RC (pre-RC, n = 422), and at C1D1 of the adjuvant phase (post-RC, n = 345). Results: Of 1063 randomized pts, 462 comprised the biomarker-evaluable population (237 D arm; 225 C arm). Patient characteristics were similar to the ITT population. Overall, the ctDNA+ rate at baseline was 57% (260/460) and decreased to 22% (94/422) after neoadjuvant treatment at pre-RC. ctDNA clearance rates from baseline to pre-RC were 41% in the D arm and 31% in the C arm. The non-pCR rate was 97% (86/89) among pts with pre-RC ctDNA+ status. Overall ctDNA+ rate post-RC was 9% (31/345). EFS benefit in the D arm vs the C arm was observed in both the baseline ctDNA+ and ctDNA− groups (Table). DFS benefit with perioperative D was observed in post-RC ctDNA+ and ctDNA− groups (Table). Conclusions: In this exploratory analysis, ctDNA+ status at pre-RC was associated with non-pCR. Higher ctDNA clearance from baseline to pre-RC in the D arm indicated the additional benefit of D plus NAC vs NAC alone. Perioperative D provided an EFS benefit to both pts with ctDNA+ and ctDNA− status at baseline; a similar trend was observed with DFS based on ctDNA status post-RC. These results further support the perioperative D regimen for pts with MIBC. Funding : AstraZeneca. Clinical trial information: NCT03732677 . EFS DFS Baseline ctDNA+ Baseline ctDNA- Post-RC ctDNA+ Post-RC ctDNA- D C D C D C D C n 137 123 99 101 9 8 129 126 Median (95% CI), months NR (NR–NR) 32.3(24.3–NR) NR(NR–NR) NR(NR–NR) 9.5(2.8–NR) 6.2(2.9–NR) NR(NR–NR) NR(NR–NR) Hazard ratio(95% CI) 0.73(0.51–1.06) 0.45(0.25–0.84) NC* 0.49(0.28–0.84) CI, confidence interval; NC, not calculable; NR, not reached. *NC due to <20 events between arms.