Faculty Bibliography

BACKGROUND:Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination. METHODS:A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles. RESULTS:Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose-limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1). CONCLUSION:The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.

UNLABELLED:. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)-key downstream effectors of LKB1- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCE/CONCLUSIONS:tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

BACKGROUND:The use of immune checkpoint inhibitors (ICIs) in the front-line treatment of advanced non-small-cell lung cancer (NSCLC) is currently the standard of care. However, as clinical trials include a very limited number of elderly patients, evidence on the safety and efficacy of using ICI-based regimens is still limited. METHODS:A virtual International Expert Panel took place in July 2022 to review the available evidence on the use of ICI-based regimens in the first-line setting in elderly patients with NSCLC and provide a position paper on the field both in clinical practice and in a research setting. RESULTS:All panelists agreed that age per se is not a limitation for ICI treatments, as the elderly should be considered only as a surrogate for other clinical factors of frailty. Overall, ICI efficacy in the elderly population is supported by reviewed data. In addition, the panelists were confident that available data support the safety of single-agent immunotherapy in elderly patients with NSCLC. Conversely, concerns were expressed on the safety of chemo + ICI-based combination, which were considered mainly related to the toxicities of chemotherapy components. Therefore, suggestions were proposed to tailor combined approaches in the elderly patients with NSCLC. The panelists defined high, medium, and low priorities in clinical research. High priority was attributed to implementing the real-world assessment of elderly patients treated with ICIs, who are mostly underrepresented in pivotal clinical trials. CONCLUSIONS:Based on the current evidence, the panelists outlined the significant limitations affecting the clinical practice in elderly patients affected by NSCLC, and reached common considerations on the feasibility, safety, and effectiveness of ICI monotherapy and ICI combinations in the first-line setting.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

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.