TEST:

VENTANA PD-L1 (SP142) Assay

These observations may help reconcile the discordant performance of the two PD-L1 assays in ICB-treated urothelial carcinoma while underscoring the role of dendritic cells in orchestrating ICB response. See related article by Galsky et al., p. XX .

Samples exhibiting discordant PD-L1 IHC and/or FISH structural abnormality patterns were shown to harbor PD-L1 SV by target-capture sequencing, with positive and negative predictive values of 94% and 96%, respectively. Our approach is an alternative to target-capture sequencing for evaluating PD-L1 gene abnormalities.

PD-L1 scoring by SP263 and 22C3 are interchangeable but not SP142 regardless of EGFR status. PD-L1 ITH was more common in EGFR-wildtype versus EGFR-mutant tumours. Extra care should be taken to select the most representative tumour core for tumours with high histological grade or TPS 1-49% as this may influence peri-operative treatment decisions.

P=N/A, N=64, Recruiting, Karolinska University Hospital | Trial completion date: May 2027 --> Mar 2025 | Trial primary completion date: Dec 2026 --> Dec 2024

The patient was started on atezolizumab+nab-paclitaxel(PTX)therapy, but progression disease(PD)was observed without obvious effect. Pembrolizumab+carboplatin+gemcitabine was started as second-line therapy, and the tumor achieved partial response(PR)but developed PD within 6 months. After that, she was administrated olaparib, but PD was observed, and after the therapy with PTX+bevacizumab, she is now treated with eribulin.

Multiplex IHC in an independent ICB-treated cohort confirmed that tumor cell-dominant PD-L1 expression was associated with shorter survival. Using different PD-L1 assays, we uncovered that SP142 may preferentially stain PD-L1-expressing DCs, key to orchestrating antitumor immunity, while tumor cell-dominant PD-L1 expression, which underlies a subset of "PD-L1 positive" specimens, is associated with poor ICB outcomes.

Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2- BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066.

P3, N=184, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Neoadjuvant immunotherapy had a more significant therapeutic effect on stage IIIA-N2 NSCLC patients by reducing immunosuppressive and inflammatory factors, improving immune function, and reducing the occurrence of adverse reactions.

P; With both SP142 and 22C3, we identified an intermediate IHC PD-L1 group within TNBCs that was supported on the molecular level. Any PD-L1 IHC expression, even though it is < 1, tended to have positive prognostic impact. We suggest that the generally accepted threshold of PD-L1 IHC positivity in TNBC should be investigated further. The Swedish Cancerome Analysis Network - Breast (SCAN-B) study was retrospectively registered 2nd Dec 2014 at ClinicalTrials.gov; ID NCT02306096.

Further refinement and a training protocol may be necessary to enhance the method's efficiency. The potential for generalizing this structured method to other IHC procedures and pathologies warrants additional research.

Patients who tested positive for IC had a significantly longer PFS than those who tested negative. Thus, PD-L1 expression may be a predictive factor of efficacy of chemoimmunotherapy in extensive-stage small cell lung cancer.

The prevalence of PD-L1 positivity among patients with stage III or IV TNBC was 37.7%. A significant association was noted between PD-L1 positivity and the tumor tissue obtained from resected specimens. Although the mechanism and clinical significance of this association remain unclear, this finding indicates a possible disparity in the PD-L1 status of samples obtained using surgical resection or biopsy.

There is significant heterogeneity in the TME and mutational profiles across LPS subtypes. MLS has a particularly immune-cold TME shown by lower infiltration of lymphocytes, T cell-inflamed scores, and PDL1+ prevalence, while DDLS has a relatively immune-hot profile. These findings are critical to develop immune modulatory strategies for LPS and provide novel insights for future studies.

DDR pathway alterations are present in numerous histologic subtypes of sarcoma. In many subtypes, DDR pathway-altered tumors were found to have increased rates of PD-L1+, dMMR/MSI-high, and TMB-high biomarkers commonly used to identify patients who may benefit from immunotherapy. Further studies to validate these associations are needed associations and could lead to a novel clinical trial exploring the use of immune checkpoint inhibitors in DDR-mutated sarcoma.

P1; Trial completion date: Mar 2026 --> May 2025 | Trial primary completion date: Feb 2026 --> Nov 2024

P2; Active, not recruiting --> Completed

BRCA mutation and PD-L1 positivity are higher in HER2-negative TNBC. Our study revealed that HER2-negative breast cancer has more basal-like clinicopathologic features, while HER2 Low TNBC has non-basal features.

Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w), in arm A preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy. To our knowledge our analysis is the largest prospective dataset regarding patients with eTNBC and low tumor burden treated with neoadjuvant chemotherapy and an immune checkpoint inhibitor. No significant differences were seen between treatment arms although numerically PD-L1 positive patients showed increased benefit from the immune therapy window. pCR rates were higher compared to the overall study population which may be attributed particularly to smaller tumor size.

Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w), in arm A preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy. In this analysis, the association between PD-L1 (IC) status and pCR rates could be reproduced in a subgroup of patients with =/> cT2 and/or N+ tumors. These results are in line with exploratory results of the NeoTRIP trial and the IMPASSION031 trial demonstrating an association of PD-L1 status with pCR rates after neoadjuvant Atezolizumab + chemotherapy in patients with high risk eTNBC similar to the population in this subgroup analysis. Our analysis in the largest group of patients with high risk eTNBC treated with neoadjuvant Atezolizumab + chemotherapy published to date demonstrated a significant association of PD-L1 status and pCR rates.

Patients were randomized 1:1 to receive either Standard of Care (SoC) or SoC plus the MUC1-based antitumor vaccine tecemotide... The results of this study indicate that in the ABCSG 34 trial, PD-L1 positivity as determined by IC and CPS was able to predict better DRFS and OS. However, in patients with residual tumor, an increase in CPS during treatment was associated with decreased OS - a result that needs to be interpreted with caution, since no "post treatment sample" can be accessed in cases of pCR. In addition, IRF1 expression both in tumor cells and TILs predicted an improved IDFS and DRFS.

This study showed in TN, TROP2 expression is notably higher in PD-L1 positive and TIL-high samples, and no significant correlation was found between TROP2 expression and inflammatory markers in the overall HER2-negative breast cancer. It provides the insight of the combination therapy of ICI and ADC targeting TROP2 in TN. Further research is warranted to explore these associations and develop personalized treatment approaches.

In eTNBC and mTNBC, PD-L1+ status was associated with more favorable long-term outcomes, possibly due to tumor-intrinsic characteristics and/or the host immune response. The vast majority of patients in the mTNBC cohort were diagnosed with de novo mTNBC; the temporal lack of PD-L1 expression and/or the lack of prior CT may contribute to diagnostic differences compared with clinical trial datasets.

The PD-L1+ prevalence in real-world samples by SP142 was lower in mTNBC vs eTNBC, by local vs central assessment, and in smaller vs larger samples. We observed lower PD-L1+ prevalence in the VANESSA real-world study than in reported prospective clinical trials assessing PD-L1 status centrally. These findings underline the importance of robust PD-L1 assessment to ensure optimal selection for therapies targeting PD-1/PD-L1 in patients with mTNBC.

The phase III IMpower110 trial differed in that regard, that it clinically evaluated both the PD-L1 TC and IC score as a predictive biomarker for Atezolizumab monotherapy in patients with metastasized or locally advanced NSCLC and gained market authorization for patients with high prevalence of PD-L1 on both tumor and/or immune cells: TC3 (≥50% TC/TPS score) and/or IC3 (≥10% IC score)...Furthermore, correlations to clinical important gene alterations will be presented. This shows that for appropriate treatment decisions by the treating physician according to different marketing authorizations it is of utmost importance that every NSCLC patient should be scored not only for PD-L1 TPS/TC but also for IC.

PD-L1 expression in ILC shows a low TC positivity rate (0-2%) with various antibody clones and a variable IC positivity rate (0-21.8%). Pleomorphic type ILC exhibits higher PD-L1 IC positivity.

The association between PD-L1 positivity and HPV positivity (78.57%) was confirmed by meta-analysis. The conclusion was that HPV-positive status has an impact on immunohistochemical expression of PD-L1 in OPSCC.

ACP1-High tumors exhibit a distinct molecular profile and cold TME, highlighting ACP1's potential role in PC pathogenesis and novel therapeutic targeting.

Assessing TB in surgical specimens can provide information about the response to treatments, such as immunotherapy, which have been introduced into the treatment of GC in recent years. In this study, we demonstrated the relationship between TB, PD-L1 and MSI status in GC: Low grade TB, assessed by methods H.Ueno and L.Wang, correlates with MSI-positive status, but not with PD-L1-status of GC.

The macroscopic form according to R. Borman, the morphological type according to the classification of WHO 5th edition, 2019, and the presence/absence of signet ring cells are statistically significant parameters, where there is a significant relationship with PD-L1 expression. Positive PD-L1 status is significantly more often detected in HBV-associated gastric carcinomas. An increase in the expression level of PD-L1 clones SP263 and SP142 are significant prognostic signs that reduce the likelihood of death in patients.

We have demonstrated statistically significant associations between manually assessed results and their matched DIA-derived quantitative scores. These results validate the manual assessment process and raise the possibility of supplementing the information fed-back to participants with fully quantitative data. The lack of associative evidence for the tonsil brings into question its usefulness as a control in this setting.

The digital cell counts demonstrated how immune markers are coexpressed in the TIME when considering TNBC molecular subtypes and DNA repair deficiency, and how combination of immune status with DNA repair deficiency status can improve the prognostic stratification in chemotherapy treated patients. These results underscore the value and potential of integrating TIME and specific tumour intrinsic alterations/phenotypes for the molecular understanding of TNBC.

The number of CD68- and/or CD163-positive cells increases with increasing PT histological grade, and these cells exhibit hybrid characteristics, resembling both histiocyte and myofibroblasts.

The incorporation of pre-treatment TILs and PD-L1 expression status as valuable tools for optimizing patient selection for immunotherapy and managing the risks associated with chemotherapy in Chinese TNBC patients.

Context: Pembrolizumab is US Food and Drug Administration (FDA)–approved for recurrent/metastatic cervical carcinomas with programmed death ligand-1 (PD-L1) combined positive score (CPS ≥ 1)... These data suggest that the Ventana SP263 assay may be a reasonable surrogate for 22C3 pharmDx in aggressive CVCs being considered for anti-PD-1 therapy, but the Ventana SP142 is unlikely to be a reliable surrogate in this setting. Larger studies are needed to prove reproducible interchangeability based on College of American Pathologists recommendations.

In primary SCCs, the expression of PD-L1, PD-1, and CD8 are not associated with high-risk clinicopathological factors. We suggest that these immunohistochemical markers are more significant in advanced cases and metastatic tissues.

P3; Trial primary completion date: Jan 2024 --> Dec 2024

SCL5A2-H across all investigated tumors was associated with increased immune infiltrate and a T cell-inflamed phenotype in addition to improved survival in multiple cancer types. Future research on SGLT2 should delineate its role in cancer formation versus its association as a potential positive prognostic marker.

FAP is a marker for cancer-associated fibroblasts and is linked to immunosuppression and neoangiogenesis, which makes future investigation clinically relevant. We found that progression of high-risk non-muscle-invasive bladder cancer to muscle-invasive disease is less in patients with lower fibroblast activation protein-α (FAP) expression, which is a marker for cancer-associated fibroblasts.

Characteristic Overall Training Set Testing Set N 348 279 69 sex (%) female 165 (47.69) 125 (45.13) 40 (57.97) male 181 (52.31) 152 (54.87 29 (42.03) age (%) old 188 (54.34) 158 (57.04) 30 (43.48) young 158 (45.66) 119 (42.96) 39 (56.52) Smoking (%) no 220 (86.96) 174 (86.57) 46 (88.46) yes 33 (13.04) 27 (13.43) 6 (11.54) Stage (%) I 71 (20.52) 48 (17.33) 23 (33.33) II 95 (27.46) 80 (28.88) 15 (21.74) III 168 (48.55) 139 (50.18) 29 (42.03) IV 12 (3.47) 10 (3.61) 2 (2.90) PD-L1_score (%) ≥ 50% 45 (12.93) 37 (13.26) 8 (11.59) < 1% 156 (44.83) 125 (44.80) 31 (44.93) 1-49% 147 (42.24) 117 (41.94) 30 (43.48) PD-L1_clone (%) 22C3 330 (94.83) 264 (94.62) 66 (95.65) SP142 17 (4.89) 14 (5.02) 3 (4.35) ZR3 1 (0.29) 1 (0.36) 0 (0.00) Pathology (%) LUAD 288 (83.48) 231 (83.70) 57 (82.61) LELC 9 (2.61) 4 (1.45) 5 (7.25) other 12 (3.48) 9 (3.26) 3 (4.35) LUSC 36 (10.43) 32 (11.59) 4 (5.80) Figure 1. Model Evaluation of Testing Set (A) and ROC of Two Sets (B).

Overall, our findings suggest that a subset of MBC and GCS cases may benefit from immune checkpoint inhibitor therapy. Our findings also illustrate unique aspects of PD-L1 expression patterns in these tumors which may harbor additional prognostic and therapeutic significance.

"High TLS gene expression signatures, particularly in the highest quartile, are associated with favorable outcomes in patients with high TMB or MSI-High status treated with pembrolizumab. These findings suggest that TLS status could serve as a potent biomarker to stratify patients more likely to benefit from ICI therapy, advocating for its integration into routine clinical assessments prior to ICI treatment in these specific group of patients."