Faculty Bibliography

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.

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.

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.

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: 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.
Copyright

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.

BACKGROUND:Tumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored. METHODS:B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI. The analysis of full-face tumor biopsies including numerous fields of view allowed a detailed spatial analysis and assessment of tumor immune heterogeneity using a multiparametric quadratic entropy metric (Rao's Q Index (RQI)). RESULTS:cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases. The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed measuring the T cell receptor-burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort. CONCLUSION/CONCLUSIONS:Baseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC.

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.