Immunotherapy For Advanced Cancer Research Articles

Comprehensive modeling of longitudinal circulating tumor DNA dynamics to predict clinical response to first-line immunotherapy and chemoimmunotherapy in advanced non-small cell lung cancer.

9525 Background: First-line immunotherapy (IO) and chemo-immunotherapy (chemo-IO) are approved for PD-L1-expressing advanced non-small cell lung cancer (NSCLC), but PD-L1 expression does not reliably predict therapeutic response. Therefore, accurate on-therapy response assessment is needed to guide clinical decision-making. Conventional radiographic imaging is the gold-standard, but may not capture the nature and timing of an immune-mediated response. We investigated whether comprehensive longitudinal circulating tumor DNA (ctDNA) dynamics could enhance prediction of clinical response. Methods: We conducted targeted error correction sequencing (TEC-Seq) of longitudinal plasma specimens and matched white blood cells (WBCs) in patients with NSCLC treated with first-line IO or chemo-IO. Plasma ctDNA variants were identified by filtering out clonal hematopoiesis (CH) and germline (GL) variants found in matched WBCs. Clinical and pathological data, including PD-L1 tumor proportion score (TPS), and imaging response by RECIST1.1 were assessed. ctDNA dynamics were modeled to predict durable clinical benefit (at 6 months), progression-free survival (PFS), and overall survival (OS). Results: A total of 143 longitudinal plasma and 24 white blood cell samples underwent TEC-Seq for 31 patients with NSCLC treated with IO (n = 17) or chemo-IO (n = 14). ctDNA variants were found in 77% (n = 24) of patients after filtering out CH and GL variants, which comprised 53% (n = 196 of 373) of all variants. Molecular response, signified by elimination of ctDNA variants, was detected in 32% (n = 10) of patients and associated with improved PFS (p = 0.0004, log rank) and OS (p = 0.017, log rank). Time to molecular response was shorter than time to best RECIST response (median 3 vs. 7.71 weeks, p = 0.048, Mann-Whitney U test). A logistic regression model incorporating molecular response, recrudescence, or emergence of new variants predicted durable clinical benefit (sensitivity 84%, specificity 76%, AUC 0.88) better than PD-L1 TPS (AUC 0.67, p = 0.046, bootstrap method). Conclusions: Comprehensive modeling of ctDNA variant dynamics predicts clinical outcome independent of PD-L1 status in patients with advanced NSCLC treated with first-line IO or chemo-IO. Verification of bona fide ctDNA variants by matched WBC sequencing is essential. Molecular response can be identified earlier than imaging response and could enable on-therapy decision-making to alter clinical outcomes.

PD-1 targeted immunotherapy for advanced hepatocellular cancer: Current utilization and outcomes in the United States.

e16647 Background: Novel oncological treatment strategies for hepatocellular carcinoma (HCC) include immunotherapies targeting programmed death protein 1 (PD-1). To date there is scarce data on the current real-world clinical utilization of immunotherapy for HCC in the US. Methods: The Flatiron Health EHR-derived de-identified database was queried in October 2019 for adult patients with advanced HCC. PD-1 targeted immunotherapy (PD-1 IMT) included Nivolumab and Pembrolizumab. Overall survival (OS) was evaluated using Cox proportional hazards models. Multivariable analyses adjusted for patient demographics (age, gender, race), documented liver disease risk factors (obesity, diabetes, alcohol abuse, hepatitis), documented liver disease complication (ascites, encephalopathy), local HCC treatment (resection, radiofrequency ablation, transarterial chemoembolization [TACE], transarterial radioembolization [TARE]) and systemic Sorafenib. Subgroup analyses were performed in patients with documented clinical performance status (Eastern Cooperative Oncology Group; ECOG) and albumin/bilirubin results (all measured nearest to HCC diagnosis). Results: A total of 2,912 patients with advanced HCC were included, of which n = 345 (11.8%) received PD-1 IMT. Utilization of PD-1 IMT continuously increased from 2004, accounting for 20.9% of all cases in 2018/19. Patients treated with and without PD-1 IMT were comparable regarding demographics, comorbidities and liver disease. PD-1 IMT was more commonly administered at academic centers (20.3% vs. 13% in non-academic centers, p < 0.001), and in patients receiving Sorafenib, TACE, TARE or HCC resection (vs. none of these treatments, each p < 0.05). Median follow-up time was 36.1 months. In univariate analyses, administration of PD-1 IMT was associated with longer OS (vs. no PD-1 IMT; HR = 0.67, 95% CI: 0.58-0.78, p < 0.001; OS rates in the table). In multivariable analyses, PD-1 IMT receipt was an independent prognosticator (vs. no PD-1 IMT; HR = 0.54, 95% CI: 0.46-0.63, p < 0.001). In a subset of n = 1560 patients, this effect persisted after adjustment for ECOG, albumin and bilirubin results (HR = 0.58; 95% CI: 0.48-0.69, p < 0.001). Conclusions: PD-1 targeted immunotherapy is increasingly used for advanced HCC, accounting for up to 20.9% of cases in 2018/19. After adjustment for potential confounders, immunotherapy was associated with an overall survival benefit. [Table: see text]

Blood-based gene expression profiling to reveal potential response biomarkers for immunotherapy in advanced lung cancer.

e15155 Background: Novel immunotherapies are becoming a viable option for advanced lung cancer treatment. High-throughput gene expression profiling (GEP) has enabled better understanding of patient responsiveness to targeted immunotherapy. However, non-invasive blood-based signatures are needed to monitor and predict response. Methods: To evaluate the predictive and prognostic role of blood-based GEP, we designed a longitudinal study by enrolling 15 patients with advanced lung cancers. A total of 65 samples were collected for RNA sequencing, ~4 blood specimens per patient, before and during anti-PD-1 treatment. We used multiple analyses, including time-course differential gene expression, principal component, lymphocyte compartment deconvolution, and genetic mutation, to search for and assess potential predictive and prognostic aspects. Results: Of 15 patients, 11 were classified as Responders (partial responders) and four were Non-Responders (one stable and three progressive diseases). Our analyses demonstrated: 1) By comparing baseline GEPs from Responders vs. Non-Responders before the first treatment, we identified potential markers (e.g., LY6E is significantly lower expressed in Responders, with Log2 Fold change = -3.44 and p = 1.83E-04) that can be used as predictors of responsiveness of the patients; 2) Immunoglobulin subunits- and T cell receptor complex-related genes were differentially expressed in Responders (DAVID analysis, p = 6.7E-3 and 2.1E-2, respectively), but not in Non-responders; 3) γδ T cells in the lymphocyte compartment were relatively increased in Responders; 4) Despite a different set of genes differentially expressed at different time points, the biggest GEP changes were at ~ week 6, after the second treatment. Additionally, we observed certain genes consistently up- or down-regulated through the whole course of treatment. Furthermore, after the first treatment, genes in the immune response pathway were regulated to different directions in Responders and Non-Responders. For example, interleukin receptor genes, such as IL18R1 and IL18RAP, and CD24 were down-regulated in Responders, but up-regulated in Non-Responders (p = 0.042, 0.023 and 0.044 respectively, t-test for the differential expression in these two groups). Conclusions: The utility of blood GEP to identify predictive and prognostic factors for precision immunotherapy is encouraging. Nevertheless, these results, predictive of the anti-PD-1 clinical response, are preliminary and need to be validated in a larger cohort.

The Role of Performance Status in Small-Cell Lung Cancer in the Era of Immune Checkpoint Inhibitors

After decades of platinum-based chemotherapy for advanced small-cell lung cancer, there has finally been a therapeutic advance. The combination of a platinum chemotherapy, etoposide, and an immune checkpoint inhibitor has yielded overall survival benefits in two successive phase 3 trials. Unfortunately, these trials only included fit patients, namely those with an Eastern Cooperative Oncology Group performance status of 0-1. In the real-world setting, roughly a third of patients with advanced small-cell lung cancer has a performance status of 2, and an additional 15% have a performance status of 3 or 4, meaning that approximately half of all patients are excluded from chemoimmunotherapy trials. Poor performance status is a known negative prognostic factor, with a dismal prognosis among patients with disease that does not respond to the first cycle of chemotherapy.We review current data on immunotherapy in advanced small-cell lung cancer and discuss how we integrate the new therapeutic options into daily practice.

Progress in Neoadjuvant Immunotherapies for Resectable Non-small Cell Lung Cancer

可切除非小细胞肺癌(non-small cell lung cancer, NSCLC)是一种潜在可治愈性疾病。尽管外科手术仍然是可切除NSCLC的主要治疗手段，但仍有部分患者术后出现局部复发和远距离转移。因此，为改善长期生存效果术前术后辅助治疗可能仍有必要。免疫检查点抑制剂已经临床试验证实其治疗效果，目前已被批准用于转移性NSCLC或部分Ⅲ期局部晚期NSCLC的一线或二线使用。免疫治疗在晚期肺癌的显著疗效使研究者开始关注免疫治疗是否用于可切除非小细胞肺癌中的新辅助治疗。本文对免疫治疗作为可切除非小细胞肺癌的新辅助治疗的研究进行综述。

Correlation between the Expression of PD-L1 in Pleural Effusion of Lung Adenocarcinoma and the Clinicopathological Features and Molecular Changes

背景与目的非小细胞肺癌的免疫治疗药物pembrolizumab需要基于包括免疫组织化学（immunohistochemistry, IHC）在内的检测结果，即通过检测程序性死亡配体1（programmed cell death protein 1, PD-L1）的表达等手段来预测治疗反应。评估肺腺癌细胞学标本免疫细胞化学（immunocytochemistry, ICC）方法检测PD-L1的可行性，并探讨PD-L1表达与临床病理及分子特征的相关性。方法收集60例肺腺癌胸水细胞学标本应用PD-L1 sp263试剂按照生产说明书进行免疫细胞化学染色，同时对胸水细胞学标本做高通量二代测序（next-generation sequencing, NGS），探讨PD-L1与驱动基因突变的相关性。结果60例肺腺癌胸水细胞块标本ICC检测中，有35例PD-L1表达阳性，阳性表达率为58.3%。本院57例组织学标本PD-L1 IHC表达的阳性率为33.3%，细胞学标本与组织学标本差异无统计学意义（P > 0.05）。60例细胞学标本中26例接受NGS检测，15例（57.7%）发现表皮生长因子受体（epidermal growth factor receptor, EGFR）突变，经统计PD-L1表达与EGFR突变未发现相关性。PD-L1的阳性表达率与研究人群的年龄、性别、是否淋巴结或远处转移及是否进行放化疗或靶向治疗均未发现相关性（P > 0.05）。结论在无手术标本可取时，胸水细胞学细胞块标本可以对PD-L1进行免疫细胞化学检测，其结果具有可行性。

The effect of liver metastasis on efficacy of immunotherapy plus chemotherapy in advanced lung cancer.

The present study aimed to evaluate the effect of liver metastases on the efficacy from the combination of PD-1/PD-L1 inhibitor with chemotherapy as first-line treatment in lung cancer using the meta-analysis. A total of 8 randomized controlled trials (RCTs) were included. In patients without liver metastases, PD-1/PD-L1 inhibitor plus chemotherapy could decrease the risk of progression by 40% and risk of death by 29% (HR = 0.60; 95%CI,0.55- 0.65 and HR = 0.71;95%CI,0.58-0.90 respectively). In patients with liver metastases, PD-1/PD-L1 inhibitor plus chemotherapy could decrease the risk of progression by 31% and risk of death by 21% (HR = 0.69;95%CI,0.58-0.81; and HR = 0.79; 95%CI,0.62-0.80, respectively). The pooled ratios of PFS-HRs and OS- HRs reported in lung cancer patients with liver metastases versus those without liver metastases were 1.11 (95%CI, 0.92-1.34) and 1.03 (95%CI, 0.80-1.35), respectively, suggesting that lung cancer patients with and without liver metastases could obtain comparable efficacy.

Computational Prediction and Validation of Tumor-Associated Neoantigens.

Tumor progression is typically accompanied by an accumulation of driver and passenger somatic mutations. A handful of those mutations occur in protein coding genes which introduce non-synonymous polymorphisms. Certain substitutions may give rise to novel, tumor-associated antigens or neoantigens, presentable by cancer cells to the host adaptive immune system. As antigen recognition is the core of an effective immune response, the identification of patient tumor specific antigens derived from transformed cells is of importance for immunotherapeutic approaches. Recent technological advances in DNA sequencing of tumor genomes, advances in gene expression analysis, algorithm development for antigen predictions and methods for T-cell receptor (TCR) repertoire sequencing have facilitated the selection of candidate immunogenic neoantigens. In this regard, multiple research groups have reported encouraging results of neoantigen-based cancer vaccines that generate tumor antigen specific immune responses, both in mouse models and clinical trials. Additionally, both the quantity and quality of neoantigens has been shown to have predictive value for clinical outcomes in checkpoint-blockade immunotherapy in certain tumor types. Neoantigen recognition by vaccination or through adoptive T cell therapy may have unprecedented potential to advance cancer immunotherapy in combination with other approaches. In our review we discuss three parameters regarding neoantigens: computational methods for epitope prediction, experimental methods for epitope immunogenicity validation and future directions for improvement of those methods. Within each section, we will describe the advantages and limitations of existing methods as well as highlight pressing fundamental problems to be addressed.

A Role for Dogs in Advancing Cancer Immunotherapy Research

While rodent cancer models are essential for early proof-of-concept and mechanistic studies for immune therapies, these models have limitations with regards to predicting the ultimate effectiveness of new immunotherapies in humans. As a unique spontaneous, large animal model of cancer, the value of conducting studies in pet dogs with cancer has been increasingly recognized by the research community. This review will therefore summarize key aspects of the dog cancer immunotherapy model and the role that these studies may play in the overall immunotherapy drug research effort. We will focus on cancer types and settings in which the dog model is most likely to impact clinical immuno-oncology research and drug development. Immunological reagent availability is discussed, along with some unique opportunities and challenges associated with the dog immunotherapy model. Overall it is hoped that this review will increase awareness of the dog cancer immunotherapy model and stimulate additional collaborative studies to benefit both man and man's best friend.

Advances in immunotherapy for colorectal cancer: a review.

Immunotherapy is a new and exciting modality of cancer treatments. Its role in gastrointestinal malignancies has been promising, especially in advanced disease. Although various therapies are available for treatment of advanced colorectal cancer, survival rates for these patients remain very poor. The application of immunotherapy in colorectal cancer has shown remarkable results for a subset of patients with mismatch-repair-deficient mutations or microsatellite instability in their tumors. This literature review evaluates the current role of immunotherapy in advanced colorectal cancer, potential challenges clinicians face with immunotherapy-based regimens, and the possible future approach of combined modality immunotherapy.

Radiation therapy for augmenting the efficacy of immunotherapy in advanced non-small cell lung cancer: a case-controlled study

This study investigated the effects of previous radiation therapy on outcomes from nivolumab in advanced NSCLC, and found that previous radiation therapy resulted in significantly higher survival in patients treated with nivolumab for advanced NSCLC http://bit.ly/3btOFSL

Blocking inflammation to improve immunotherapy of advanced cancer.

The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T-cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

Anti-PD-L1 (atezolizumab) as an immune primer and concurrently with extended-field chemoradiotherapy for node-positive locally advanced cervical cancer

BackgroundThere is a lack of data exploring the use and optimal timing of immunotherapy and chemoradiation therapy (CRT) in node-positive cervical cancer. Further translational research into mechanisms of response and...

Identification of recurrence marker associated with immune infiltration in prostate cancer with radical resection and build prognostic nomogram

BackgroundSome historic breakthroughs have been made in immunotherapy of advanced cancer. However, there is still little research on immunotherapy in prostate cancer. We explored the relationship between immune cell infiltration and prostate cancer recurrence and tried to provide new ideas for the treatment of prostate cancer.MethodsProstate cancer RNA-seq data and clinical information were downloaded from the TCGA database and GEO database. The infiltration of 24 immune cells in tissues was quantified by ssGSEA. Univariate Cox regression analysis was used to screen for immune cell types associated with tumor recurrence, weighted gene co-expression network analysis (WGCNA) and LASSO were used to identify hub genes which regulate prognosis in patients through immune infiltration. Then, the nomogram was constructed based on the hub gene to predict the recurrence of prostate cancer, and the decision curve analysis (DCA) was used to compare the accuracy with the PSA and Gleason prediction models.ResultAnalysis showed that Th2 cells and Tcm related to prostate cancer recurrence after radical prostatectomy, and they are independent protective factors for recurrence. Through WGCNA and Lasso, we identified that NDUFA13, UQCR11, and USP34 involved in the infiltration of Th2 cells and Tcm in tumor tissues, and the expression of genes is related to the recurrence of patients. Based on the above findings, we constructed a clinical prediction model and mapped a nomogram, which has better sensitivity and specificity for prostate cancer recurrence prediction, and performed better in comparison with PSA and Gleason’s predictions.ConclusionThe immune cells Th2 cells and Tcm are associated with recurrence of PCa. Moreover, the genes NDUFA13, UQCR11, and USP34 may affect the recurrence of PCa by affecting the infiltration of Th2 cells and Tcm. Moreover, nomogram can make prediction effectively.

728P - High PD-L1 expression is associated with treatment response to pembrolizumab in patients with advanced biliary tract cancer

BackgroundPembrolizumab has shown promising results for patients with programmed cell death ligand-1 (PD-L1)-positive solid tumors. However, data on immunotherapy for biliary tract cancers are limited, and biomarkers to identify appropriate candidates for immunotherapy needs to be defined. MethodsA total of 153 patients with advanced biliary tract cancers were included (gallbladder n=48, distal bile duct n=17, perihilar bile duct n=32, intrahepatic bile duct n=49, and ampulla of vater n=7). Patients were screened for PD-L1 expression by a prototype immunohistochemistry assay (PharmDx). Of PD-L1-positive patients, 12 patients were treated with pembrolizumab. Treatment response was evaluated and correlated with PD-L1 immunohistochemistry, microsatellite instability (MSI) status, tumor-infiltrating lymphocytes (TIL), and CD8+ T cells density. Results74% (113 of 153) of patients showed tumoral PD-L1 positivity at 1% cut off, and 8.5% (13 of 153) patients showed high PD-L1 expression (tumor proportion score ≧ 50). Of 122 patients with MSI status, only one patient had MSI-H tumor. Twelve patients were treated with pembrolizumab, and all treated patients received prior standard chemotherapy. Two (16.7%) patients had dramatic treatment response, and the rest showed no response. Both two responders had high PD-L1 expression (tumor proportion score ≧ 50), and high PD-L1 expression was associated with treatment response (P=0.045) None of treated patients was MSI-H. Of two responders, one showed the highest TIL and CD8+ cells density. However, TIL and CD8+ positive cells densities were not significantly associated with treatment response. ConclusionsApproximately 10% of patients with advanced biliary tract cancers revealed high PD-L1 expression, and high PD-L1 expression was associated with treatment response of pembrolizumab. MSI-H was rare in biliary tract cancers. We suggest that PD-L1 expression need to be evaluated to identify patients who would benefit from immunotherapy for advanced biliary tract cancers. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

P1.04-61 Neutrophil-Lymphocyte Ratio: A Predictive Biomarker of Immunotherapy in Lung Cancer?

Identifying predictive biomarkers of immunotherapy in advanced non-small cell lung cancer (NSCLC) is essential to select the patients that could benefit more from this revolutionary therapy. Besides PD-L1 expression, neutrophil-lymphocyte ratio (NLR) has been explored as a potential predictor of clinically meaningful outcomes. Aim: Assess if NLR is an independent predictor of response to immunotherapy in advanced NSCLC. Retrospective study of patients with locally advanced or metastatic NSCLC treated with immunotherapy in the second or further lines setting in a Multidisciplinary Thoracic Tumor Unit between 2015 and 2018. Pre-treatment NLR was calculated from baseline peripheral blood cell counts. NLR was categorized as a binary variable: “low” (<5) or “high” (≥5). Cox regression models were used for overall survival (OS) and progression-free survival (PFS) analysis. From a total of 63 patients, 49 were treated with nivolumab and 14 with pembrolizumab. At the beginning of immunotherapy, baseline patient characteristics were: men: 79.4%; median age (IQR): 62 (56-70) years; ever smokers: 82.5%; ECOG PS 0-1: 82.5%; adenocarcinoma: 63.5%; squamous cell carcinoma: 31.7% and NSCLC-NOS: 4.8%; stage IV: 76.2%; PD-L1 expression <1%: 47.6%. Twenty-three patients (36.5%) received immunotherapy in the third or further lines of treatment. Median PFS and OS were 5 months (2-10) and 8 months (4-13), respectively. After adjusting for gender, age, tobacco habits, ECOG PS, histology and PD-L1 expression, "high" NLR was an independent predictive factor of worse PFS (HR 2.22; 95% CI 1.06-4.66; p 0.035) and OS (HR 2.74; 95% CI 1.19-6.30; p 0.017). In our cohort, patients with NLR≥5 had a higher risk of disease progression and death compared to those with NLR<5. NLR is an inexpensive and affordable biomarker that could help to predict response to immunotherapy. Further large prospective studies are needed to validate this biomarker and to establish the optimal cut-off level.

4O - Novel dendritic cell based immunotherapy for advanced cancer

BackgroundImmune-checkpoint inhibitors (ICI) such as Ipilumimab and Nivolumab have made long-term survival a real possibility for advanced cancer patients. Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized treatment strategy using patient’s own immune cells may be a promising approach for treating non-responding patients. Natural circulating dendritic cells (nDC) such as CD1c+ DC (cDC2) subset and plasmacytoid DC (pDC) are essential for efficient activation of immune responses after ICI therapy. Thus understanding the condition of these cells in patients and devising new strategies to improve their functions may help improve response to ICI in advanced cancer patients. MethodsTo investigate this we measured the number and phenotype of nDC in 29 advanced cancer patients versus 21 age and gender-matched healthy controls using flow cytometry. We further identified that inhibition of the p38 MAPK pathway using small molecule inhibitors in cDC2 cells increases their immune-stimulatory capacity, measured by functional assays. ResultsThe number of pDC were significantly reduced in cancer patients as compared to healthy controls (1221 vs 2843 pDC/mL) (p-value<0.01). Although the number of cDC2 were slightly reduced in cancer patients (4476 vs 5053 of cDC2/mL), a good proportion of patients had sufficient number of DC eligible for a DC-based immunotherapy. Patient cDC2 were immune-suppressed with low secretion of immune-stimulatory cytokines (IL-12) and impaired homing to lymph-nodes. We identified that the p38 MAPK signalling pathway was controlling immune-suppression in cDC2 cells. Inhibiting this pathway restored the secretion of IL-12 in all patients (n=5), increased the homing of DC to lymph-node chemokines, and prevented them from secreting the immune-suppressive cytokine, IL-10. ConclusionsThe number and phenotype of nDC are suppressed in advanced cancer patients. Inhibition of p38 MAPK can restore the function of patient cDC2 subset. Co-culture of these p38-inhibited cDC2 with pDC further show promising results important for developing advanced DC vaccines. Our study has paved the way for a phase I clinical trial of adoptive transfer of p38-MAPK inhibited cDC2 in 24 advanced cancer patients. Legal entity responsible for the studyUniversity of Nottingham. FundingUniversity of Nottingham. DisclosureAll authors have declared no conflicts of interest.

Checkpoint inhibitors plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials.

Background:We conducted a meta-analysis to evaluate the efficacy and safety of upfront add-on immunotherapy for advanced non-small cell lung cancers (NSCLC).Methods:We performed a literature search on first-line chemotherapy ± immunotherapy in NSCLC. We utilized Revman version 5.3 to calculate the estimated pooled hazard ratio for overall survival (OS) and progression-free survival (PFS) and pooled risk ratio for objective response rate (ORR), all-grade and high-grade adverse events with 95% CI.Results:We analyzed 4322 patients. The pooled hazard ratios for OS, PFS and ORR were 0.74 (95% CI: 0.62–0.88; p = 0.0007), 0.62 (95% CI: 0.57–0.68; p = 0.00001) and 1.51 (95% CI: 1.3–1.74; p = 0.00001), respectively. The pooled risk ratios for all-grade and high-grade adverse events were 1.01 (95% CI: 0.99–1.03; p = 0.27) and 1.17 (95% CI: 1.07–1.28; p = 0.0006), respectively.Conclusion:Add-on immunotherapy significantly improves PFS, OS and ORR for the first-line treatment of advanced NSCLC with a reasonable safety profile.

Association Between FDA Label Restriction and Immunotherapy and Chemotherapy Use in Bladder Cancer

This research letter discusses the association between label restrictions by the US Food and Drug Administration on first-line immunotherapy for advanced bladder cancer and subsequent changes in practice.

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

The emergence of immunotherapy in oncology requires the discovery, validation and subsequent adoption of robust, sensitive and specific predictive and prognostic biomarkers for daily practice. Until now, anti-PD-L1 immunohistochemistry (IHC) on tissue sections has been the only validated companion diagnostic test for first-line immunotherapy for advanced and metastatic cancer, notably non-small-cell lung cancer (NSCLC). However, detection of this biomarker presents limitations that have stimulated the development of other biomarkers and other approaches. Within this context, the use of a liquid biopsy (LB) could provide an important complementary or alternative added value to PD-L1 IHC. In this review, we discuss how LBs have been used in the field of immuno-oncology (I-O) to predict response, relapse or adverse advents for patients undergoing immune-checkpoint inhibitor (ICI) therapy (anti-PD-1/PD-L1 and CTLA-4) and we highlight recent developments. Circulating tumor cells (CTCs), cell-free DNA (cfDNA), proteins and cytokines detected in plasma as well as circulating T-lymphocytes are discussed as potential sources for developing new I-O biomarkers. The quantification of cfDNA as a predictive biomarker, as well as its sequencing for the determination of tumor mutational burden, is already well advanced. Additionally, the quantification of PD-L1 from CTCs, bound on exosomes or free in plasma, as well as the determination of cytokines, are also being actively investigated with promising results having recently been published. Lastly, analysis of T-lymphocytes, especially by analyzing the T-cell receptor, has recently emerged as a valuable biomarker that might become relevant for the prediction of response to ICIs. While LBs have not yet been implemented in routine I-O clinical practice, recent promising data and rapidly advancing technologies indicate that this approach has the potential to soon personalize the clinical management of cancer patients receiving ICIs.