First exploration of the on-treatment changes in tumor and organ uptake of a radiolabeled anti PD-L1 antibody during chemoradiotherapy in patients with non-small cell lung cancer using whole body PET.

BACKGROUND: In patients with locally advanced unresectable non-small cell lung cancer (NSCLC), durvalumab, an anti-programmed cell death ligand-1 (PD-L1) antibody, has shown improved overall survival when used as consolidation therapy following concurrent chemoradiotherapy (CRT). However, it is unclear whether CRT itself upregulates PD-L1 expression. Therefore, this study aimed to explore the changes in the uptake of the anti PD-L1 antibody [89Zr]Zr-durvalumab in tumors and healthy organs during CRT in patients with NSCLC. METHODS: Patients with NSCLC scheduled to undergo CRT were scanned 7±1 days after administration of 37±1 MBq [89Zr]Zr-durvalumab at baseline, 1-week on-treatment and 1 week after finishing 6 weeks of CRT. First, [89Zr]Zr-durvalumab uptake was visually assessed in a low dose cohort with a mass dose of 2 mg durvalumab (0.13% of therapeutic dose) and subsequently, quantification was done in a high dose cohort with a mass dose of 22.5 mg durvalumab (1.5% of therapeutic dose). Tracer pharmacokinetics between injections were compared using venous blood samples drawn in the 22.5 mg cohort. Visual assessment included suspected lesion detectability. Positron emission tomography (PET) uptake in tumoral and healthy tissues was quantified using tumor to plasma ratio (TPR) and organ to plasma ratio, respectively. RESULTS: In the 2 mg dose cohort, 88% of the 17 identified tumor lesions were positive at baseline, compared with 69% (9/13) for the 22.5 mg cohort. Although the absolute plasma concentrations between patients varied, the intrapatient variability was low. The ten quantitatively assessed lesions in the 22.5 mg cohort had a median TPR at baseline of 1.3 (IQR 0.7-1.5), on-treatment of 1.0 (IQR 0.7-1.4) and at the end of treatment of 0.7 (IQR 0.6-0.7). On-treatment, an increased uptake in bone marrow was seen in three out of five patients together with a decreased uptake in the spleen in four out of five patients. CONCLUSIONS: This study successfully imaged patients with NSCLC with [89Zr]Zr-durvalumab PET before and during CRT. Our data did not show any increase in [89Zr]Zr-durvalumab uptake in the tumor 1-week on-treatment and at the end of treatment. The changes observed in bone marrow and spleen may be due to an CRT-induced effect on immune cells. TRIAL REGISTRATION NUMBER: EudraCT number: 2019-004284-51.

Predictive Value of Combined Positive Score and Tumor Proportion Score for Immunotherapy Response in Advanced NSCLC.

Introduction: In advanced-stage NSCLC, tumor proportion score (TPS) is typically used to predict the efficacy of immune checkpoint inhibitors (ICIs). Nevertheless, in other cancer types, the combined positive score (CPS), which covers programmed death-ligand 1 (PD-L1) expression on both tumor and surrounding immune cells, is used. We investigated the predictive value of CPS in comparison to TPS in advanced NSCLC. Methods: A monocenter, retrospective study was performed in patients with advanced NSCLC treated with ICI monotherapy between 2015 and 2021. Hematoxylin and eosin and PD-L1 were stained on baseline tumor biopsy samples to score PD-L1 by both TPS and CPS. Positivity for TPS and CPS was defined as a score of 1% or above. Progression-free survival and overall survival (OS) were assessed for TPS and CPS scores. Results: Among the 187 included patients, PD-L1 positivity was found in 112 patients (59.9%) by TPS and 135 patients (72.2%) by CPS. There was no significant difference in OS between TPS- and TPS+ patients (p = 0.20). Nevertheless, CPS+ patients did have a longer OS than CPS- patients (p = 0.006). OS was superior in both TPS-/CPS+ and TPS+/CPS+ as compared with TPS-/CPS- cases (p = 0.018 and p = 0.015, respectively), whereas no considerable differences in OS were found between TPS-/CPS+ and TPS+/CPS+ cases. Conclusions: This retrospective real-world population study revealed that CPS differentiated OS better than TPS in patients with advanced NSCLC with ICI monotherapy. Remarkably, this was driven by the performance of the TPS-/CPS+ subgroup, indicating that CPS may be a better predictive biomarker for ICI efficacy.

Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC.

Importance: Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy. Objective: To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin-stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022. Exposures: All patients received anti-PD-(L)1 monotherapy. Main Outcomes and Measures: Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR. Results: Overall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (≥250 cells/mm2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P = .006; OS: HR, 0.74; P = .03) and validation (PFS: HR = 0.80; P = .01; OS: HR = 0.75; P = .001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (<1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65). Conclusions and Relevance: In these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.

The effect of tumor size and metastatic extent on the efficacy of first line pembrolizumab monotherapy in patients with high PD-L1 expressing advanced NSCLC tumors.

BACKGROUND: Tumor size and metastatic extent may influence tumor response to immunotherapy in non-small cell lung cancer (NSCLC). The aim of this study was to examine the relationship between both baseline sum of longest diameters (bSLD) and number of metastatic organs (NMO) and the tumor response to pembrolizumab. Secondly, we aimed to analyze the association of baseline SLD and NMO with progression-free survival (PFS) and overall survival (OS). METHODS: This retrospective study included patients with high PD-L1 expressing tumors (≥50%) and a good performance score (ECOG ≤ 2) that received first-line pembrolizumab monotherapy. Tumor response was calculated as the 'SLD-change score' and 'early treatment discontinuation' within 3 months on therapy (ETD). The relationship of both bSLD (based on RECIST v1.1) and NMO with tumor response and survival outcome (PFS, OS) was evaluated. RESULTS: No significant differences in SLD-change score could be found using bSLD (OR = 1.010, 95%CI = 0.999-1.021), or using NMO at baseline (OR = 1.608, 95%CI = 0.943-2.743). A bSLD cut-off value of 90 mm was found to be most distinctive for ETD. This cut-off value showed a significant difference for PFS (HR = 2.28, 95%CI = 1.12-4.64, p = 0.023) and OS (HR = 2.99, 95%CI = 1.41-6.34, p = 0.004). NMO also showed a difference for PFS and OS, however, not statistically significant. CONCLUSIONS: Tumor size and metastatic extent could not discriminate for tumor response, however, a bSLD of 90 mm could differentiate for PFS and OS.