Funded Projects

Although about a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease, a majority will experience death and relapse from their cancer. Exciting recent advances in the use of immune checkpoint inhibition in this early stage space presents a promising way forward for our patients. As the most commonly mutated oncogene, activating KRAS mutations are found in 30% of lung adenocarcinomas; G12C mutations have been associated with higher risk of recurrence following resection. Adagrasib (MRTX849), a potent, highly selective novel small molecule inhibitor of KRAS G12C, has shown promise in previously treated advanced NSCLC. Our study represents a novel application of precision oncology in the resectable NSCLC disease setting with the neoadjuvant use of adagrasib monotherapy or in combination with immune checkpoint inhibition. We will identify safety and clinical efficacy signals of both of these therapeutic approaches. Leveraging our institutional expertise of using single- cell transcriptomics of tumor- infiltrating lymphocytes (TIL), we will evaluate neoantigen-specific transcriptional programs with a focus on KRAS-specific changes, and correlate with clinical outcomes. Overall, our study aims to ultimately improve cure rates of resectable KRAS G12C-mutated NSCLC.

Rearrangement of the BRAF gene results in a potent oncogene that is a driver in 2.8% of NSCLC with BRAF alterations. To date there is no approve targeted therapy for any cancer type with BRAF fusions. Studies by our group and others have shown that mutant-specific BRAF kinase inhibitors do no inhibit BRAF fusion kinases. Instead, pan-RAF inhibitors seem more effective as therapy for cancer cells harboring these fusions. We therefore hypothesize that targeting BRAF fusions with pan-RAF inhibitors are likely to be effective therapy for this molecularly defined subset of NSCLC. Our goal in this proposal is to generate the preclinical data necessary to propel a phase 1 clinical trial of a pan-RAF inhibitor specific to patients with NSCLC harboring a BRAF fusion. We have generated seven preclinical disease models with BRAF rearrangement, including two NSLC patient-derived xenograft models with matching cell lines that will allow this project to go forward immediately. In Aim 1 we propose to generate additional NSCLC PDX, organoid and cell line models that will expand the platforms available to examine the efficacy of these BRAF inhibitors. We will test the efficacy of three pan-RAF inhibitors (LY3009120, belvarafenib, KIN-2787) in vitro and in vivo in Aim 2. We believe that combination therapy may eventually be necessary to extend the duration of response to BRAF targeted therapy. To find candidates that can be exploited for combination therapy, in Aim 3 we will map the signaling pathways that are activated by BRAF fusions in isogenic cell lines and inhibited specifically by BRAF inhibitors in cells with BRAF fusions. Given that resistance to therapy is inevitable, we will seek to generate resistance to the three pan-RAF inhibitors in vitro and in vivo and then identify and validate potential mechanisms of resistance. To be able to bring the goals of this proposal to fruition, I have assembled a team with clinical, translational and basic research expertise to help guide me. As a thoracic oncologist with clinical trial expertise, I am ideally situated to translate the findings of this study to the clinic.

The targeted-therapy (TT) osimertinib is frontline standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) gene. However, nearly all patients develop resistance, at which point treatments are limited. While revolutionary for many cancers, anti-PD-(L)1 immune checkpoint blockade (ICB) has been ineffective in EGFR-mutated(m) NSCLC. Targeting angiogenesis, and specifically vascular endothelial growth factor (VEGF), may be key to changing this. VEGF promotes immunosuppression through multiple mechanisms including inhibition of cytotoxic T-cell trafficking and promotion of regulatory T-cell proliferation. Pre-clinical and clinical evidence has revealed activated EGFR to be a dominant regulator of angiogenesis in EGFRm NSCLC, with increased expression of VEGF and hypoxia inducible factor-1α observed in EGFRm compared to wild-type NSCLC. Clinically, combination chemotherapy with anti-PD-L1 and VEGF blockade has shown efficacy signals in EGFRm NSCLC. However, whether upregulated VEGF potentiates the uninflamed tumor immune microenvironment (TIME), and underlies the observed synergy of these therapies in EGFRm NSCLC, remains unexplored. It is further unknown if VEGF inhibition can be combined with PD-1 blockade to promote benefit in the absence of chemotherapy, or whether blockade of additional checkpoints can further expand anti-tumor immune populations, specifically NK cells, which appear to be upregulated in EGFRm NSCLC responsive to ICB. To address these impactful questions, we have designed a single-arm translationally-focused phase 2 clinical trial assessing the efficacy of tiragolumab (anti-TIGIT) plus atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) in advanced TT-refractory, ICB-naïve, EGFRm NSCLC. Critically, the proposed analyses detailed herein of tumor and blood samples obtained pre- and on-treatment will focus on (1) immunopathologic features of ICB resistance in EGFRm-NSCLC and (2) TIME infiltration and immunologic reprogramming imparted by these therapies. The findings from this study will help to define the innate barriers preventing induction of durable anti-tumor immunity by ICB in EGFRm NSCLC, and identify strategies to overcome them.

Though the introduction of immune checkpoint inhibitors (ICI) has improved outcomes for patients with stage III non-small-cell lung cancer, most patients do not have robust tumor responses to ICI and real-world patients discontinue ICI due to toxicity at a higher rate than clinical trial populations. There is an unmet need to develop predictive models to identify patients at risk of poor ICI response, high risk of ICI toxicity, and high risk of non-cancer mortality, as these patients are unlikely to benefit from ICI and may require treatment intensification or de-intensification, selection of alternative therapies, or enrollment on clinical trials. In this proposal we seek to leverage the richness and national scale of Veterans Affairs (VA) clinical data to develop statistical models to predict ICI efficacy, toxicity, and non-cancer mortality. We will evaluate specific hypotheses generated from preclinical research and use machine-learning approaches to identify new predictors from high-dimensional VA healthcare data. These models will be integrated into a unified multistate model, allowing prediction of the individualized overall survival benefit of ICI for each patient. Clinical decision-making based on model predictions will be compared to other decision making strategies using decision-curve analysis. This work will identify novel biomarkers of ICI efficacy and toxicity, validate putative ICI effect modifiers from the preclinical literature, and develop the first unified model for ICI clinical benefit. If successful, this tool can be used for patient counseling, physician decision-making, and identification of patients likely to benefit from alternative therapies, treatment de-escalation, or clinical trial enrollment.

Despite recent advances, locally advanced non-small cell lung cancer (LA-NSCLC) continues to have a high degree of morbidity and mortality related to both disease progression and sequelae from treatment. The purpose of this study is to develop and evaluate a more personalized radiation therapy (RT) approach with the potential to reduce time and financial burden to patients and increase tumor control. Patients undergoing fractionated RT with concurrent systemic therapy for LA-NSCLC will be treated to a total dose of 60 Gy with the number of fractions determined by ability to meet key dose constraints resulting in a shorter treatment course and higher biologic effective dose (BED) among those treated with shorter fractionation. To reduce the iterative time to determine fractionation schedule and standardize the"‘isotoxic hypofractionation" approach, we will employ a previously developed automated RT planning technique after delineation of the tumor and organs at risk. Fifty patients will be enrolled in a prospective non-randomized 2-stage trial to test the primary objective of whether isotoxic hypofractionation results in an acceptable rate of grade 2 or higher toxicity. Secondary endpoints will include G3+ toxicity, local control, progression free survival and overall survival. Finally, to better inform future "isotoxic" dosing strategies we will evaluate additional predictors of radiation toxicity using established retrospective cohorts through the Stanford Cancer Institute and the Veteran’s Affairs Information and Computing Infrastructure (VINCI).

Our laboratory has demonstrated the potency of the abscopal effect in studies showing that high-dose radiation therapy delivered to primary tumors in combination with dual immune checkpoint blockade can significantly inhibit the growth of satellite tumors. The implication of such results is that radiation therapy has remote effects which are immune-mediated and that new radiation protocols can be devised to exploit our naturally occurring defenses against cancer. Previous studies have shown that immune-mediated tumoricidal effects can be augmented by combining high-dose radiation therapy delivered to a primary tumor site with low-dose radiotherapy (LDRT) targeting secondary tumors. Tumor response is further enhanced if systemic agents are employed to induce immune-checkpoint blockade (ICB). Such protocols employing conventional LDRT are known to reduce the number of regulatory T cells (Tregs) and to activate natural killer cells, thereby modulating the tumor microenvironment (TME). Our laboratory project seeks to test a modification of LDRT called pulsed low-dose-rate radiotherapy (PLDR). By providing radiation in repeated very low doses, the PLDR regimen may reduce the encasement of tumors with stromal elements, thus removing a barrier to infiltrating immune-reactive cells. We propose to use the immunocompetent lung cancer murine model which we developed for our earlier research combining HDRT with anti-PD1 and anti-CTLA-4 antibodies. HDRT will again be delivered to primary tumors in combination with dual ICB. Additionally, LDRT will be delivered to secondary tumors, both in conventional form and as PLDR. The results will thus test an innovative method for exploiting the emerging synergies of radiation and ICB. A demonstration of the superior therapeutic utility of PLDR in our animal model would be of immediate relevance to clinical trials seeking improved strategies for treating patients with metastatic lung cancer.

Background: In recent years, an increasing incidence of lung cancer among young patients (<50 years) has been reported in Europe, Asia, and the United States. Young patients with lung cancer are more likely to be women, of Asian or Hispanic descent, have adenocarcinoma histology, and are more likely to present with distant metastases at diagnosis. Although young patients with lung cancer are more likely to be diagnosed at a disruptive time in their lives and face greater mental health and financial challenges than older patients with lung cancer, we lack data regarding their specific psychosocial needs. The lack of inclusion of young patients in survivorship studies has created a knowledge gap that we propose to remedy with the proposed study.

Aim and Hypothesis: The overarching aim of this study is to define the psychosocial needs of young patients with lung cancer and evaluate important cancer care delivery factors, including financial toxicity, gender and racial differences and study participants’ experiences with the healthcare system. We hypothesize that young patients will have greater unmet psychosocial needs and financial toxicity than older patients with lung cancer.

Methods: This study will utilize an expert, multi-disciplinary research team aligned with patient advocates to deploy an explanatory sequential mixed methods design to understand the needs of young patients with lung cancer. We will conduct a cross-sectional two-arm survey regarding psychosocial distress and financial toxicity among a diverse patient population utilizing two validated questionnaires, the Psychosocial Screen for Cancer (PSSCAN-R) questionnaire and the COmprehensive Score for financial Toxicity (COST) assessment. After the quantitative data collection is completed, we will conduct a preliminary analysis that will guide the discussion in the next phase, where we will conduct four focus groups with young patients with lung cancer to expand and obtain in-depth answers about the issues discovered in the survey portion of the study. The study team will collaborate with experienced biostatisticians and qualitative data researchers to conduct the appropriate statistical analysis.

Results and Dissemination Plan: The study results will be submitted to an international conference and later be published in a high-impact journal. In addition, we will disseminate the study results to the lung cancer patient community via a series of webinars; these webinars will be recorded and later shared with patient advocacy groups and lung cancer organizations.

Long-term Outcomes: Our data will yield insights to inform the oncology community of the barriers encountered by young patients with lung cancer and will allow us to develop the first clinical and research program for young patients with lung cancer in the nation.

Hispanics/LatinX comprise the largest-growing minority group in the United States (U.S.). They account for 18.5% of the total U.S. population1 and are projected to become the largest group in the U.S. by 2045, surpassing NHW. Despite large national representation in the U.S., data demonstrates that this population faces barriers to healthcare access. These barriers are often due, but not limited to socioeconomic status, lack of health insurance, limited medical literacy, language barriers, structural racism, and perceived discrimination. Studies show that Hispanics/LatinX have the highest uninsured rates compared to any other ethnic/racial group, thus limiting their ability to receive equitable health care. This lack of equitable care often leads to Hispanics/LatinX forgoing or delaying medical care, avoiding screening, placing them at elevated risk of an advanced stage of cancer diagnosis. Unlike NHW, cancer remains the most common cause of death in the Hispanic/LatinX population.

LC is the leading cause of cancer-related death for Hispanic/LatinX men and the second most common cause of death for Hispanic/LatinX women. LC carries a 5-year overall survival rate of less than 20%, mainly due to advance stage at diagnosis. Survival rates are even lower for Hispanics/LatinX (13% vs 17%), who are more likely to be diagnosed at advanced stages of LC than their NHW counterparts (59% vs 52%). To increase the rates of early detection, different organizations have supported the use of LDCT as a screening modality in eligible individuals, after results from the NLST showed a 20% mortality reduction in LC with the use of LDCT for screening. Currently, The U.S. Preventive Services Task Force (USPSTF) recommends annual screening for LC in adults 50–80 years of age with at least a 20-pack year smoking history who are current smokers or have quit within the last 15 years. This criterion was extrapolated from the high-risk features in subjects that participated in the NLST that ultimately led to the LC screening recommendations. Unfortunately, the population in the NLST is not an accurate representation of the U.S population, as 95% of the participants were white and only 1.8% were Hispanics. Additionally, studies have shown that LatinX individuals are less aware of LC screening than NHW, but when informed, they are more LatinX interested in pursuing screening (90.7%) compared with non-LatinX (67%).

Besides tobacco use, having a previous malignancy is a risk factor for LC. HNC survivors are at increased
risk of second primary lung cancer compared to the general population, largely due to their heavy smoking history. Patients with tobacco related HNC have up to a 13% risk of developing second primary LC. Currently, the guidelines recommend performing a 3-month post treatment for subjects with head and neck malignancies treated with curative intent. However, NCCN does not advise performing imaging surveillance beyond 6 months in this patient population, unless there are signs and/or symptoms to suggest cancer recurrence. In reference to LC screening, The NCCN recommends annual screening with LDCT for HNC survivors with a smoking history of 20 pack years or more. However, no prospective studies have been performed to assess the risk of second primary LC in this high-risk population. Of the few studies that have been completed, one study completed a post hoc secondary analysis of the NLST to evaluate the incidence of second primary lung cancer in HNC survivors screened with low dose CT (LDCT) versus chest x-ray (CXR). Out of X participants, 171 HNC survivors had undergone screening. Of these, 90.1% identified as White, 4.1% as Black, and 0% as Hispanic or LatinX and lung cancer was identified in 20 (12%) of the HNC survivors screened. A total of 15% (12/82) and 9% (8/89) of the HNC survivors screened with LDCT and CXR, respectively, were diagnosed with LC. The study found a higher LC incidence in HNC survivors compared to participants without head and neck cancer, with an adjusted rate ratio of 2.54 (95% CI, 1.63-3.95). Additionally, the study found an average smoking history of 80 pack years amongst HNC survivors compared to 48 pack years in the rest of the study population.

The study proposed here will fill an important gap and assess the awareness and eligibility of lung cancer
screening in Hispanic/LatinX HNC survivors via a survey questionnaire and understand the barriers to
screening via qualitative interviews. We will create the first lung cancer screening program tailored for and focused exclusively on Hispanic/LatinX HNC survivors.

Despite significant progress in the development of novel biomarkers and therapies for lung cancer, such progress has not equitably benefitted all population groups in the United States (US). Racial and ethnic minorities, low income, uninsured, and underinsured individuals with non-small cell lung cancer (NSCLC) continue to experience disparate access to diagnostics tests and treatments, and experience inferior outcomes. These disparities are, at least, partially driven by social context (i.e., social determinants of health). Patients with NSCLC experience high rates of financial hardship and unmet supportive needs, making them a population likely to have high rates of health-related social needs. The prevalence of social needs in patients with NSCLC and their impact on healthcare utilization, cancer outcomes, and quality of life (QOL) remains unknown. To fill this important knowledge gap, we propose an observational, prospective cohort study of 150 patients with unresectable lung cancer receiving first-line systemic therapy. Our study has two primary goals (Aims): 1) Prospectively quantify the prevalence of social needs and determine the associations between social needs, acute care utilization, and QOL; 2) investigate how patient’s social needs influence oncology providers’ clinical decisions for outpatient cancer care of adults with unresectable NSCLC. To achieve these goals, we will conduct serial survey assessments of 150 patients with unresectable NSCLC and conduct semi-structured interviews with 30 oncology providers. This study is significant as it is the first study longitudinally evaluating social needs during cancer therapy in patients with NSCLC. This study will fill a key knowledge gap and inform interventions focused on identifying and supporting patients at risk of social adversity during cancer treatment.

Anti–PD-1 therapy has transformed the management of NSCLC, but only a subset of patients respond to anti–PD-1 therapy, and responses are rarely curative. Understanding the effects of anti–PD-1 therapy on the composition and functional state of tumor-associated immune subsets can identify mechanisms of response and resistance to anti–PD-1 therapy and provide insights into rational combination strategies to improve upon response rates. Although the effects of anti–PD-1 therapy within the tumor immune microenvironment in preclinical and human subjects have been previously reported, we propose to broadly characterize the effects of anti–PD-1 therapy on the tumor draining lymph nodes (TDLN). Studying the TDLN is particularly valuable because it is the primary sites at which the tumor antigen exposure and the main site of immune T-cell differentiation. To determine the effect of ICI response in the lymph node, we have created an immunocompetent murine model that recapitulates early-stage treatment and outcomes in patients. Additionally, we have characterized TDLN T cells from early-stage cancer patients and have been able to recapitulate our preclinical findings of unique memory T-cell subsets. Our preliminary results of the immune cell type composition, checkpoint expression, and cytokine expression within TDLNs suggest that there are major remodeling events within the TDLN mediated by anti–PD-1 therapy that are critical for conferring effective antitumor long-term immune responses. We demonstrate that unique memory T cell subsets undergo significant activation, expansion, and maturation in response to anti–PD-1 therapy, to shape antitumor programming in TDLNs. Importantly, our proposed study will provide a methodological demonstration in both a murine model and human TDLN that simultaneous uses Flowcytometry, functional immune assays and single cell sequencing that will enable deep interrogation of the immune profile to PD-1 inhibition resistant and responsive patients.

On-/off-target resistance mechanisms to RET tyrosine kinase inhibition (TKI) are not identified in ~40% of patients with RET fusion-positive lung cancers. As such, focusing solely on genomic alterations (e.g. mutation/amplification) limits our ability to develop novel therapies for all patients. This project addresses the unmet need of identifying and characterizing alternate resistance mechanisms to selective RET TKI therapy via epigenetic mechanisms leading to altered programs of gene expression. As with other oncogene-TKI pairs, we hypothesize that epigenetic re-programming and lineage plasticity drives resistance to RET TKIs. Serial pre- and post-TKI tumor samples will be interrogated (DEG/GSEA analysis) via complementary methylome (EPIC) and transcriptomic (RNAseq) profiling. Pathologic review and immunohistochemical profiling for markers of squamous (p40, CK5/6), small cell (chromogranin, synaptophysin), and epithelial-mesenchymal (E/N-cadherin, vimentin) transformation will be performed. Candidate resistance pathways will be explored in engineered isogenic overexpression/knockout models and our institutional library of xenografts generated from patients treated with a selective RET TKI on a registrational program or standard of care. Genetic manipulation of targets that we and others have associated with licensing lineage plasticity (e.g. myrAKT, MYC, EZH2, and beta-catenin) in RET fusion-positive models to induce histologic transformation will be performed. These analyses will define strategies to constrain or abrogate therapeutic resistance.

RET fusions occur in 2-3% cases of lung cancer and there are currently two FDA-approved RET-specific inhibitors, selpercatinib and pralsetinib, for the treatment of patients with RET fusion positive lung or thyroid cancers. Therapeutic resistance eventually emerges, however, and studies have shown that RET-dependent mechanisms of resistance include acquired resistance mutations that alter drug binding. Further, RET fusions and mutations are heterogeneous and the impact of specific fusion partners and RET variants on drug sensitivity is poorly understood. In a recent publication in Nature, our group reported that for a related driver oncogene, EGFR, both primary and acquired resistance mutations can be classified into distinct structural groups that correlate with drug sensitivity and resistance. This structure-function based classification has important advantages 1) structure-based groups predicted drug response significantly better than standard exon-based approaches, 2) this classification enabled us to match drugs for more than ~99% of atypical mutations where currently less than 50% of mutations have an FDA approved drug. In addition, preliminary preclinical and clinical data suggests that two RET-independent mechanisms of resistance- signal bypass and lineage shift-may also drive resistance even in the presence of effective RET inhibition. Applying methodologies we established for elucidating EGFR inhibitor resistance, we will develop a structure-function based classification which can immediately impact clinical decisions for selecting therapies; comprehensively characterize RET-dependent and -independent mechanisms of resistance and biomarkers to assess them; and develop rational therapeutic strategies to overcome resistance which can guide patient selection for future clinical studies.