Facts and Hopes on Biomarkers for Successful Early Clinical Immunotherapy Trials: Innovative Patient Enrichment Strategies.

Despite the clinical validation and unequivocal benefit to patients, the development of cancer immunotherapies is facing some key challenges and the attrition rate in early phases of development remains high. Identifying the appropriate patient population that would benefit most from the drug is on the critical path for successful clinical development. We believe that a systematic implementation of patient enrichment strategies early in the drug development process and trial design, is the basis for an innovative, more efficient, and leaner clinical development to achieve earlier a clear proof of concept or proof of failure.

Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer: an open-label, randomized controlled phase 3 trial (ORIENT-3).

Background: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.

Methods: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy.

Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials.

Background: The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer.

fdrci: FDR confidence interval selection and adjustment for large-scale hypothesis testing.

Motivation: Approaches that control error by applying a priori fixed discovery thresholds such as 0.05 limit the ability of investigators to identify and publish weak effects even when evidence suggests that such effects exist. However, current false discovery rate (FDR) estimation methods lack a principled approach for identification of discovery thresholds other than 0.

Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2).

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.

Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

Background: The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC).

Methods: We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC.

Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study.

Introduction: Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here.

Methods: In this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group.

RNA-Binding Protein Polymorphisms as Novel Biomarkers to Predict Outcomes of Metastatic Colorectal Cancer: A Meta-analysis from TRIBE, FIRE-3, and MAVERICC.

RNA-binding proteins (RBPs) regulate many posttranscriptional cellular activities. Accumulating evidence suggests associations between RBPs with colonic tumorigenesis and chemosensitivity. We investigated the prognostic and predictive values of SNPs of genes encoding RBPs in metastatic colorectal cancer (mCRC), using clinical and genomic data from three randomized clinical trials of standard first-line chemotherapy for mCRC (TRIBE, FIRE-3, and MAVERICC).

Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer.

Background: Immunogenic cell death (ICD) is a tumor cell death involving both innate and adaptive immune responses. Given published findings that oxaliplatin, but not irinotecan, drives ICD, we investigated whether single nucleotide polymorphisms (SNPs) in the ICD pathway are associated with the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).

Methods: Two randomized clinical trials data were analyzed: discovery cohort, FOLFOX/bevacizumab arm (MAVERICC); validation cohort, FOLFOXIRI/bevacizumab arm (TRIBE); and two control cohorts, FOLFIRI/bevacizumab arms (both trials).

Development of a gene expression-based prognostic signature for IDH wild-type glioblastoma.

Background: We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations.

Methods: Samples were collected from newly diagnosed patients with IDH wild-type glioblastoma in the ARTE, TAMIGA, EORTC 26101 (referred to as "ATE"), AVAglio, and GLARIUS trials, or treated at UCLA. Transcriptional profiling was achieved with the NanoString gene expression platform.

Combination of variations in inflammation- and endoplasmic reticulum-associated genes as putative biomarker for bevacizumab response in KRAS wild-type colorectal cancer.

Chemotherapy combined with the angiogenesis inhibitor bevacizumab (BVZ) is approved as a first-line treatment in metastatic colorectal cancer (mCRC). Limited clinical benefit underpins the need for improved understanding of resistance mechanisms and the elucidation of novel predictive biomarkers. We assessed germline single-nucleotide polymorphisms (SNPs) in 180 mCRC patients (Angiopredict [APD] cohort) treated with combined BVZ + chemotherapy and investigated previously reported predictive SNPs.

Disease Monitoring Using Post-induction Circulating Tumor DNA Analysis Following First-Line Therapy in Patients with Metastatic Colorectal Cancer.

Purpose: We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy.

Experimental Design: The Sequencing Triplet With Avastin and Maintenance (STEAM) was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered concurrently or sequentially, versus FOLFOX-BEV in first-line mCRC. Evaluation of biomarkers associated with treatment outcomes was an exploratory endpoint.

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older.

Stromal organization as predictive biomarker for the treatment of colon cancer with adjuvant bevacizumab; a post-hoc analysis of the AVANT trial.

Purpose: Intra-tumoral stroma has become increasingly important in understanding tumor biology, tumor progression and clinical outcome. The amount itself, quantified as the tumor-stroma ratio (TSR), has proven to be prognostic in stage I-III colon cancer. Also, alterations in stromal organization have been found to provide prognostic and predictive information in certain cancers.

AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3.

AMP-activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway-related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy).

Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer.

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients.

MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer.

Purpose: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC). MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV.

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315).

Predictive potential of tumour-stroma ratio on benefit from adjuvant bevacizumab in high-risk stage II and stage III colon cancer.

Background: The tumour-stroma ratio (TSR) has proven to be an independent prognostic factor in colon cancer.

Methods: Haematoxylin eosin tissue slides of patients from the AVANT trial were microscopically scored for TSR and categorised as stroma -low or stroma -high. Scores were correlated to the primary and secondary endpoint disease-free survival (DFS) and overall survival (OS).

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT → TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population.

Patients And Methods: ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years.

MODUL-a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach.

Purpose: The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response.

Methods: MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study.

Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.

The critical role of angiogenesis in promoting tumor growth and metastasis has been well established scientifically, and consequently blocking this pathway as a therapeutic strategy has demonstrated great clinical success for the treatment of cancer. The holy grail however, has been the identification of patients who derive significant survival benefit from this class of agents. Here we attempt to delineate the diverse mechanisms related to anti-VEGF including its role as an anti-vascular, anti-angiogenic or an anti-permeability factor and review the most promising predictive biomarkers interrogated in large clinical trials, that identify patients who may derive significant survival advantage with VEGF inhibition.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

Background: In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC.

Patients And Methods: We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies.