Faculty Bibliography

Many decades in the making, immunotherapy has demonstrated its ability to produce durable responses in several cancer types. In the last decade, immunotherapy has shown itself to be a viable therapeutic approach for non-small cell lung cancer (NSCLC). Several clinical trials have established the efficacy of immune checkpoint blockade (ICB), particularly in the form of anti-programmed death 1 (PD-1) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies and anti-programmed death 1 ligand (PD-L1) antibodies. Many trials have shown progression free survival (PFS) and overall survival (OS) benefit with either ICB alone or in combination with chemotherapy when compared to chemotherapy alone. The identification of biomarkers to predict response to immunotherapy continues to be evaluated. The future of immunotherapy in lung cancer continues to hold promise with the development of combination therapies, cytokine modulating therapies and cellular therapies. Lastly, we expect that innovative advances in technology, such as artificial intelligence (AI) and machine learning, will begin to play a role in the future care of patients with lung cancer.

Objectives/UNASSIGNED:The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US). Methods/UNASSIGNED:genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Results/UNASSIGNED:Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). Conclusions/UNASSIGNED:-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.

Objectives/UNASSIGNED:Immune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status. Methods/UNASSIGNED:genomic aberration, and ECOG performance status 0-1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR). Results/UNASSIGNED:The EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0-52.7) and 38.4 months (range, 33.1-44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6-24.3) and 21.1 months (95% CI, 16.2-28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7-9.2); 88 patients (38.6%; 95% CI, 32.2-45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]). Conclusions/UNASSIGNED:Real-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.

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 Immune checkpoint inhibitors (ICI) have revolutionized the management of lung tumors decreasing mortality rates. However, the response rates to these ICI drugs are limited, and identifying those patients who are most likely to benefit remains a clinical challenge. Due to the complex nature of the host immune response, tissue-based biomarker development for immunotherapy (IO) is challenging. Consequently, there is a critical unmet need to develop accurate, validated imaging biomarkers to predict which Non-Small Cell Lung Cancer (NSCLC) patients will benefit from IO. Airway deformations such as central airway obstruction can be considered an important manifestation of cancer aggressiveness or metastatic disease and may have a significant impact on therapeutic refractoriness. In this study, we sought to evaluate whether quantitative measurements of lung airway morphology (QuaLM) on baseline CT scans are associated with response and overall survival in NSCLC patients treated with ICI. Methods In this retrospective study, 80 cases who underwent 2-3 cycles of PD1/PD-L1 ICI therapy (nivolumab/pembrolizumab/ atezolizumab) were included. RECIST v1.1 was used to define 'responders' and 'non-responders'. Patients were randomly divided into a training (n=40) and a test set (n=40). A region growing algorithm is applied to the trachea, identified by Hough transform, to segment bronchi and bronchioles (figure 1a). 14 QuaLM features were extracted from segmented airway on CT scans. Wilcoxson ranksum test is used to identify the predictive QuaLM features. The top 4 QuaLM features in conjunction with a linear discriminant machine learning classifier were used to predict the response to IO. We also built a QuaLM risk score using the least absolute shrinkage and selection operator (LASSO) Cox regression model to predict overall survival (OS). Results The response prediction model trained with top QuaLM features (table 1) predicts responders to ICI with an area under research operating characteristic curve (ROC AUC) of 0.67+/-0.08 (figure 1.b) in the training (St) and AUC=0.63 in the test set (Sv). The airway radiomics risk-score was found to be significantly associated with OS in St (HR=2.34, 95% CI:[1.08-5.07], P=0.008) and Sv (HR=2.55, 95% CI:[0.8- 8.1], P=0.034) (figure 1.c). Conclusions QuaLM features were able to distinguish responders from non-responders and also were found to be associated with OS for NSCLC patients treated with ICI. With additional validation, QuaLM could potentially serve as an imaging biomarker of ICI response assessment for NSCLC patients. This could allow the selection of NSCLC patients who will benefit from IO and help design more rational clinical trials with a combination of IO

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: 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