TMB + PD-L1 expression

This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.

Atezolizumab, when added to carboplatin and etoposide, improved both progression-free survival and overall survival. Biomarker development has stalled as PD-L1 expression and tumor mutational burden have not been useful predictive biomarkers. However, based on the significant survival improvements, both atezolizumab and durvalumab were approved by the US Food and Drug Administration to be given with first-line chemotherapy, and these regimens represent the new standards of care for SCLC.

This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.

In the validation cohort, the immunotherapy efficacy of patients with KDM5C mutations was better than that of KDM5C wild-type patients, with median overall survival 21 months (95% CI, 12.4 to 29.6) and 11 months (95% CI, 8.9 to 13.1) (hazard ratio for death, 0.63; 95% CI, 0.26 to 1.53). Conclusion KDM5C mutations are associated to better efficacy of immunotherapy and have potential value for guiding clinical practice.

BRCA and PALB2 mutations were found in a significant subgroup of PDACs. These mutations were associated with a distinct molecular profile potentially predictive for response to immune-checkpoint inhibitor therapy. Therefore, these data provide a rationale to evaluate PARP inhibitors in combination with immune-checkpoint inhibitors in patients with BRCA/PALB2-mutated PDAC.

A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles. In this review, we describe the cutting-edge progress made in patients with lung cancer, the optimal duration of ICI treatment, ICIs in some special populations, the unique response patterns during ICI treatment, the emerging predictive biomarkers, and our understanding of primary and acquired resistance mechanisms to ICI treatment.

Our study has identified that TP53 confers worse survival and response to platinum chemotherapy compared to BAP1. Overall PDL1 expression and TMB is low in patients with MPM resulting in limited benefit from single agent PD-1/PD-L1 agent.

From these biomarkers, peripheral blood-based biomarkers are promising options for the prediction of immunotherapy efficacy with ease of access, repeatability and low cost. This review provides an overview of recent developments on the biomarkers in immunotherapy efficacy together with comments on future perspectives.

Nevertheless, efforts are ongoing to help prime prostate tumors by turning a "cold" prostate cancer "hot" and thus rendering them more susceptible to immunotherapy. Combination treatments, use of molecular biomarkers, and use of new immunotherapeutic agents provide opportunities to enhance the immune response to prostate tumors.

ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.

Conclusions Genomic alteration signatures might define subsets of lung cancer tumors with no PD-L1 expression to complement TMB and PD-L1 on the selection criteria for patients whom may benefit from checkpoint inhibitors. Ethics Approval The study was approved by Neogenomics Institution’s Ethics Board and external IRB, approval number 420160280.

Conclusions Genomic alteration signatures might define subsets of lung cancer tumors with no PD-L1 expression to complement TMB and PD-L1 on the selection criteria for patients whom may benefit from checkpoint inhibitors. Ethics Approval The study was approved by Neogenomics Institution’s Ethics Board and external IRB, approval number 420160280.

The results of our study will exhibit the efficacy and tolerability of durvalumab as maintenance therapy after daily carboplatin plus radiotherapy.

Interpreting the tumour-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumour type-specific testing.

For patients with a high TMB, nivolumab plus ipilimumab contributed an extra 2.04 QALYs at a cost of $69182.50 per QALY. Nivolumab plus ipilimumab as first-line therapy makes a better cost-effective strategy than chemotherapy in advanced NSCLC patients with PD-L1 expression levels ≥50% and ≥1% or a high TMB, at a willingness-to-pay threshold of $150,000 per QALY, but not in the patients with a PD-L1 expression <1%.

Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.

Indel mutational burden among TCGA MSI-L tumors was significantly higher than that of MSS tumors (P=0.016). These results suggest that MSI-L tumors may have a distinct tumor phenotype and be potentially immunogenic in EGJ adenocarcinoma.

Novel concurrent mutations were identified including CDH1 mutations. Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for "off-label" PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.

Moreover, patients with high ITS harbored the immunotherapy-sensitive characteristics including high TMB and NAL, ultraviolet light damage, impaired DNA damage repair pathway, arrested cell cycle signaling, and frequent mutations in NF1 and SERPINB3/4. Overall, these findings deserve prospective investigation in the future and may help guide clinical decisions on ICIs therapy for patients with melanoma.

Several other candidate biomarkers were investigated including tumor mutational burden, gene expression signatures, single gene mutations, human endogenous retroviruses, the gastrointestinal microbiome, and peripheral blood laboratory markers. While individually these biomarkers have yet to explain the heterogeneity of treatment response to immunotherapy, using aggregate information from these biomarkers may inform clinically useful predictive biomarkers.

PD-L1 expression, tumor mutation burden, neoantigens, specific gene mutations, circulating tumor DNA, human leukocyte antigen class I, tumor microenvironment, peripheral inflammatory cells, and microbiome are discussed in detail. To sum up, this review provides information on the current application and future prospects of ICI biomarkers.

KRAS G12D/TP53 co-mutation drives immune suppression and might be a negative predictive biomarker for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with lung adenocarcinoma.

This case provides the evidence of the effective role of toripalimab and PD-1 combined with local radiotherapy in PSC patients, which was the first application as far as we know.

Combined positive score (CPS) ≥ 1 is the minimum PD-L1 expression threshold necessary for gastric/gastroesophageal junction (GEJ) cancer patients to qualify for treatment with pembrolizumab; however, studies suggest that patients with higher CPS scores may derive greater benefit...The two patient cases presented suggest that that perhaps by testing CPS in all gastrointestinal (GI) cancer patients, beyond those with gastric/gastroesophageal cancer, and defining an appropriate CPS threshold, PD-L1 expression may better predict ICI benefit for GI cancer patients irrespective of tumor type. Further studies are needed to verify this hypothesis.

Based on data contained in this review, assessment of TMB status and PD-L1 expression may help enhance the prediction of response to checkpoint inhibition in some tumors, such as NSCLC and melanoma. In this rapidly growing area of research, further exploratory biomarkers are being investigated including tumor-infiltrating lymphocytes, immune profiling (e.g., effector T cells or regulatory T cells), epigenetic signatures, T-cell receptor repertoire, proteomics, microbiome, and metabolomics.

Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.

No abstract available

Secondary endpoints are objective response, duration of response, overall survival, and safety. The results of this study will provide evidence on the safety and antitumor activity of niraparib and dostarlimab combination in patients with advanced, HRD-positive and PD-L1 ≥ 1% NSCLC and/or MPM.

Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM.

Texture parameters derived from PET, known to indicate glucose uptake distribution, were correlated with expression of PD-L1 mRNA but not with expression of PD-1, CTLA-4 and TMB. Thus, tumoral heterogeneity could be a surrogate marker for the identification of PD-L1 level in NSCLC.

Significant molecular differences were observed in GEP-NENs by tumor location and grade, indicating differences in carcinogenic pathways and biology.

Investigator's choice of carboplatin or cisplatin was allowed. These findings may help to identify patients with ES-SCLC who are most likely to derive long-term clinical benefit following D + EP treatment. Paz-Ares, L. G. et al., ESMO 2020, Madrid, Spain, submitted as LBA Funding: AstraZeneca

43/56 pts received nivolumab, 15 pembrolizumab in different therapy lines (from 1st to 5th). The combination of different biomarkers may better predict responses to I/O than PD-L1 alone and improve the selection of patients that benefit from I/O treatment.

43/56 pts received nivolumab, 15 pembrolizumab in different therapy lines (from 1st to 5th). The combination of different biomarkers may better predict responses to I/O than PD-L1 alone and improve the selection of patients that benefit from I/O treatment.

Investigator's choice of carboplatin or cisplatin was allowed. These findings may help to identify patients with ES-SCLC who are most likely to derive long-term clinical benefit following D + EP treatment. Paz-Ares, L. G. et al., ESMO 2020, Madrid, Spain, submitted as LBA Funding: AstraZeneca

43/56 pts received nivolumab, 15 pembrolizumab in different therapy lines (from 1st to 5th). The combination of different biomarkers may better predict responses to I/O than PD-L1 alone and improve the selection of patients that benefit from I/O treatment.

Investigator's choice of carboplatin or cisplatin was allowed. These findings may help to identify patients with ES-SCLC who are most likely to derive long-term clinical benefit following D + EP treatment. Paz-Ares, L. G. et al., ESMO 2020, Madrid, Spain, submitted as LBA Funding: AstraZeneca

Most surprisingly, we found that PD-L1 blockade combined with docetaxel did not promote an anti-tumor response. These findings uncover that PD-1/PD-L1 blockade monotherapy may be the optimal therapeutic schedule in NSCLC patients harboring KRAS mutations.

Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits in anti-PD-1 therapy for NSCLC and probably for other cancers.

This study revealed the demographic, molecular and immuno-microenvironment characteristics of CD47 expression in NSCLC. We identified tumour CD47 expression as an independent prognostic factor for recurrence in resected NSCLC. Our findings illustrate the potential of anti-CD47 treatment in NSCLC.

Therefore, tumor mutation burden, gene expression signatures, microsatellite instability, tumor-infiltrating lymphocytes, viral antigens, and the oral microbiota are being investigated as predictive biomarkers. Finally, we delineate other challenges and future prospects for improving patient outcomes, including the major challenge of identifying and validating predictive biomarkers that need to be addressed in future studies.