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.
High levels of evidence from randomised trials and meta-analyses demonstrate an absolute overall survival (OS) benefit of 5-8% for cisplatin-based neoadjuvant chemotherapy (NAC) in patients with MIBC, before radical cystectomy (RC) and pelvic lymph node dissection (PLND) [1-2]. This is currently the standard treatment for patients with non-metastatic MIBC according to both EAU and AUA Guidelines. Nevertheless, up to 50% of patients are unfit to receive cisplatin-based chemotherapy and will instead undergo upfront RC with lower chances of survival.
Inhibition of the PD-1/PD-L1 checkpoint has demonstrated significant benefit in patients with unresectable and metastatic BC in the second-line setting and in platinum-ineligible PD-L1+ patients as first-line treatment using different agents. Additionally, checkpoint inhibitors are increasingly tested also in the neoadjuvant setting either as monotherapy or in combination with chemotherapy or CTLA-4 checkpoint inhibitors.
Out of these, atezolizumab and pembrolizumab have been investigated in the neoadjuvant setting in the first publication from the ABACUS trial [3], in the PURE-01 trial [4] and in other available clinical trials. Despite that, immunotherapy alone, or in combination, is not yet approved in the neoadjuvant setting.
In their novel publication from the ABACUS phase II trial, Szabados and colleagues [5] report the final result on two-year disease-free (DFS) and overall (OS) survival including novel tissue-based biomarkers and circulating tumour DNA (ctDNA).
The primary endpoint analysis was focused on pathologic complete response (pCR), showing pCR rate of 31% (95% CI 21–41) in all patients and 37% (95% CI 22–55) in PD-L1–positive patients and correlated biomarkers (CD8+ T cells, PD-L1, TMB, fibroblast activation protein [FAP], and CD8+/GZMB+ double positive T cells) with the pCR. Moreover, in the novel publication, the focus of this secondary endpoint highlighted new associated biomarkers interacting with the survival estimates including new (forkhead box P3 protein [FOXP3], major histocompatibility complex [MHC] class I molecules, and CD8+/CD39+ double positive T cells.
In summary, the ABACUS trial is a multicenter, single-arm, phase 2 trial that investigated two cycles of neoadjuvant atezolizumab in patients with histologically confirmed MIBC (T2-4aN0M0) who were either ineligible for or refused cisplatin-based neoadjuvant chemotherapy. Participants were planned to receive two cycles of 1200 mg atezolizumab in 21-d cycles and scheduled to undergo RC and pelvic lymph node dissection 4–8 weeks following enrollment. Exploratory biomarker analysis was conducted on both baseline and matched cystectomy samples. Secondary endpoints included DFS (time from enrollment until relapse or death, whichever occurred first), OS (time from enrollment until death due to any cause), safety assessments, and surgical complication rates.
Between May 2016 and June 2018, 95 patients were prospectively accrued and received experimental medication. Of these, 87 patients underwent RC and the median follow-up was 25 months (95% CI 25–26).
The 2-yr DFS rate was 68% (95% CI 58–76). The 2-yr DFS rate in patients with a pCR was 85% (95% CI 65–94). Higher T-stage (T3–4) both at baseline (hazard ratio [HR] 2.4 [95% CI 1.0–5.6], p = 0.045) and at cystectomy (HR 13 [95% CI 3.7–43], p < 0.001), and node-positive disease at surgery (HR 6.6 [95% CI 2.4–18], p < 0.001) correlated with poor DFS. The two-year OS rate was 77% (95% CI 68–85).
Regarding the association of biomarker expression and clinical outcome Baseline PD-L1 and tumour 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 tumour 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 points4], p = 0.22) or TMB (RR 0.80 [95% CI 0.38–1.7], p = 0.54) and relapse.
In conclusion, the first message from this secondary analysis of the ABACUS trial is of great clinical importance, sustaining the role of neoadjuvant immunotherapy as a feasible and life-saving option for cisplatin-ineligible patients resulting in reliable clinical response and high DFS in lieu of no new safety signals for adverse events and surgical treatment not being associated with increased risk for intra/postoperative complications.
Additionally, exploratory pre-and post-treatment biomarker analyses including a serial ctDNA analysis correlated with outcomes and may inform the development of personalised therapy in the future.
References