Faculty Bibliography

Background: Pembro (programmed cell death protein-1 [PD-1] inhibitor) +/- platinum (Pt)-based induction chemotherapy (ICT), with pembro maintained until disease progression (PD), is a standard 1L treatment for advanced/metastatic NSCLC; long-term benefits are limited to a small subset of patients. Nira, a poly (ADP-ribose) polymerase inhibitor (PARPi), promotes PARP trapping, activates the STING pathway, recruits T cells, and upregulates programmed death-ligand 1 (PD-L1), making it a promising partner for PD-1 inhibitors. Nira crosses the blood-brain barrier in animal models with 34-fold higher brain tissue exposure than other PARPis, suggesting it may reduce risk/progression of brain metastasis (BM). Nira + pembro has shownanti-tumour activity and acceptable safety in triple-negative breast and Pt-resistant ovarian cancer (TOPACIO/KEYNOTE-162), and as 1L therapy in advanced/metastatic NSCLC (JASPER). Trial design: ZEAL-1L (NCT04475939) is a phase 3, randomised, double-blind trial comparing efficacy/safety of 1L maintenance therapy with oral nira (200/300 mg/day) + intravenous pembro (200 mg on Day 1 of each 21-day cycle; maximum 35 cycles from 1L ICT initiation) versus placebo + pembro in adults with histologically/cytologically confirmed Stage IIIB-IV NSCLC without known driver mutations and stable disease or partial/complete response to 4-6 cycles of 1L Pt-based ICT + pembro. Patients with asymptomatic BM (off corticosteroids and anticonvulsants for >=7 days) are permitted. Approximately 650 patients will be randomised (1:1), with stratification by histology, PD-L1 status and response to 1L therapy. Treatment will continue until PD, unacceptable toxicity, death, or loss to follow-up. Imaging occurs every 6 weeks (Q6W) for 48 weeks/until PD, and Q12W for patients on treatment thereafter. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Time to central nervous system progression is a key secondary endpoint; others include investigator-assessed PFS, PFS and OS by PD-L1 status, quality of life, safety, and pharmacokinetics. Exploratory analyses are planned. Enrolment began November 2020

Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.

BACKGROUND:Immune checkpoint inhibitors (ICIs) can cause life-threatening cardiovascular adverse events (CVAEs) that may not be attributed to therapy. The outcomes of clinical trials may underestimate treatment-related adverse events due to restrictive eligibility, limited sample size, and failure to anticipate selected toxicities. We evaluated the incidence and clinical determinants of CVAEs in real-world population on ICI therapy. PATIENTS AND METHODS:Among 2 687 301 patients diagnosed with cancer from 2011 to 2018, 16 574 received ICIs for any cancer. Patients in the ICI and non-ICI cohorts were matched in a 1 : 1 ratio according to age, sex, National Cancer Institute comorbidity score, and primary cancer. The non-ICI cohort was stratified into patients who received chemotherapy (N = 2875) or targeted agents (N = 4611). All CVAEs, non-cardiac immune-related adverse events occurring after treatment initiation, baseline comorbidities, and treatment details were identified and analyzed using diagnosis and billing codes. RESULTS:Median age was 61 and 65 years in the ICI and non-ICI cohorts, respectively (P < 0.001). ICI patients were predominantly male (P < 0.001). Lung cancer (43.1%), melanoma (30.4%), and renal cell carcinoma (9.9%) were the most common cancer types. CVAE diagnoses in our dataset by incidence proportion (ICI cohort) were stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). Anti-cytotoxic T-lymphocyte-associated protein 4 increased the risk of heart failure [versus anti-programmed cell death protein 1; hazard ratio (HR), 1.9; 95% confidence interval (CI) 1.27-2.84] and stroke (HR, 1.7; 95% CI 1.3-2.22). Pneumonitis was associated with heart failure (HR, 2.61; 95% CI 1.23-5.52) and encephalitis with conduction disorders (HR, 4.35; 95% CI 1.6-11.87) in patients on ICIs. Advanced age, primary cancer, nephritis, and anti-cytotoxic T-lymphocyte-associated protein 4 therapy were commonly associated with CVAEs in the adjusted Cox proportional hazards model. CONCLUSIONS:Our findings underscore the importance of risk stratification and cardiovascular monitoring for patients on ICI therapy.

Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks.

Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. "Liquid biopsies" are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a sensitivity of 52.6% (p < 0.001). Tissue-NGS showed significantly higher sensitivity and accuracy across multiple patient subgroups, both in newly diagnosed and treated patients, as well as in metastatic and nonmetastatic disease. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, ALK, and NTRK1. In summary, tissue-NGS detects significantly more clinically relevant alterations and therapeutic targets compared to plasma-NGS, suggesting that tissue-NGS should be the preferred method for molecular testing of lung adenocarcinoma when tissue is available. Plasma-NGS can still play an important role when tissue testing is not possible. However, given its low sensitivity, a negative result should be confirmed with a tissue-based assay.

BACKGROUND:We developed and validated a prognostic and predictive computational pathology risk score (CoRiS) using H&E stained tissue images from patients with early-stage non-small cell lung cancer (ES-NSCLC). METHODS:which comprised surgery + chemotherapy were used to validate CoRiS as predictive of added benefit to adjuvant chemotherapy (ACT) by comparing survival between different CoRiS defined risk groups. FINDINGS/RESULTS:(HR = 0.46, adj. P = .08). INTERPRETATION/CONCLUSIONS:CoRiS is a tissue non-destructive, quantitative and low-cost tool that could potentially help guide management of ES-NSCLC patients.

The aim of this study is to evaluate whether NIS radiomics can distinguish lung adenocarcinomas from granulomas on non-contrast CT scans, and also to improve the performance of Lung-RADS by reclassifying benign nodules that were initially assessed as suspicious. The screening or standard diagnostic non-contrast CT scans of 362 patients was divided into training (S_t, N = 145), validation (S_v, N = 145), and independent validation (S_iv, N = 62) sets from different institutions. Nodules were identified and manually segmented on CT images by a radiologist. A series of 264 features relating to the edge sharpness transition from the inside to the outside of the nodule were extracted. The top 10 features were used to train a linear discriminant analysis (LDA) machine learning classifier on St. In conjunction with the LDA classifier, NIS radiomics classified nodules with an AUC of 0.82 ± 0.04, 0.77, and 0.71 respectively on S_t, S_v, and S_iv. We evaluated the ability of the NIS classifier to determine the proportion of the patients in S_v that were identified initially as suspicious by Lung-RADS but were reclassified as benign by applying the NIS scores. The NIS classifier was able to correctly reclassify 46% of those lesions that were actually benign but deemed suspicious by Lung-RADS alone on S_v.