Perioperative Immunotherapy in Non-Small Cell Lung Cancer.

OPINION STATEMENT: The standard of care in patients with early-stage non-small cell lung cancer (NSCLC) following surgical resection has been adjuvant chemotherapy for the last two decades, despite modest improvements in survival and high rates of disease recurrence. Numerous clinical trials have reported practice-changing findings demonstrating a benefit in disease-free survival (DFS) or event-free survival (EFS) with perioperative immunotherapy. This has led to several recent regulatory approvals supporting the use of adjuvant immunotherapy or neoadjuvant immuno-chemotherapy in NSCLC, and such therapies are now an integral component of care for early-stage disease. However, in select cases, such as in the presence of certain tumor oncogenes associated with immunotherapy resistance, the use of checkpoint inhibitors in the perioperative setting should generally be avoided. This speaks to the importance of integrating routine tissue-based molecular profiling, that evaluates for tumor oncogene mutations and PD-L1 expression, into our practice when caring for patients with early-stage NSCLC. While an overall survival (OS) advantage has yet to be firmly established from many of the recent studies evaluating perioperative immunotherapy, it is expected that an OS benefit and higher rates of cure will become evident as these data mature, especially among patients with greater levels of tumor PD-L1 expression.

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab. METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response. CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

Real-world progression-free survival (rwPFS) and the impact of PD-L1 and smoking in driver-mutated non-small cell lung cancer (NSCLC) treated with immunotherapy.

PURPOSE: Prior data suggest driver-mutated NSCLC, especially EGFR and ALK tumors, poorly respond to immunotherapy. However, little research using real-world cohorts have been performed, nor is it clear whether PD-L1 and smoking history are predictive of outcomes in such tumors. This study assessed rwPFS in a large cohort with driver-mutated advanced NSCLC treated with single-agent PD-1/PDL-1 inhibitors. METHODS: Real-world data from 1746 patients were analyzed and rwPFS with immunotherapy was determined for EGFR, ALK, BRAF, and KRAS tumors. Kaplan-Meier curves characterized rwPFS and correlated with PD-L1 and smoking history. Comparisons were tested using log-rank. RESULTS: Median rwPFS and the percent progression-free at 12 months were greater among KRAS (3.3 months, 21.1%) and BRAF (3.6 months, 20.6%) as compared to EGFR (2.5 months, 8.1%) and ALK tumors (2.3 months, 11.2%). KRAS tumors with PD-L1 ≥ 1% had longer rwPFS than PD-L1 < 1% tumors (4.1 versus 3.2 months, p = 0.001). PD-L1 positivity did not predict rwPFS in EGFR, ALK, or BRAF tumors. However, a smoking history was associated with longer rwPFS in EGFR (2.6 versus 2.3 months, p = 0.048) and ALK tumors (3.0 versus 2.1 months, p = 0.049) as compared to no smoking history. CONCLUSION: Real-world PFS with immunotherapy was greater in KRAS and BRAF as compared to EGFR and ALK tumors. PD-L1 positivity was predictive in KRAS and not associated with rwPFS in other mutation types. While median rwPFS was short for EGFR and ALK tumors, small subsets were progression-free at 12 months. Better characterizing these subsets that benefit, along with developing strategies to overcome immunotherapy resistance in EGFR/ALK tumors are needed.

Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas.

Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in gastric, breast, and lung cancer. We characterized the molecular subtypes of non-small cell lung cancer (NSCLC) expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. 9790 NSCLC tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median, 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden (TMB) (≥10 mutations per megabase; 44% vs. 28% in Q1, p < 0.001). Increased KK-LC-1 expression was associated with increased M1 macrophage abundance. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB. TCR-T therapy directed against KK-LC-1 should be considered in patients whose clinical features reflect these characteristics.

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors.

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.

Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC).

The emergence of immunotherapy has dramatically changed how non-small cell lung cancer is treated, and longer survival is now possible for some patients, even those with advanced disease. Although some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Given this, biomarkers that predict response to therapy are essential, and testing for tumor programmed death ligand 1(PD-L1) expression is the current standard. The extent of PD-L1 expression determined by immunohistochemistry (IHC) has demonstrated a correlation with treatment response, although limitations with this marker exist. Recently, tumor mutational burden has emerged as an alternative biomarker, and studies have demonstrated its utility, irrespective of the PD-L1 level of a tumor. Gene expression signatures, tumor genotype (such as the presence of an oncogenic driver mutation), as well as the density of tumor-infiltrating lymphocytes in the tumor microenvironment also seem to affect response to immunotherapy and are being researched. Peripheral serum markers are being studied, and some have demonstrated predictive ability, although most are still investigational and need prospective validation. In the current article, the authors review the biomarker PD-L1 as well as other emerging and investigational tissue-based and serum-based markers that have potential to better predict responders to immunotherapy.

Outcomes of patients with disease recurrence after treatment for locally advanced non-small cell lung cancer detected by routine follow-up CT scans versus a symptom driven evaluation.

OBJECTIVES: The majority of patients with locally advanced non-small cell lung cancer (LANSCLC) will recur after receiving multimodal treatment with curative intent. Current guidelines recommend routine follow-up with computerized tomography (CT) scans, though minimal data exist on the utility of this approach nor has an optimal follow-up strategy to detect recurrence been defined. This study examined whether survival varied if relapse was detected with scheduled follow-up CT versus symptoms, and whether the pattern of recurrence affected these outcomes. MATERIALS AND METHODS: Single institution retrospective review of patients who had undergone definitive management of LANSCLC with chemoradiotherapy +/- surgical resection. Standard follow-up testing consisted of routine exam and chest CT beginning at every 3 months in the first year and decreasing to annually after the fifth year. RESULTS: 311 patients were assessed, of which 167 patients recurred and were evaluable. 104 progressions were detected by follow-up and 63 by symptoms. For the entire group, there was no difference in overall survival (OS) for those detected by scans vs. symptoms (7.6 vs. 6.1 months, p = 0.797). After excluding patients with oligometastatic (1-3) brain metastases (OBM), OS was superior in patients with scan detected relapse (7.5 vs. 3.4 months, p = 0.013). CONCLUSIONS: Routine surveillance by CT chest detects more localized disease than symptom driven follow-up, though OS does not differ. This null result is largely driven by the favorable outcomes for patients with OBM who present symptomatically. A strategy of both chest and brain imaging could be considered and warrants further investigation.

First-Line Therapies for Metastatic Lung Adenocarcinoma Without a Driver Mutation.

Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non-small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.

Identifying and managing the adverse effects of immune checkpoint blockade.

Immunotherapy has revolutionized the field of oncology. By inhibiting the cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed death-1 (PD-1) immune checkpoint pathways, multiple studies have demonstrated greatly improved survival in locally advanced and metastatic cancers including melanoma, renal, lung, gastric, and hepatocellular carcinoma. Trials in other malignancies are ongoing, and undoubtedly the number of drugs in this space will grow beyond the six currently approved by the Food and Drug Administration. However, by altering the immune response to fight cancer, a new class of side effects has emerged known as immune-related adverse events (irAEs). These adverse events are due to overactivation of the immune system in almost any organ of the body, and can occur at any point along a patient's treatment course. irAEs such as endocrinopathies (thyroiditis), colitis, and pneumonitis may occur more commonly. However, other organs such as the liver, heart, or brain may also be affected by immune overactivation and any of these side effects may become life threatening. This review presents an approach to promptly recognize and manage these toxicities, to hopefully minimize morbidity and mortality from irAEs.

Use of a new availability index to evaluate the effect of policy changes to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) on the food environment in New Orleans.

OBJECTIVE: Changes to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) occurred in 2009 when supplemental foods offered through the programme were updated to align with current dietary recommendations. The present study reports on a new index developed to monitor the retail environment's adoption of these new food supply requirements in New Orleans. DESIGN: A 100-point WIC Availability Index (WIC-AI) was derived from new minimum state stocking requirements for WIC vendors. A sample of supermarkets, medium and small food stores was assessed in 2009 before changes were implemented and in 2010 after revisions had gone into effect. WIC-AI scores were utilized to compare differences in meeting requirements by store type, WIC vendor status and year of measurement. SETTING: Supermarkets, medium and small WIC and non-WIC food stores in New Orleans, Louisiana, USA. RESULTS: At baseline supermarkets had the highest median WIC-AI score (93·3) followed by medium (69·8) and small food stores (48·0). Small WIC stores had a higher median WIC-AI score at baseline than small non-WIC stores (66·9 v. 38·0). Both medium and small WIC stores significantly increased their median WIC-AI scores between 2009 and 2010 (P<0·01). The increased median WIC-AI score in small food stores was largely attributed to increased availability of cereals and grains, juices and fruit, and infant fruit and vegetables. CONCLUSIONS: The WIC-AI is a simple tool useful in summarizing complex food store environment data and may be adapted for use in other states or a national level to inform food policy decisions and direction.

The influence of the WIC food package changes on the retail food environment in New Orleans.

OBJECTIVE: To examine the effect of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) food package changes on availability of healthy foods in small stores. DESIGN: Pre-post comparison group design with repeat in-store observations. SETTING: New Orleans. PARTICIPANTS: Small stores (n = 102; 77% of total) were visited in 2009. Of these, 91% were observed again in 2010, including both WIC (n = 27) and non-WIC (n = 66) stores. INTERVENTION: The 2009 WIC food package changes to include healthier foods. MAIN OUTCOME MEASURES: Change in store availability of fruits, vegetables, lower-fat milks, whole wheat bread, and brown rice. Change in number of varieties and shelf length of fruits and vegetables. ANALYSIS: Difference-in-differences analysis using logit models for change in availability and regression models for change in number of varieties or shelf length. RESULTS: The WIC stores were more likely to improve availability of lower-fat milks than non-WIC stores (adjusted odds ratio, 5.0, 95% confidence interval, 1.2-21.0). An even greater relative improvement was seen with whole grains. The WIC stores showed a relative increase in number of varieties of fresh fruits (0.9 ± 0.3; P < .01) and shelf length of vegetables (1.2 ± 0.4 meters; P < .01). CONCLUSIONS AND IMPLICATIONS: Results suggest that WIC changes improved the availability of healthy foods in small stores in New Orleans. Similar changes throughout the country could have a significant impact on neighborhood food environments.

Car ownership and the association between fruit and vegetable availability and diet.

OBJECTIVE: Nearly all research on the food environment and diet has not accounted for car ownership - a potential key modifying factor. This study examined the modifying effect of car ownership on the relationship between neighborhood fruit and vegetable availability and intake. METHODS: Data on respondents' (n=760) fruit and vegetable intake, car ownership, and demographics came from the 2008 New Orleans Behavioral Risk Factor Surveillance System. Shelf space data on fresh, frozen, and canned fruits and vegetables were collected in 2008 from a random sample of New Orleans stores (n=114). Availability measures were constructed by summing the amount of fruit and vegetable shelf space in all stores within defined distances from respondent households. Regression analyses controlled for demographics and were run separately for respondents with and without a car. RESULTS: Fruit and vegetable availability was positively associated with intake among non-car owners. An additional 100 m of shelf space within 2 km of a residence was predictive of a half-serving/day increase in fruit and vegetable intake. Availability was not associated with intake among car owners. CONCLUSIONS: Future research and interventions to increase neighborhood healthy food options should consider car ownership rates in their target areas as an important modifying factor.

Measuring the food environment: a systematic technique for characterizing food stores using display counts.

Marketing research has documented the influence of in-store characteristics-such as the number and placement of display stands-on consumer purchases of a product. However, little information exists on this topic for key foods of interest to those studying the influence of environmental changes on dietary behavior. This study demonstrates a method for characterizing the food environment by measuring the number of separate displays of fruits, vegetables, and energy-dense snack foods (including chips, candies, and sodas) and their proximity to cash registers in different store types. Observations in New Orleans stores (N = 172) in 2007 and 2008 revealed significantly more displays of energy-dense snacks than of fruits and vegetables within all store types, especially supermarkets. Moreover, supermarkets had an average of 20 displays of energy-dense snacks within 1 meter of their cash registers, yet none of them had even a single display of fruits or vegetables near their cash registers. Measures of the number of separate display stands of key foods and their proximity to a cash register can be used by researchers to better characterize food stores and by policymakers to address improvements to the food environment.

The effects of Hurricane Katrina on food access disparities in New Orleans.

Disparities in neighborhood food access are well documented, but little research exists on how shocks influence such disparities. We examined neighborhood food access in New Orleans at 3 time points: before Hurricane Katrina (2004-2005), in 2007, and in 2009. We combined existing directories with on-the-ground verification and geographic information system mapping to assess supermarket counts in the entire city. Existing disparities for African American neighborhoods worsened after the storm. Although improvements have been made, by 2009 disparities were no better than prestorm levels.

The association between obesity and urban food environments.

Several studies have examined associations between the food retail environment and obesity, though virtually no work has been done in the urban South, where obesity rates are among the highest in the country. This study assessed associations between access to food retail outlets and obesity in New Orleans. Data on individual characteristics and body weight were collected by telephone interviews from a random sample of adults (N = 3,925) living in New Orleans in 2004-2005. The neighborhood of each individual was geo-mapped by creating a 2-km buffer around the center point of the census tract in which they lived. Food retailer counts were created by summing the total number of each food store type and fast food establishment within this 2-km neighborhood. Hierarchical linear models assessed associations between access to food retailers and obesity status. After adjusting for individual characteristics, each additional supermarket in a respondent's neighborhood was associated with a reduced odds for obesity (OR 0.93, 95% CI 0.88-0.99). Fast food restaurant (OR 1.01, 95% CI 1.00-1.02) and convenience store (OR 1.01, 95% CI 1.00-1.02) access were each predictive of greater obesity odds. An individual's access to food stores and fast food restaurants may play a part in determining weight status. Future studies with longitudinal and experimental designs are needed to test whether modifications in the food environment may assist in the prevention of obesity.

Disparities in food access: does aggregate availability of key foods from other stores offset the relative lack of supermarkets in African-American neighborhoods?

OBJECTIVE: Recent work demonstrates the importance of in-store contents, yet most food access disparity research has focused on differences in store access, rather than the foods they carry. This study examined in-store shelf space of key foods to test whether other types of stores might offset the relative lack of supermarkets in African-American neighborhoods. METHODS: New Orleans census tract data were combined with health department information on food stores open in 2004-2005. Shelf space of fruits, vegetables, and energy-dense snacks was assessed using a measuring wheel and established protocols in a sample of stores. Neighborhood availability of foods was calculated by summing shelf space in all stores within 2km of tract centers. Regression analyses assessed associations between tract racial composition and aggregate food availability. RESULTS: African-American neighborhoods had fewer supermarkets and the aggregate availability of fresh fruits and vegetables was lower than in other neighborhoods. There were no differences in snack food availability. CONCLUSIONS: Other store types did not offset the relative lack of supermarkets in African-American neighborhoods in the provision of fresh produce, though they did for snack foods. Altering the mix of foods offered in such stores might mitigate these inequities.

The importance of a multi-dimensional approach for studying the links between food access and consumption.

Research on neighborhood food access has focused on documenting disparities in the food environment and on assessing the links between the environment and consumption. Relatively few studies have combined in-store food availability measures with geographic mapping of stores. We review research that has used these multi-dimensional measures of access to explore the links between the neighborhood food environment and consumption or weight status. Early research in California found correlations between red meat, reduced-fat milk, and whole-grain bread consumption and shelf space availability of these products in area stores. Subsequent research in New York confirmed the low-fat milk findings. Recent research in Baltimore has used more sophisticated diet assessment tools and store-based instruments, along with controls for individual characteristics, to show that low availability of healthy food in area stores is associated with low-quality diets of area residents. Our research in southeastern Louisiana has shown that shelf space availability of energy-dense snack foods is positively associated with BMI after controlling for individual socioeconomic characteristics. Most of this research is based on cross-sectional studies. To assess the direction of causality, future research testing the effects of interventions is needed. We suggest that multi-dimensional measures of the neighborhood food environment are important to understanding these links between access and consumption. They provide a more nuanced assessment of the food environment. Moreover, given the typical duration of research project cycles, changes to in-store environments may be more feasible than changes to the overall mix of retail outlets in communities.