Introduction

Immune checkpoint Inhibitors (ICIs) such as Atezolizumab/Bevacizumab (ATEZO/BEV) and Tremelimumab/Durvalumab (STRIDE) have shown promising results compared to Sorafenib in treating patients with advanced HCC. However, with median follow-up durations of 18 months and 33 months in the IMbrave150 and HIMALAYA trials respectively, the long-term survival outcomes of these therapies remain unknown. This study aims to predict the long-term survival outcome of these therapies through a reconstructed individual participant data meta-analysis.

Aims & Methods

Medline and Embase databases were searched for relevant studies. We included Phase II – IV randomized controlled trials (RCTs) with Kaplan-Meier survival curves on the use of Sorafenib in treating advanced HCC. We identified studies relating to the use of ATEZO/BEV or STRIDE in patients with advanced HCC. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). We extracted individual patent data using the methods outlined by Guyot et al¹ and conducted an aggregate pooling with the arcsine-transformed survival probabilities in a random effects model using MetaSurv to predict long-term survival outcomes at 12, 36 and 60 months follow-up. Restricted mean survival time (RMST) analysis was used to estimate the survival benefit of ATEZO/BEV or STRIDE versus Sorafenib at 60-months follow-up.

Results

A total of 29 RCTs were included, with 336, 393 and 5525 individuals treated with ATEZO/BEV, STRIDE and Sorafenib respectively. The median OS for patients on ATEZO/BEV, STRIDE and Sorafenib were 19.1 months (CI: 17.1 – 23.9) 16.4 months (CI: 14.5 – 20.4) and 10.8 months (CI: 10.5 – 11.2) respectively. The predicted 12-, 36- and 60-months survival for patients receiving ATEZO/BEV was 60.51% (CI: 59.32 – 61.88%), 27.08% (CI: 24.93 – 29.28%) and 18.21% (CI: 13.38 – 23.65%) respectively. The predicted survival at 12-, 36-, and 60-months for patients receiving STRIDE was 55.23% (CI: 53.95 – 56.49%), 21.36 (CI: 19.37% - 23.42%) and 13.36% (CI: 9.27 – 18.20%) respectively. Compared to Sorafenib, the mean survival of ATEZO/BEV and STRIDE were 4.68 months (CI: 2.40 – 6.95 months) and 3.25 months (CI: 1.16 – 5.34 months) longer respectively. RMST analysis revealed no significant difference in OS between ATEZO/BEV versus STRIDE at 12-, 36-, and 60-months. The median PFS was 6.90 months (CI: 5.80 - 8.30), 3.85 months (CI: 3.67 - 5.35), and 4.07 months (CI: 3.81 - 4.18) for ATEZO/BEV, STRIDE, and sorafenib respectively. At 44-months, ATEZO/BEV had a statistically significantly longer PFS of 2.92 months (CI: 1.21 – 4.63 months, p<0.01) compared to STRIDE.

Conclusion

Compared to Sorafenib, there is projected clinically meaningful increases survival of ATEZO/BEV and STRIDE relative to Sorafenib. In addition, an extended analysis of PFS to 44-months suggests a significantly longer PFS of ATEZO/BEV over STRIDE. Our study suggests that ICIs could be considered as first-line agents in treating advanced HCC. However, these data are based on historical survival data from sorafenib and there is still limited data for the respective ATEZO/BEV and STRIDE treatment regimes. There remains a need for further studies to better define the sequencing of therapies beyond the first-line setting.

References

1. Guyot P, Ades AE, Ouwens MJNM, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Medical Research Methodology. 2012;12(1):9.

Introduction

Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor. Few patients benefit from second-line chemotherapy, while most experience side effects, highlighting the need for biomarkers. The PREDICT trial examined in aPDAC patients whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) but found no association. In our translational study we hypothesized that the responsiveness of the tumor immune microenvironment (TiME) might determine second-line therapy outcome and examined whether treatment-naive tissue immune features are also reflected in the peripheral blood after one line of chemotherapy.

Aims & Methods

In the PREDICT trial, patients received 5-FU/LV plus nanoliposomal irinotecan second-line after gemcitabine/nab-paclitaxel (Gem-nabPac) first-line therapy. We stratified PREDICT patients by shortest vs. longest TTF2. Treatment-naive primary tumor tissues from 20 patients were analyzed by NanoString transcriptomic profiling and multiplexed immunohistochemistry to characterize differences in the TiME. Peripheral blood mononuclear cells (PBMCs) were obtained immediately before second-line therapy from 82 patients and analyzed using multiparameter flow cytometry with an automated gating procedure and gene expression profiling via RT-qPCR. A feature selection and machine learning pipeline integrated PBMC and clinical data to derive a minimal predictor for TTF2 outcome and prognosis that was validated across different treatment regimens on an independent external cohort of 30 patients with aPDAC.

Results

Treatment-naive tumors of patients in the long-TTF2 group exhibited an immune-active (“hot”) TiME with CXCR3⁺ CD8⁺ cytotoxic T cell infiltration into the cancer cell compartment via CXCR3-dependant inflammatory chemokine signaling. Analysis of PBMCs obtained directly before second-line therapy showed that these immune features were sustained over one line of treatment and reflected in PBMCs. A PBMC-based machine learning model (“TTF2Pred”) identified a 7-feature immune signature that accurately distinguished long vs. short TTF2 patient groups outperforming multivariate clinical data or CA19-9 benchmark models. TTF2Pred robustness was confirmed by external validation and showed the best overall performance post-Gem-nabPac first-line treatment. Among the seven TTF2Pred features, long-TTF2 patients exhibited more circulating CXCR3⁺ activated T cells and plasmacytoid dendritic cells, while short-TTF2 patients had more circulating platelet–leukocyte (platelet-monocyte, platelet-neutrophil) aggregates and exhausted T cells.

Conclusion

PDAC patients with an immune-active, treatment-naïve TiME have a better outcome on second-line therapy, and these tissue characteristics are reflected in circulating PBMCs after one line of chemotherapy. A parsimonious circulating PBMC-based signature offers a minimally invasive predictor of second-line outcome that could inform personalized therapy.

Introduction

Recent advances in treatment approaches for lesions around 20 mm in size including wide-field endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), or endoscopic full-thickness resection (EFTR), increase the importance of the accuracy in tumor size measurement due to higher risks of perforation in en bloc EMR for lesions ≥25 mm⁽¹⁾, unexpectedly prolonged operation time in ESD, or incomplete resection in EFTR for lesions ≥20 mm⁽²⁾. However, available data on the accuracy of tumor size measurement for lesions ≥20 mm is scarce.

Aims & Methods

We aimed to assess the accuracy and the presence of biases in tumor size measurement for lesions ≥20 mm, and factors related to underestimated lesion size as 20 mm using large-scale, prospectively-collected data from en bloc resected specimens. In this post-hoc analysis of an ESD cohort study, pathologically-proven colorectal epithelial neoplasms resected in en bloc fashion were included from the data of the CREATE-J study^{(3, 4)}. Exclusion criteria were neuroendocrine tumor, residual or recurrent lesions after previous treatments, colitis-associated dysplasia, or insufficient data. The reference standard was pathologically-measured lesion size. Study measurements were endoscopic measurement accuracy defined within a 5 mm margin of error, the proportion of lesions with a size discrepancy ≥10 mm or ≥20 mm, and terminal digits preferences in endoscopically assessed lesion size. In addition, we examined characteristics and predictors of endoscopically 20 mm lesions with pathologically ≥ 25 mm size.

Results

Of 1889 en bloc resected lesions in 1809 patients, a total of 61 lesions (14 neuroendocrine tumors, 34 residual lesions, 4 colitis-related lesions, and 9 lesions with insufficient data) in 60 patients were excluded. Finally, 1828 lesions in 1749 patients were analyzed. The accuracy of endoscopic measurement in total, 20-29 mm, 30-39 mm, and 40- mm size categories was 53.4%, 63.7%, 47.5%, and 40.3%, respectively. Discrepancies of ≥10 mm or ≥20 mm occurred in 19.1% and 4.5% of lesions, respectively. Size measurement inaccuracies tended to be more frequent with increasing endoscopic lesion size (Table). In terminal digits of an endoscopic size measurement, endoscopists strongly preferred to select 0 (65.2%, 1192/1828) or 5 (30.0%, 548/1828). Of 366 endoscopically 20 mm lesions, 26.7% were found to be pathological ≥ 25 mm lesions. Multivariate analysis revealed that endoscopic 20-mm sized lesions with pathological ≥ 25-mm were significantly associated with polypoid lesions [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.1-6.8] and laterally spreading tumors granular type (OR 2.0, 95% CI: 1.1-3.5).

Table. Lesions with the difference between endoscopic and pathologic lesion sizes ≥ 10 mm and ≥ 20 mm

Conclusion

Colonoscopists may be inaccurate and biased in the measurement of lesion size in large colorectal lesions. These findings suggest potential risks associated with size-based therapeutic decisions for large colorectal lesions ≥20 mm.

References

1. Burgess NG, Bassan MS, McLeod D, Williams SJ, Byth K, Bourke MJ. Deep mural injury and perforation after colonic endoscopic mucosal resection: a new classification and analysis of risk factors. Gut. 2017;66(10):1779-89.
2. Didden P, van Eijck van Heslinga RAH, Schwartz MP, Arensman LR, Vleggaar FP, de Graaf W, et al. Relevance of polyp size for primary endoscopic full-thickness resection of suspected T1 colorectal cancers. Endoscopy. 2022;54(11):1062-70.
3. Kobayashi N, Takeuchi Y, Ohata K, Igarashi M, Yamada M, Kodashima S, et al. Outcomes of endoscopic submucosal dissection for colorectal neoplasms: Prospective, multicenter, cohort trial. Dig Endosc. 2022;34(5):1042-51.
4. Ohata K, Kobayashi N, Sakai E, Takeuchi Y, Chino A, Takamaru H, et al. Long-term Outcomes After Endoscopic Submucosal Dissection for Large Colorectal Epithelial Neoplasms: A Prospective, Multicenter, Cohort Trial From Japan. Gastroenterology. 2022;163(5):1423-34.e2.