Faculty Bibliography

Tumor vasculature is a key component of the tumor microenvironment that can influence tumor behavior and therapeutic resistance. We present a new imaging biomarker, quantitative vessel tortuosity (QVT), and evaluate its association with response and survival in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) therapies. A total of 507 cases were used to evaluate different aspects of the QVT biomarkers. QVT features were extracted from computed tomography imaging of patients before and after ICI therapy to capture the tortuosity, curvature, density, and branching statistics of the nodule vasculature. Our results showed that QVT features were prognostic of OS (HR = 3.14, 0.95% CI = 1.2 to 9.68, P = 0.0006, C-index = 0.61) and could predict ICI response with AUCs of 0.66, 0.61, and 0.67 on three validation sets. Our study shows that QVT imaging biomarker could potentially aid in predicting and monitoring response to ICI in patients with NSCLC.

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.

Background: The Ph1 AMBER study (NCT02817633) showed that cobolimab (GSK4069889, TIM-3 inhibitor) + dostarlimab (PD-1 inhibitor) had an acceptable safety profile in heavily pretreated, PD-1/PD-L1 relapsed/refractory (RR), advanced or metastatic NSCLC. COSTAR Lung (NCT04655976) compares efficacy and safety of cobolimab + dostarlimab and SOC chemotherapy (CT, docetaxel; Arm A) to dostarlimab + docetaxel (Arm B) to docetaxel (Arm C) in PD-1/PD-L1 RR NSCLC.
Method(s): This is an ongoing global, multicenter, parallel-group treatment, randomized, Ph2, open-label, 3-arm study, with potential Ph3 expansion. Pts are >=18 years, with advanced/metastatic NSCLC who received <=2 prior lines of therapy including anti-PD-1/PD-L1 therapy plus platinum-based CT only. Other inclusion criteria include documented disease progression (PD) on prior therapy, no sensitizing EGFR, ALK or ROS-1 mutations, and ECOG PS 0-1. Pts randomized 2:2:1 to Arms A, B, or C will receive cobolimab (300mg IV), dostarlimab (500 mg IV), and/or docetaxel (75 mg/m2 IV) Q3W. Cobolimab + dostarlimab will continue until PD, unacceptable toxicity, withdrawal, investigator decision, or death. Docetaxel will continue for >=4 cycles or until unacceptable toxicity or PD. Primary endpoint: OS in Arms A or B vs C. Secondary endpoints: OS in Arm A vs B and investigator-assessed confirmed objective response rate (ORR); progression-free survival (PFS) and duration of response (RECIST v1.1); quality of life assessments; safety; and tolerability. Exploratory endpoints: investigator-assessed confirmed ORR and PFS (iRECIST), pharmacokinetics, biomarkers of response, and pt-reported efficacy/tolerability.
Result(s): Discussion:
Conclusion(s): Approximately 250 pts will be randomized to Ph2 portion with interim analysis planned after >=18 weeks follow-up; with an additional 500 pts (Arms A-B [n=200 each] and Arm C [n=100]) in Ph3 portion

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.

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.

BACKGROUND:T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity. METHODS:SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures. RESULTS:T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis. CONCLUSIONS:mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.

4-1BB has been considered a promising target in cancer immunotherapy for decades. Nevertheless, early 4-1BB-targeted agent demonstrated significant liver immuno-toxicity. A new wave of 4-1BB-based therapy is being developed to circumvent hepatotoxicity with bispecific molecule that directs 4-1BB agonism to the tumor microenvironment by targeting tumor-associated immune checkpoint molecule, PD-L1.

PURPOSE/OBJECTIVE:Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic (PK) properties, including long half-life (~24 hours), extensive tissue distribution, dose-dependent PK, and central nervous system penetration, however BM-specific anti-tumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN/METHODS:A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and PK properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with anti-tumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg BID in the Phase 1b cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and anti-tumor activity in BM evaluated. RESULTS:Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM ({greater than or equal to}40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS:These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM.

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.