Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers
. Biomarkers may facilitate identification of these ...responding tumors
. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer
. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
Neoadjuvant immunotherapies hold promise in muscle-invasive bladder cancer (MIBC).
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.
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.
Two cycles of atezolizumab were given prior to radical cystectomy. Serial tissue and blood samples were collected.
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.
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.
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.
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.
Abstract only
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Background: Biomarker analysis predicting outcome with neoadjuvant atezolizumab in muscle invasive bladder cancer (MIBC) was performed. This includes previously unreported findings ...with FOXP3 and MHC1. Methods: Sequential tissue obtained from 95 patients in the ABACUSstudy (NCT02662309) which investigated two cycles of atezolizumab prior to cystectomy in MIBC patients. Multiplex immunohistochemistry staining, Foundation One analysis and RNA sequencing was performed on paired pre- and post- treatment samples. CD8+ T cells, fibroblast activation protein (FAP), granzyme – B (GZMB), FOXP3, MHC1, PD-L1 expressions were analyzed and correlated with outcome. Results: After a median follow up of 13.1 months, 31% had a pathological complete response (pCR) and 18% have relapsed. 40% were PD-L1 positive at baseline and 73%, 19% and 8%had inflamed, excluded and desert phenotype respectively. CD8/GZMB and CD8/MHC1 expression prior to therapy was significantly associated with response in inflamed tumors. CD8, PDL1, GZMB and MHC1 expression all increased with treatment in this group of patients. Immune desert phenotype at baseline, showed low and static expression of immune biomarker. TGFb correlated with relapse in excluded phenotypes. Treatment was associated with increase in cell cycle genes and FAP, both of which were associated with relapse. FOXP3 expression correlated with CD8 and increased with therapy in responding tumors. Combining FAP (high) to CD8 (low) and MHC1 (low) increased the positive predictive value for relapse. TMB did not correlate with outcome or increase with therapy. FGF DNA alterations were associated with response. Conclusions: MIBCs have high T effector immune expression, which may account for high pCR rates. Biomarkers at baseline and after treatment can predict outcome. Assessment of multiple biomarker within algorithms improves accuracy in predicting outcome. FOXP3 expression correlates with activated T cell expression, potentially accounting for the counterintuitive findings. Clinical trial information: NCT02662309.
The reaction of homophthalic anhydride with 1
H
-indol-3-carbaldimines was used for the preparation of
trans
- and
cis
-2-alkyl-3-indolyl-1-oxotetrahydroisoquinolin-4-carboxylic acids
3a–d.
The ...stereochemistry of the reaction was investigated by means of
1
H NMR spectroscopy. The carboxylic group of
trans
-
3a–d
was transformed stereoselectively via 4-hydroxymethyltetrahydroisoquinolin-1-ones into 4-(phthalimidomethyl)-derivatives
trans
-
6a,b
and 4-(imidazolylmethyl)-derivatives
trans
-
8b–d
. Compounds
trans
-
6a,b
and
8b–d
were tested for antiaromatase activity, and the preliminary results showed that the phthalimidomethylisoquinolinone
trans
-
6b
at 50 μM concentration decreased the aromatase enzyme activity with 40%.
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