TEST:

VENTANA PD-L1 (SP263) Assay

P1/2, N=60, Completed, MedPacto, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> May 2024

PD-1 expression on immune cells is associated with a lower recurrence rate in HCC, suggesting a role in HCC recurrence. The therapeutic use of adjuvant anti-PD-1 antibodies should thus be viewed critically and investigated further.

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.

These results indicate that while there is strong interobserver concordance among pathologists at higher TPS levels, the performance of AI algorithms is less consistent. The study underscores the need for further refinement of AI tools to match the reliability of expert human evaluation, particularly in critical clinical decision-making contexts.

PD-L1 expression may differ between preoperative biopsy specimens and surgical specimens. PD-L1 expression evaluated using small biopsy specimens may be largely influenced by chance due to intra-tumoral heterogeneity.

P3, N=1210, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P=N/A; Recruiting --> Completed | Phase classification: P2 --> PN/A | N=30 --> 15 | Trial completion date: Jun 2024 --> Nov 2024 | Trial primary completion date: Jun 2023 --> Oct 2024

In this controlled experiment the PD-L1 assays 28-8 and SP263 concordance was high. The scoring algorithms for GEJ, GC, and EAC samples were observed as highly correlated; minor differences were likely driven by the distinct PD-L1 monoclonal antibody clones utilized in the IHC assays. These data suggest that the 2 assays are comparable for evaluating PD-L1 expression at the TAP ≥ 5% and CPS ≥ 5 cutoffs.

P2; Trial completion date: Feb 2025 --> Sep 2025 | Trial primary completion date: Feb 2025 --> Sep 2025

P1; Suspended --> Active, not recruiting

Higher CD8+ T cell density was a prognostic marker for disease-free survival in EC, including within NSMP (p<0.05). In summary, the four WHO molecular subtypes of EC exhibit distinct TIME subtypes, complementing molecular classification and providing insights for optimizing EC immunotherapy strategies.

P1/2; Phase classification: P1b/2a --> P1/2 | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Oct 2022 --> May 2024

P3; Trial completion date: Apr 2035 --> Sep 2033 | Trial primary completion date: Jun 2029 --> Aug 2032

In conclusion, our results indicate that histopathologic findings in patients treated with ICI therapy are not diagnostic and varied. Additionally, these results are in line with recent studies showing an expansion on CD8+ T cell subset in patients under ICI treatment and highlight the synergism of polytherapy.

P3; N=290; Not yet recruiting; Sponsor:ETOP IBCSG Partners Foundation

KRAS mutation status did not significantly influence ICI efficacy, although a non-significant trend towards better survival was observed in KRAS-MT patients treated with first-line ICI. These findings contribute to the ongoing research in this field.

OS subgroup analysis showed comparable treatment effect by TAP score at 10% cutoff, CPS at cutoff 10, and TC score at 1% cutoff. TAP score and CPS at these cutoffs exhibited substantial concordance. Results indicate that the quicker, visually estimated TAP score and CPS may be interchangeable for clinical measurement of PD-L1 expression in patients with ESCC.

P2; Phase classification: P3 --> P2 | Trial primary completion date: Aug 2024 --> May 2027

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

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.

Multivariate analysis identified tumor size as an independent predictor of overall survival. These findings emphasize the relevance of TIME characteristics in understanding LR-HCC and point to promising avenues for targeted and immune-based therapies, contributing to the optimization of clinical management for this distinct cancer subtype.

Background Neo-CheckRay (NCT03875573) demonstrated high rates of pathological complete response (pCR) after immune-modulating stereotactic body radiation therapy (iSBRT) to the primary BC in combination with the anti-PD-L1 durvalumab (durva) in high-risk early-stage luminal BC...Pts were randomized 1:1:1 to ARM 1: paclitaxel q1w x12 with iSBRT at week 4 (3x8 Gy targeting the primary tumour, avoiding lymph nodes and normal breast tissue), followed by dose-dense epirubicin/cyclophosphamide q2w x4; ARM 2 : arm 1 + durva q4w x5; and ARM 3 : arm 1 + durva + oleclumab (anti-CD73) q2w x4 then q4w x3...Table: 2O All Arm 1 Arm 2 Arm 3 n 135 45 45 45 pts, % B: PD-L1 negative* 58.5 57.8 57.8 60.0 W6: no tumor 32.2 13.5 46.3 34.9 W6: TILs increase 14.0 16.2 12.2 14.0 W6: PD-L1 IC increase 42.7 31 48 48 pCR rate, % All pts 28.9 17.8 33.3 35.6 B: PD-L1 negative* 24.0 3.8 34.6 33.3 W6: no tumor 48.7 40.0 47.4 53.3 W6: TILs increased 17.6 0.0 20.0 33.3 W6: PD-L1 IC increased 24.0 0.0 46.0 40.0 TILs: pts, % B: TILs ≥ 1% 51.5 51.2 50.0 53.3 W6: TILs ≥ 1% 26.8 28.1 27.3 25.0 PD-L1: pts, % B: PD-L1 IC ≥ 1% 57.0 57.8 57.8 55.6 W6: PD-L1 IC ≥ 1% 70.5 48.3 85.7 82.1 B: PD-L1 TC ≥ 1% 22.2 24.4 17.8 24.4 W6: PD-L1 TC ≥ 1% 29.9 13.8 42.9 37.0 B: PD-L1 CPS ≥ 1% 39.3 37.8 40.0 40.0 W6: PD-L1 CPS ≥ 1% 54.5 37.9 66.7 63.0 B, baseline; pts, patients; W6, week 6. *Stratification factor.Conclusions In pts treated with iSBRT+durva, PD-L1 increase or absence of tumor at W6 is associated with higher pCR rate at surgery.

The majority of patients received ICIs during second line therapy or beyond as opposed to first line therapy (148, 56% vs 114, 44%), with 201 patients (77%) receiving nivolumab (SD – 94, LD – 107) and 61 patients (23%) receiving pembrolizumab (SD-60; LD-1). No differences in OS were seen between the LD-ICI and SD-ICI cohorts, whether used initially or during later lines of therapy (p=0.988).Conclusions The use of a CPS cutoff >=5 for predicting outcomes in MSS advanced gastric adenocarcinomas probably needs to be standardized with respect to various platforms and re-visited for relevance in real world practice. Low dose immune checkpoint inhibitors can be evaluated in combination with chemotherapy in patients where standard dosing is not feasible due to logistics, pending evidence from prospective trials.

This preliminary study supports the use of AI algorithms for the scoring of PD-L1 and TILs in patients with NSCLC.

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.

Updated analyses from POSEIDON after median FU of >5 y showed durable long-term OS benefit with the approved regimen of T+D+CT (vs CT alone). These results support its use as a 1L treatment option for pts with mNSCLC, including harder-to-treat subgroups such as those with PD-L1 TC <1%.

The updated findings, based on greater EFS maturity and further follow-up, are expected to shed further light on the full clinical benefit of the perioperative regimen with durvalumab and longer-term safety of this regimen.

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.

P1; Recruiting --> Suspended

At the inverse probability of treatment weighting analysis used to balance baseline covariates, the uPath categories confirmed to be independently associated with OS and PFS. This preliminary analysis suggests that AI-based, digital pathology tools such as uPath PD-L1 (SP263) can be used to optimize already available biomarkers for immune-oncology treatment in patients with NSCLC.

When we replaced FVC (%) in the multivariable analysis with forced expiratory volume in 1 s (%), diffusing lung capacity for carbon monoxide (DLco; %), or DLco (absolute), each of the pulmonary function factors showed a significant association with iOS. Pre-immunotherapy FVC (%) predicted immunotherapy-related outcomes in NSCLC patients, regardless of initial stage at diagnosis and prior treatment modalities.

Our results indicate a high intratumoral heterogeneity evaluated with 99mTciPD-L1 SPECT/CT that does not fully correlate with FDG, these preliminary findings may help explain discrepancy in biopsy sites; Therefore, this new imaging tool could be a potential diagnostic biomarker for selection and response to immunotherapy, as well as auxiliary in biopsy sampling.

P2, N=0, Withdrawn, Nykode Therapeutics ASA | N=130 --> 0 | Recruiting --> Withdrawn

A subset of PTC showed co-expression of PD-L1 and CTLA-4. These findings suggest the need for further investigation to utilise combinational immunotherapy, including anti-PD-L1 and anti-CTLA-4.

V3 patients had poor outcomes regardless of PD-L1 status, while V1 patients with PD-L1 negativity had better outcomes. These biomarkers offer key insights into treatment outcomes for ALK-positive patients.

Albeit PD-L1 scoring is challenging, it provided at least moderate interobserver agreement in our study. TPS demonstrated the highest, while IC exhibited the lowest concordance. As threshold values changed, the interobserver agreement varied.

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.

In conclusion, our study validates the feasibility and accuracy of PD-L1 IHC on cytology cell blocks and direct smears for NSCLC, showing high concordance, despite occasional discrepancies likely due to intratumoural heterogeneity. These findings underscore cytology’s utility in PD-L1 assessment for NSCLC management, confirming its potential as an alternative when formalin-fixed paraffinembedded specimens are unavailable. This supports the use of cytology samples in clinical decision-making and highlights the need for specialized training in PD-L1 interpretation.

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.

Neuroblastoma is not generally a highly immunogenic tumour. However, in the present study, we have found a good percentage of these tumours with PD-L1 expression; this expression appears to be higher in better differentiated tumours, e.g. differentiating neuroblastoma and nodular ganglioneuroblastoma. This finding may represent a new potential therapeutic target for these tumours.

Our study showed the heterogeneity in PD-L1 expression with respect to major oncogenic drivers in Turkey. KRAS, BRAF, MET mutations and ALK and ROS1 rearrangements were more frequent, while EGFR and HER2 mutations were less frequent compared with the overall PD-L1 expression levels. Molecular testing of non-small cell lung carcinomas (NSCLC) for oncogenic driver mutations has become standard in pathology practice.

PD-L1 expression was significantly correlated with tumour location using the 22C3 pharmDx assay (CPS, p=0.014; TPS, p=0.033). Notable concordance was found among PD-L1 assays, suggesting their potential interchangeability in HNmSCC.