Publications by authors named "Edward Garon"

Introduction: RELAY, a global double-blind, placebo-controlled phase 3 study (NCT02411448) found statistically significant improvement in progression-free survival (primary end point) for ramucirumab (RAM) plus erlotinib (ERL) (RAM + ERL) in patients with untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59, 95% confidence interval [CI]: 0.46-0.

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The treatment of non-small cell lung cancer has made major strides with the use of immune checkpoint inhibitors, but there remains a significant need for therapies that can overcome immunotherapy resistance. Dendritic cell (DC) vaccines have been proposed as a therapy that can potentially enhance the antitumor immune response. We have embarked on a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDCs) modified to express the chemokine CCL21 (CCL21-DC) given in combination with pembrolizumab.

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Article Synopsis
  • Dual immune checkpoint blockade (ICB) using CTLA4 and PD-(L)1 inhibitors shows improved anti-tumor effectiveness and immune toxicity compared to PD-(L)1 inhibitors alone in advanced non-small-cell lung cancer (NSCLC) patients.
  • Patients with mutations in STK11 and/or KEAP1 genes benefit more from the combination treatment compared to those receiving only PD-(L)1 inhibitors, as shown in the POSEIDON trial.
  • The loss of KEAP1 serves as a strong predictor for the success of dual ICB, as it leads to a more favorable outcome by changing the tumor's immune environment to better engage CD4 and CD8 T cells for anti-tumor activity. *
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Background: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib.

Methods: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines.

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Neoantigen immunoediting drives immune checkpoint blockade efficacy, yet the molecular features of neoantigens and how neoantigen immunogenicity shapes treatment response remain poorly understood. To address these questions, 80 patients with non-small cell lung cancer were enrolled in the biomarker cohort of CheckMate 153 (CA209-153), which collected radiographic guided biopsy samples before treatment and during treatment with nivolumab. Early loss of mutations and neoantigens during therapy are both associated with clinical benefit.

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Introduction: The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance.

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To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients.

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Objective: This study tested sleep disturbance as a mediator through which stigma and discrimination predict psychological distress and physical symptom burden in adults with lung cancer.

Methods: Lung cancer patients on active oncological treatment ( N = 108; 74.1% stage IV) completed questionnaires on lung cancer stigma, sleep, distress, and physical symptoms at study entry and at 6- and 12-week follow-up.

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Introduction: gene mutations are drivers of NSCLC. The RELAY double-blind, placebo (PBO)-controlled phase 3 study revealed superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus PBO (PBO + ERL) in patients with untreated advanced NSCLC and an activating mutation. This exploratory analysis evaluated potential associations between exon 19 deletion (ex19del) variants and clinical outcomes.

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Background: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types.

Methods: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W).

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Importance: Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC).

Objective: To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost.

Design, Setting, And Participants: This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition).

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Health-related quality of life (HRQoL) is an important consideration in cancer clinical research, which can be substantially influenced by cancer treatment procedures and medications. The treatment landscape for early-stage (stage I-III) non-small cell lung cancer (NSCLC) is rapidly evolving. In this light, it is important to evaluate the most suitable instruments for HRQoL assessment and timing.

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Objectives: In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs).

Patients And Methods: Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy.

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Introduction: Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment.

Methods: This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC.

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Purpose: Effective treatments for resectable non-small-cell lung cancer (NSCLC) are limited and relapse rates are high. The interleukin (IL)-1β pathway has been linked with tumor development and progression, including in the Canakinumab Anti-Inflammatory Thrombosis Outcomes cardiovascular study in which IL-1β pathway inhibition with canakinumab reduced lung cancer incidence and mortality in an exploratory analysis.

Methods: CANOPY-A (ClinicalTrials.

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Introduction: In the REVEL trial, ramucirumab plus docetaxel demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with placebo plus docetaxel for treatment of metastatic non-small cell lung cancer (NSCLC) that progressed during or after platinum-based chemotherapy. Since the approval of ramucirumab plus docetaxel, immune checkpoint inhibitors (ICIs), either as single agents or in combination with chemotherapy, have become the standard of care for first-line treatment of patients with advanced NSCLC. However, efficacy and safety data for ramucirumab plus docetaxel after prior ICI treatment from randomized controlled clinical studies are lacking.

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Background: Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation.

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Introduction: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), has exhibited clinical activity in a phase 1 expansion cohort of patients with PD-L1-high advanced NSCLC.

Methods: This adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1-high advanced NSCLC. Primary end points were progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.

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Patients from historically under-represented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the USA. As these patients often have limited English proficiency, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than 12,000 consent events at a large cancer centre and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays the translation costs) than for industry-sponsored studies (for which the translation costs are covered by the sponsor).

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Although pembrolizumab confers clinical benefit in non-small cell lung cancer (NSCLC), only a subset of patients will respond due to a heterogenous tumor microenvironment. KEYNOTE-495/KeyImPaCT is an ongoing biomarker-directed, adaptively randomized phase 2 study investigating first-line pembrolizumab (200 mg every 3 weeks) + lenvatinib (20 mg daily), anti-CTLA-4 quavonlimab (25 mg every 6 weeks) or anti-LAG-3 favezelimab (200 mg or 800 mg every 3 weeks) in advanced NSCLC. Patients were categorized by T-cell-inflamed gene expression profile (TcellGEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab.

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Article Synopsis
  • Plasma cell-free DNA (cfDNA) serves as a noninvasive biomarker for identifying cell death across different organs, which can help in detecting and monitoring diseases.
  • The study presents a comprehensive tissue methylation atlas created from 521 noncancer samples, identifying specific methylation patterns that aid in accurately determining the tissue origin of cfDNA.
  • A new deep-learning model called supervised tissue deconvolution is developed, which shows improved sensitivity and accuracy for analyzing cfDNA, with applications in disease diagnosis and tracking treatment effects.
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