TEST:

VENTANA PD-L1 (SP142) Assay

P2, N=110, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Apr 2027 --> Apr 2029 | Trial primary completion date: Apr 2024 --> Apr 2026

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.

The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

The combined SII-SP142 biomarker can be readily and universally obtained at a low cost in clinical practice, without requiring advanced genomics technology or specialized expertise. Although further studies are needed to confirm that the combined SII-SP142 biomarker is widely applicable, it should help clinicians to identify the best patients for combined chemotherapy with atezolizumab in ES-SCLC.

Intra-patient heterogeneity in PD-L1 expression was observed between the PT and matched LNM. This disagreement in PD-L1 status may emphasize the importance of considering different tumor sites for analyses to select patients for immunotherapy.

This study identifies TILs cut-offs predictive of PD-L1 positivity, suggesting the need for institutions to tailor these thresholds based on the selected PD-L1 clone and treatment. Evaluating TILs solely at the tumor edge may overlook the complexity of tumor immune infiltration. While TLS presence correlates with higher PD-L1 expression, particularly with the SP142 clone, its exact predictive value for PD-L1 remains to be clarified. The SP142 clone exhibits higher positivity rates compared to 22C3.

No abstract available

This study highlights distinct molecular profiles in metastatic prostate cancer (PCa) based on metastasis site, underlining the importance of personalized treatment strategies. The findings, particularly the variations in gene mutations and AR signaling, are crucial in tailoring management approaches for advanced PCa.

"Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958."

The increased immune cell infiltrate and prevalence of T-cell inflamed status among ANTXR1H NENs suggests these tumors might be more responsive to treatment with ICIs. As trials incorporating intratumoral injections of SVV-01 in combination with ICIs are underway, further investigation of clinical and molecular associations with ANTXR1 expression in NENs is warranted.

These data suggest that TN-ILC had higher frequency of CDH1, ERBB2, AKT1, ARID1A mutations, higher M2 macrophages and neutrophils and lower M1 macrophages and CD8 T cells infiltration and, lower T cell inflamed signature. High TMB and AR expression can translate into use of immunotherapy (ICI) and AR antagonists in these patients. Additonal analysis to determine the optimal biomarker for ICI response in TN-ILC is needed.

The inter-assay discrepancy in the PD-L1 expression status on tumor cells between the 22C3 and SP142 assays, reflecting an imbalance of the CD274 splicing variants, could be a primary-resistance mechanism to the pembrolizumab monotherapy in highly PD-L1-expressing NSCLCs.

We have demonstrated that TNF induces trastuzumab resistance through mucin 4 (MUC4) upregulation and it is an independent biomarker of poor response to therapy in HER2+ breast cancer...TNF blockade was achieved with etanercept (E), which blocks the soluble (sTNF) and transmembrane isoform of TNF, or with the dominant negative protein INB03 (DN) which neutralizes only sTNF...MUC4 is associated with poorly-infiltrated TNBC, and sTNF blockade downregulates its expression decreasing MTS when combined with anti-PD-1. We propose the TNF as a new target for the treatment of TNBC, and MUC4 as a predictive biomarker to guide a combined treatment of TNF blockers with immunotherapy.

P2; Not yet recruiting --> Recruiting

P2; Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> Feb 2024 | Trial primary completion date: Oct 2023 --> Feb 2024

Pts with untreated stage II/III eTNBC and a primary tumour >2 cm were randomised 1:1 to placebo or atezo 840 mg q2w + neoadjuvant CT (nab-paclitaxel 125 mg/m2 qw for 12 wk, then doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q2w for 8 wk)...Among pts without pCR, 14/70 (20%) in the atezo arm vs 33/99 (33%) in the placebo arm received additional adjuvant systemic therapy, most often capecitabine (4/70 [6%] vs 26/99 [26%])... The significant pCR benefit with the addition of atezo to CT for eTNBC translated into numerically improved EFS, DFS and OS. Longterm safety results are consistent with previous reports. Previously presented at ESMO-BC, LBA1, Carlos Barrios et al.

PDL1 CPS score did not correlate with medullary thyroid carcinoma IMTCGS grade. However, a subset of both low-grade and high-grade MTCs demonstrated PDL1 CPS scores ≥1 as estimated by two independent pathologists and could warrant further exploration in future studies as a potential therapeutic avenue for patients unresponsive to conventional TKI treatments.

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.

E1L3N by CyCIF was highly concordant to IHC. There is a good concordance between TPS scores measured by various PD-L1 antibodies despite differences in staining quality. Additional work is underway to compare the performance of the antibodies in diverse immune cell types and in relation to additional immune regulators to better understand variability in staining.

P2; Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Melanoma patients with ARID mutations exhibited higher prevalence of markers associated with ICI response, including TMB-H, and immune-related signatures. Our data also suggests improved survival outcome in patients with ARID2 mutations, irrespective of anti-PD1 therapy.

Standard therapy comprised an investigator-selected carboplatin doublet (paclitaxel, gemcitabine or pegylated liposomal doxorubicin [PLD]) for 6 cycles, followed by maintenance niraparib in patients with a complete or partial response or stable disease. Conclusion The apparent difference in atezolizumab treatment effect according to investigator-selected chemotherapy doublet, including more favourable outcomes with atezolizumab in the gemcitabine subgroup, may be attributable to selection bias towards gemcitabine in poorer-prognosis patients and the small sample sizes of the paclitaxel and gemcitabine subgroups. Ongoing translational work may reveal further differences and hypotheses.

Postoperative adjuvant fluorouracil plus epirubicin HCl plus cyclophosphamide(FEC)plus paclitaxel(PTX)therapy was administered...Capecitabine was selected for treatment of the recurrent lesion...At this time, eribulin mesylate was selected, along with intensity-modulated radiation therapy(IMRT)...Subsequently, liver metastasis was detected, and the drug was switched to vinorelbine ditartrate(a drug with less non-hematological toxicity)...About half a year later, ie, in October 2021(11 years after the surgery), we detected an increase in the size of the liver metastasis and selected atezolizumab and nab-PTX for treatment. Applicable regimens of drug therapy are still available at present and drug therapy has been continued based on a discussion and mutual understanding of the adverse reactions, etc. with the patient. Few reports have been published concerning long-term survivors among TN breast cancer cases.

OSCC tumors were more likely to be TMB-H compared to BT and HGSOC, with increased mutational prevalence in multiple genes like PIK3CA, FBXW7, CDKN2A, FAT1, pTERT but no ER or PR positivity. Additionally, OSCC tumors also had increased expression of many IC genes, infiltration of M1 Macrophages and higher T-cell inflamed frequency. One limitation of this study is the small sample size of OSCC compared to HGSOC, but further characterization of this rare histological subtype with a poor prognosis may lead to identification of therapeutic targets.

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.

P2; Recruiting --> Active, not recruiting

"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; 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.

Patients were stratified by carboplatin doublet (paclitaxel, gemcitabine or PLD), TFIp (6–12 vs >12 months), BRCA status (mutated vs non-mutated) and PD-L1 status (PD-L1-expressing immune cells on <1% vs ≥1% tumour area vs non-informative by SP142)...Results Between November 2018 and January 2022, 417 patients were randomised (14% BRCA-mutated, 36% PD-L1-positive, 66% TFIp >12 months, 11% prior PARPi after front-line chemotherapy, 54% prior bevacizumab); most (71%) received carboplatin+PLD...The safety profile was as expected from prior experience of these drugs. Conclusion Combining atezolizumab with chemotherapy and maintenance niraparib for late-relapsing rOC did not significantly improve PFS, ORR or maintenance PFS.

P2; Trial primary completion date: Sep 2023 --> Jan 2023

P2; Trial completion date: Jan 2026 --> Aug 2024

405.9A11 provided the most convincing PD-L1 expression results. Pathologists should report PD-L1 expression in a combined manner, including both the status of HRS cells and the percentage of PD-L1-positive ICs.

Our study demonstrated a high concordance between HER2 expression by IHC and ERBB2 gene expression by WTS in UC. Differences in ADC target expression between ERBB2-high vs. ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high ERBB2 expression and survival advantage warrants further investigation.

P2; N=160; Not yet recruiting; Sponsor:Institut Curie

PD-L1 (SP142) expression was lower in recurrent/metastatic TNBCs, and substantial cases showed discordance in its expression between primary and recurrent/metastatic sites, suggesting that multiple sites may need to be tested for PD-L1 (SP142) when considering atezolizumab therapy. PD-L1 (SP142)-positive TNBCs seems to be associated with favorable clinical outcomes.

We elucidate molecular and immunologic mechanisms of metastatic tropism in advanced PCa. These data may facilitate future drug development.

To our knowledge, this is the first article on the effect of preservation time and preservation temperature of paraffin sections on PD-L1 expression in breast cancer. Long-term storage of paraffin sections of unstained invasive breast cancer can lead to antigen loss of PD-L1 (SP142). Refrigerated storage of paraffin sections can delay antigen loss, with best results at 4 °C or -20 °C, and a storage time of no more than 4 weeks is recommended.

P2; Trial completion date: Jul 2024 --> Dec 2022 | Active, not recruiting --> Terminated; This study has been terminated due to Lack of Accrual.

No abstracts available

P2; Trial primary completion date: Apr 2023 --> Apr 2025