TEST:

VENTANA PD-L1 (SP263) Assay

PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.

P1/2, N=88, Active, not recruiting, Galecto Biotech AB | Recruiting --> Active, not recruiting | Trial completion date: Apr 2024 --> Nov 2025 | Trial primary completion date: Jul 2023 --> May 2024

PD-L1 expression in NSCLC is associated with adverse clinicopathological features and recurrence; therefore, it could be utilized to predict poor prognosis. Furthermore, the high PD-L1 expression of SP142 in tumor-infiltrating ICs could be a potential marker for low metastasis.

Digital pathology may help in PD-L1 scoring, serving as a second opinion consultation platform in challenging cases. Computational and artificial intelligence tools will improve clinical decision-making and patient outcomes.

PD-L1 CDx assays are critical for patient selection for anti PD1/PD-L1 checkpoint inhibitor treatment. Recently, it was reported that post translational modifications on PD-L1 can affect antibody detection thereby resulting in false negative diagnosis in a PD-L1 CDx assay.Using whole slide digital image analysis, quantitative mass spectroscopy and immunohistochemistry, we have developed and validated a multimodality workflow to quantitatively characterize total and glycosylated PD-L1 levels in FFPE tumor resections.We have investigated the impact of PD-L1 glycosylation on the detection sensitivity for two different PD-L1 antibody clones (73-10 and SP263) that are used in CDx assays and demonstrate that these clones are not affected by this post-translational modification.

"72% of HNSCC patients in our cohort showed PD-L1 positivity and it was not associated with any patient demographic characteristics or aggressive pathological features. Positive PD-L1 expression may have a beneficial effect on overall survival in HNSCC."

The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.

P3, N=30, Completed, AstraZeneca | Active, not recruiting --> Completed

P3, N=169, Active, not recruiting, Arcus Biosciences, Inc. | Recruiting --> Active, not recruiting | N=750 --> 169

Integrating MIBC subtyping, IHC of immune markers and patient outcomes data provides a biological framework that allows for potential biomarker identification for this lethal disease. The studies presented here underscore the existence of heterogeneity in immune phenotypes within tumor subtypes. A deeper understanding of the association between these tumor subtypes and their immunological states is crucial to guide treatment decisions, particularly for patients facing worse prognostic outcomes.

In this work, we present PD-L1 Quantitative Continuous Scoring (PD-L1 QCS) to digitally assess PD-L1 expression (Ventana SP263 assay), and analyze its utility for identification of patient subgroups with higher likelihood of treatment response. 368 digitized whole slide images (WSI) of fresh biopsy and archival samples were obtained from the PACIFIC trial (NCT02125461), including 126 patients who received placebo and 242 patients who received Durvalumab post-cCRT [1]... We investigated a computational pathology approach for selecting patients for treatment with the PACIFIC regimen and compared it against established manual pathology scoring. Results indicate that PD-L1 QCS TC proportion scoring can increase prevalence, while PD-L1 QCS TC density scoring has the potential to identify an even larger patient subgroup with increased survival benefit.

For the threshold of TPS≥1% (cut-off established for adjuvant therapy with Nivolumab), agreement rates of AI scores with human GT scores were 92.5% for cohort 1 (22C3) and 96.4% for cohort 2 (SP263)... Across 136 UC samples stained with two PD-L1 antibody clones, and derived from a total of four institutions and three scanner models, the fully automatic AI system showed excellent agreement with human pathologist scores. These results on challenging validation data show the potential of AI applications to standardize and optimize PD-L1 scoring and demonstrate consistency and safety of suitable AI-based systems for application in clinical routine.

Eligible patients with completely resected stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) received one to four 21-day cycles of cisplatin-based doublet chemo and were subsequently randomized 1:1 to receive atezo 1200 mg q3w (16 cycles) or BSC. AEs leading to atezo discontinuation occurred in 21.3% of patients treated with atezo.Conclusions The IMpower010 Asian subpopulation showed an OS trend favoring atezo vs BSC in the PD-L1 TC ≥1% stage II-IIIA population, as was observed in the global population, although OS data were not formally tested in either population at the first OS IA. With longer follow-up, the safety findings for atezo in the IMpower010 Asian subpopulation remained broadly unchanged, were consistent with those of the global IMpower010 population and were in line with the known safety profile of atezo.

Introduction IMpower151 (NCT04194203) was a phase 3 study to evaluate the efficacy and safety of atezolizumab, bevacizumab, carboplatin, plus paclitaxel or pemetrexed (ABCP) vs BCP, as 1L treatment for metastatic nsqNSCLC. This finding is based on the exploratory analysis of a single clinical trial with limited sample size. It needs further investigation in other cohorts of tumor tissues and with larger clinical potential in blood samples as well.

Anti-TIGIT MOA-related genes and signatures correlated with efficacy in ociperlimab + tislelizumab-treated 1L PD-L1+ NSCLC. Combining anti-TIGIT MOA-related factors with PD-L1 expression identified a subgroup of patients with improved efficacy.Table. Efficacy Analyses in Patient SubgroupsCutoff: aTop 1/3; bMedian; cTC≥25%

Next, the approach was compared against manual TC scoring at 1%, 25% and 50% cut-off. In durvalumab treated patients, median overall survival (mOS) in the PD-L1 QCS BM+ subgroup (prevalence 54.3%) was 12.1 months longer than in the BM- subgroup (19.9m vs. 7.8m, HR=0.45, CI [0.33, 0.60])... We compared a computational pathology approach for continuous PD-L1 scoring for the selection of mNSCLC patients for anti-PD-L1 treatment against established manual scoring. Our results suggest that PD-L1 QCS has the potential to identify a larger patient subgroup that retains benefit from anti-PD-L1 treatment and more precisely identifies non-responders.

Cadonilimab plus chemo showed significant improvement in OS and PFS regardless of PD-L1 status and manageable safety profile, which could be a new standard first-line treatment option for advanced G/GEJ adenocarcinoma.Cutoff date: Aug 18, 2023

Of 92 patients with available treatment details, the majority received intravenous chemotherapy, nine (9.8%) received tyrosine kinase inhibitors and four (4.4%) received immunotherapy (pembrolizumab)...G12C mutation and PS ≥ 2 were also associated with inferior PFS and OS. Experience with targeted therapy for KRAS mutations remains an area of future exploration due to the unavailability of these agents in India.

P2, N=43, Completed, Gruppo Oncologico Italiano di Ricerca Clinica | Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> Feb 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

In our study, PD-L1 expression was significantly higher in squamous cell carcinomas and lower in adenocarcinomas, and was positively associated with MET and KRAS mutations, as well as the wild-type EGFR gene state. Nonetheless, additional studies are needed to further validate those associations and determine the clinical significance for immune checkpoint inhibitors of these factors.

Background: Among patients (Pts) with resectable (R) NSCLC in the AEGEAN trial, perioperative durvalumab (D) + neoadjuvant chemotherapy (CT) significantly improved pathological complete response (pCR) and event-free survival (EFS), with manageable safety, vs. neoadjuvant CT alone... These exploratory analyses are expected to shed light on the predictive utility of ctDNA in Pts treated with neoadjuvant D + CT.

Material/Methods It was a retrospective single-center analysis involving OC and PX patients who underwent radical RT (66Gy prescribed to the primary tumor, given in 30 fx/6 weeks) with or without concurrent chemotherapy (Cisplatin 100 mg/m2 i.v. every three weeks or 40 mg/m2 i.v weekly)...In univariate analysis we did not find any predictive factors for RT response. The main limitation of our study was very small group sizes.

1. Ours is the first study to demonstrate that SP263 and E3L1N can reliably be used to evaluate PD-L1 in PCs as there is good concordance with the reference clone 22C3. 2.

Our results suggest that constitutive PD-L1 expression likely occurs due to upregulation of IL6-JAK-STAT3/ interferon alpha response pathways and provides a biologic rationale for evaluating response to immune checkpoint inhibitors and identifying potential exceptional responders in sUC.

Our findings indicate that digital pathology has a strong potential as a reliable alternative to light microscopy for assessing PD-L1 expression.Utilizing the SP263 clone and 50% threshold in PD-L1 assessment can lead to more reliable and consistent results.

The prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

Analysis of progression-free survival (PFS) after the first line of treatment with immune checkpoint inhibitors (ICIs) in 30 pts with stage IV KRAS-mutated NSCLC and high PD-L1 showed a trend favoring patients presenting a co-mutation (mPFS 13.7mo KRAS co-mutated vs. 3.6mo in KRAS only; HR 0.26; CI 95% 0.09-0.070; p=0.19). Conclusions These findings emphasize the importance of further exploring PD-L1 role in KRAS mutated patients, especially by taking into account accompanying mutations in other genes evaluated by NGS.

Conclusions PD-L1 expression shows dynamic changes during course of disease. Consensus guidelines are needed for PD-L1 testing including time points of re-assessment, number of biopsies to be obtained and judgement of specimens.

In ESCC, the concordance of PD-L1 evaluation among observers is good, and the immune cell score is still an important factor affecting the concordance of interpretation among observers. Cases near the specific threshold are still the difficult problem of interpretation. SP263 had the highest CPS score of the four assays. SP263 cannot identify all 22C3 positive cases, but had good concordance with 22C3.E1L3N and SP142 showed high concordance.

"These neoplasms have shown variable response to immunotherapy which appears to be influenced by genetic and protein expression profiles, including factors such as mismatch repair status, tumor mutational burden, and checkpoint ligand expression. In the present paper, an extensive review of PD-L1 expression in various gynecologic cancer types is discussed, providing a guide for their pathological assessment and reporting."

Different assays and platforms are available, each associated with distinct scoring systems and threshold values specific to the ICI compound used, i.e. CPS≥10 for pembrolizumab and IC ≥ 1 % for atezolizumab. Each assay must be used on its designated platform, namely the Dako for 22C3 pharmDx and the Ventana for VENTANA SP263. It is important to remark that CPS and IC identify different patient cohorts and, therefore, are not interchangeable.

P1, N=24, Active, not recruiting, Imugene Limited | Recruiting --> Active, not recruiting | N=88 --> 24

The ICC test using CPS was 0.676 and 0.578 for the ≥1 and ≥ 10 cut-offs respectively, and 0.729 and 0.467 respectively for the same cut-offs using TPS. This suggests that the three antibodies under investigation cannot be used interchangeably, especially the 22C3 and SP142 clones which showed statistically significant difference when TPS was tested at a ≥ 10 cut-off.

LBC specimens had comparable performance to CBs in PD-L1 assessment and predicting treatment response to PD-L1-defined therapy.

P1; Suspended --> Recruiting

P1; N=24 --> 48

T-DXd demonstrated clinically meaningful ORR in patients with HER2-expressing gynecological tumors, irrespective of number of prior lines of therapy, use of prior HER2 or TOP1 inhibitor therapy, and presence or absence of biomarkers relevant to individual cohorts. Safety of T-DXd was consistent with the known profile. These data support T-DXd as a potential treatment for patients with gynecological HER2-expressing tumors who have progressed on prior therapy.

P1; Phase classification: P1b --> P1 | N=232 --> 321

Our study results emphasize the importance of detecting PD-L1 expression in multiple tumor lesions from the same patient. In MIBC, CD8+ TIL density could be used as a prognostic marker for predicting the status of PD-L1 expression.

These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.

Clinical Trial Registration Number: NCT04813107 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. The pCR rates in both group 1 (APL-1202 plus tislelizumab) and group 2 (tislelizumab) exceeded thresholds to trigger expansion to stage 2 of the 2-stage design. The activity and safety of neoadjuvant APL-1202 plus tislelizumab support further evaluation of this novel regimen (NCT04813107). Clinical trial information: NCT04813107.

Critically, there was a marked improvement in the placement of cases into more consistent clinical groupings. This small study is evidence that the use of image analysis tools may improve consistency in assessing tumours for PD-L1 expression and may therefore result in more consistent prediction to targeted treatment options.