Faculty Bibliography

BACKGROUND:The anti-programmed death receptor-1 (anti-PD-1) pembrolizumab is approved as first-line monotherapy for metastatic non-small cell lung cancer (mNSCLC) with PD-ligand 1 (PD-L1) tumor expression ≥50%. Most studies comparing PD-L1 results by immunohistochemistry (IHC) assay type have been conducted by prespecified and, in most cases, highly experienced, trained pathologists; however, knowledge is limited regarding the current use and concordance of PD-L1 assays in the real-world clinical setting. Our aim was to study the distribution of PD-L1 tumor expression by IHC assay type among patients with mNSCLC in US oncology practices. METHODS:This retrospective observational study utilized de-identified, longitudinal data from a large US electronic medical record database. Eligible patients were adults (≥18 years) with histologically/cytologically confirmed initial diagnosis of metastatic or recurrent NSCLC from October 2015 through December 2017. We determined PD-L1 testing trends and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type. RESULTS:The 12,574 eligible patients (mean age, 69 years) included 6,620 (53%) men and 86% with positive smoking history. Of 4,868 evaluable tests, 3,799 (78%), 195 (4%), 165 (3%), and 709 (15%) used the Agilent 22C3 pharmDx, Agilent 28-8 pharmDx, Ventana PD-L1 (SP142) Assay, and laboratory-developed tests (LDTs, including SP263), respectively. The percentages of tests scoring PD-L1 tumor expression of ≥50% were 33%, 32%, 10%, and 23%, respectively. Measured PD-L1 tumor expression varied across the four assay types (χ2 p < 0.001) and across three assay types excluding SP142 (p < 0.001), with no significant difference between 22C3 and 28-8 assays (p = 0.96). The PD-L1 testing rate increased from 18% in the fourth quarter of 2015 to 71% in the fourth quarter of 2017. CONCLUSIONS:In the real-world clinical setting, we observed that measured PD-L1 tumor expression is concordant using the 22C3 and 28-8 assays; however, the SP142 assay and LDTs appear discordant and could underestimate high PD-L1 positivity. Further study is needed to evaluate the association between PD-L1 tumor expression and response to therapy.

BACKGROUND:The absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before and after treatment with nivolumab, are indicative markers of overall survival (OS) and evaluated change in NLR as a predictive marker of response in non -small cell lung cancer (NSCLC) patients treated with nivolumab. METHODS:A total of 109 patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio were examined with Kaplan-Meier curves and proportional hazard model. RESULT/RESULTS:Post-treatment NLR ≥5 after two cycles of nivolumab was associated with poor OS (median OS in NLR = <5 vs NLR = ≥5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2) months respectively, p<0.001). In addition NLR increased in non-responders after two cycles of nivolumab by 6.6±21.8 as compared to responders (p = 0.027). CONCLUSIONS:Post-treatment ANC, ALC and NLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response in NSCLC patients treated with nivolumab.

Adenocarcinomas and active granulomas can both have a spiculated appearance on computed tomography (CT) and both are often fluorodeoxyglucose (FDG) avid on positron emission tomography (PET) scan, making them difficult to distinguish. Consequently, patients with benign granulomas are often subjected to invasive surgical biopsies or resections. In this study, quantitative vessel tortuosity (QVT), a novel CT imaging biomarker to distinguish between benign granulomas and adenocarcinomas on routine non-contrast lung CT scans is introduced. Our study comprised of CT scans of 290 patients from two different institutions, one cohort for training (N = 145) and the other (N = 145) for independent validation. In conjunction with a machine learning classifier, the top informative and stable QVT features yielded an area under receiver operating characteristic curve (ROC AUC) of 0.85 in the independent validation set. On the same cohort, the corresponding AUCs for two human experts including a radiologist and a pulmonologist were found to be 0.61 and 0.60, respectively. QVT features also outperformed well known shape and textural radiomic features which had a maximum AUC of 0.73 (p-value = 0.002), as well as features learned using a convolutional neural network AUC = 0.76 (p-value = 0.028). Our results suggest that QVT features could potentially serve as a non-invasive imaging biomarker to distinguish granulomas from adenocarcinomas on non-contrast CT scans.

The current standard of Response Evaluation Criteria in Solid Tumors (RECIST)-based tumor response evaluation is limited in its ability to accurately monitor treatment response. Radiomics, an approach involving computerized extraction of several quantitative imaging features, has shown promise in predicting as well as monitoring response to therapy. In this article, we provide a brief overview of radiomic approaches and the various analytical methods and techniques, specifically in the context of predicting and monitoring treatment response for non-small cell lung cancer (NSCLC). We briefly summarize some of the various types of radiomic features, including tumor shape and textural patterns, both within the tumor and within the adjacent tumor microenvironment. Additionally, we also discuss work in delta-radiomics or change in radiomic features (e.g., texture within the nodule) across longitudinally interspersed images in time for monitoring changes in therapy. We discuss the utility of these approaches for NSCLC, specifically the role of radiomics as a prognostic marker for treatment effectiveness and early therapy response, including chemoradiation, immunotherapy, and trimodality therapy.

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corepressors rebalances to coactivator function, activating lineage-differentiation genes that dominantly antagonize MYC (the master transcription factor coordinator of replication) to terminate malignant self-replication. Physiologic self-replication continues, because the master transcription factors in tissue stem cells activate stem cell, not terminal-differentiation, programs. Druggable corepressor proteins are thus the barriers between self-replicating cancer cells and the terminal-differentiation fates intended by their master transcription factor content. This final common pathway to oncogenic self-replication, being separate and distinct from the normal, offers the favorable therapeutic indices needed for clinical progress.

BACKGROUND:IL-15 induces the activation and proliferation of NK and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) over recombinant human IL-15 (rhIL-15) in animal models, we performed this first-in-human Phase I trial of ALT-803 in patients with advanced solid tumors. METHODS:Patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer were treated with ALT-803 0.3-6 mg/kg weekly i.v. or 6-20 mg/kg weekly s.c. for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. RESULTS:Twenty-four patients were enrolled; eleven received i.v. and 13 received s.c. ALT-803. Of these patients, 9 had melanoma, 6 renal, 3 head and neck, and 6 lung cancer. Although total lymphocyte and CD8+ T cell expansion were modest, NK cell numbers rose significantly. Neither anti-ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well-tolerated, with adverse effects including fatigue and nausea most commonly with i.v. administration, while painful injection site wheal was reported most commonly with s.c. ALT-803. CONCLUSIONS:Subcutaneous ALT-803 produced the expected NK cell expansion and was well-tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in advanced cancer patients. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anti-cancer agents.