Faculty Bibliography

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.

Squamous cell lung cancers (lung squamous cell carcinomas [LUSCs]) are associated with high mortality and a lack of therapies specific to this disease. Although recurrent molecular aberrations are present in LUSCs, efforts to develop targeted therapies against receptor tyrosine kinases, signaling transduction, and cell cycle checkpoints in LUSCs were met with significant challenges. The present therapeutic landscape focuses on epigenetic therapies to modulate the expression of lineage-dependent survival pathways and undruggable oncogenes. Another important therapeutic approach is to exploit metabolic vulnerabilities unique to LUSCs. These novel therapies may synergize with immune checkpoint inhibitors in the right therapeutic context. For example, the recognition that alterations in KEAP1-NFE2L2 in LUSCs affected antitumor immune responses created unique opportunities for targeted, metabolic, and immune combinations. This article provides a perspective on how lessons learned from the past influence the current therapeutic landscape and opportunities for future drug development for LUSCs.

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.

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRAS^G12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

Objective: Immunotherapy used with or without chemotherapy has demonstrated significant clinical outcomes for non-small cell lung cancer (NSCLC) patients. The CheckMate-227 trial has shown that nivolumab plus ipilimumab indicates significant survival benefits as first-line treatment for non-squamous, advanced NSCLC patients. The KeyNote-189 trial has also concluded that pembrolizumab plus chemotherapy achieves efficacy for patients with the same disease characteristics as in CheckMate-227. The paper studied the cost-effectiveness of nivolumab plus ipilimumab vs. pembrolizumab plus chemotherapy as the first-line treatment for non-squamous, advanced NSCLC for adult patients from the US payer's perspective.
Method(s): A Markov model was built to analyze the cost-effectiveness of nivolumab plus ipilimumab in the first-line treatment of metastatic NSCLC. The health outcomes were estimated in quality-adjusted life-years (QALYs) and were obtained from the literature. The cost information was from Veteran Affairs (VA) catalogue Federal Supply Schedule (FSS) price in 2021. In addition to the base case incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB), probabilistic and one-way sensitivity analyses were also conducted to examine the impact of uncertainties on the results.
Result(s): In the base case, the incremental costs and QALYs in the nivolumab plus ipilimumab group were ($87, 795.30) and (0.13) for advanced NSCLC patients regardless of PD-L1 expression, which led to an ICER of $674, 610.82 per QALY and an INMB of $68, 273.98. When parameters varied from the deterministic estimates, the INMB results were the most sensitive around the utility of progressive disease state for both groups. The probability sensitivity analysis showed that using a willingness-to-pay threshold of $150,000 per QALY, the probability of nivolumab plus ipilimumab being cost-effective was 87.3%.
Conclusion(s): Nivolumab plus ipilimumab was not found to be cost-effective at the willingness to pay threshold of $150,000 per QALY as compared with pembrolizumab plus chemotherapy for non-squamous, metastatic NSCLC patients.
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PURPOSE/OBJECTIVE:Tumor-associated vasculature is distinguished its convolutedness, leakiness, and chaotic architecture, which facilitates the creation of a treatment resistant tumor microenvironment. Measurable differences in these attributes might help stratify patients by potential benefit of systemic therapy. In this work, we present a new category of radiomic quantitative tumor-associated vasculature (QuanTAV) biomarkers and investigate their ability to predict outcomes across multiple cancers, imaging modalities, and treatment regimens. EXPERIMENTAL DESIGN/METHODS:We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization using routine pre-treatment radiology (computed tomography or contrast-enhanced MRI) from 558 patients total, who received one of four therapeutic intervention strategies for breast (n=371) or non-small cell lung cancer (NSCLC, n=187). QuanTAV response scores and risk scores/groups were derived and then assessed for response and survival prediction for each therapy. RESULTS:Classifiers of QuanTAV measurements significantly (p<.05) predicted response in held out testing cohorts alone (AUCs=0.63-0.71). Similarly, QuanTAV risk scores were prognostic of recurrence-free survival in treatment cohorts for breast cancer chemotherapy-only (p=0.0022, HR=1.25, 95% CI 1.08-1.44, C-index=.66) and NSCLC chemoradiation+surgery (p=0.039, HR=1.28, 95% CI 1.01-1.62, C-index=0.66) cohorts. QuanTAV high/low risk groups were independently prognostic among all treatments, including chemotherapy-only NSCLC patients (p=0.034, HR=2.29, 95% CI 1.07-4.94, C-index=0.62). CONCLUSIONS:Across domains, we observed an association of vascular morphology on CT and MRI - as captured by metrics of vessel curvature, torsion, and organizational heterogeneity - and treatment outcome. Our findings suggest the potential of shape and structure of the tumor-associated vasculature as biomarkers for multiple cancers and treatments.

Introduction/UNASSIGNED:Evidence supports the addition of immunotherapy to definitive chemoradiation for unresectable stage IIIA NSCLC. Adding pembrolizumab to neoadjuvant chemoradiation in patients with resectable stage IIIA NSCLC requires study for safety and feasibility. Methods/UNASSIGNED:Patients with resectable stage IIIA NSCLC received neoadjuvant cisplatin, etoposide, and pembrolizumab concurrently with thoracic radiotherapy of 45 Gy in 25 fractions. Patients without progression underwent resection followed by 6 months of consolidation pembrolizumab. Safety and feasibility were defined as less than or equal to 30% grade 3 or higher pulmonary toxicity or any grade 4 or 5 nonhematologic toxicity. A total of 10 patients were to be enrolled initially. If less than or equal to two patients had events, another 10 were to be enrolled. Results/UNASSIGNED:The study closed after enrolling nine patients. The median age was 66 (range: 49-76) years. A total of 67% were female. Median follow-up was 38.3 months. Serious adverse events occurred in seven patients, including two grade 5 events: one sudden cardiac arrest in the neoadjuvant phase and one fatal pneumocystis pneumonia after resection. Eight patients were assessable for response. The overall response rate was 67%. Six underwent complete resection. Four achieved pathologic complete response, whereas one additional patient had complete nodal clearance. Median progression-free survival has not been reached. The 3-year overall survival was 64%. Conclusions/UNASSIGNED:Adding pembrolizumab to neoadjuvant concurrent cisplatin, etoposide, and radiotherapy in resectable stage IIIA NSCLC resulted in an encouraging pathologic complete response rate. Higher-than-expected toxicities necessitated trial closure after meeting the rule for infeasibility. The relationship of grade 5 events to the addition of pembrolizumab is unclear.

Objective/UNASSIGNED:(AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (INV). We sought to develop and evaluate a quantitative imaging method to determine invasiveness of small, ground-glass lesions on computed tomography (CT) chest scans. Methods/UNASSIGNED:N=162). Results/UNASSIGNED:(AUC=0.909, p<0.001). Conclusions/UNASSIGNED:radiomics to the routine visual assessment of CT scans help better differentiate adenocarcinoma subtypes and can aid in clinical decision making. Further prospective validation in this direction is warranted.

Immune checkpoint inhibitors (ICIs) show prominent clinical activity across multiple advanced tumors. However, less than half of patients respond even after molecule-based selection. Thus, improved biomarkers are required. In this study, we use an image analysis to capture morphologic attributes relating to the spatial interaction and architecture of tumor cells and tumor-infiltrating lymphocytes (TILs) from digitized H&E images. We evaluate the association of image features with progression-free (PFS) and overall survival in non-small cell lung cancer (NSCLC) (N = 187) and gynecological cancer (N = 39) patients treated with ICIs. We demonstrated that the classifier trained with NSCLC alone was associated with PFS in independent NSCLC cohorts and also in gynecological cancer. The classifier was also associated with clinical outcome independent of clinical factors. Moreover, the classifier was associated with PFS even with low PD-L1 expression. These findings suggest that image analysis can be used to predict clinical end points in patients receiving ICI.