Seroconversion rates following COVID-19 vaccination among patients with cancer.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. On comparison with solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematologic malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than with mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer.

BACKGROUND: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking. PATIENTS AND METHODS: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 µm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy. RESULTS: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days. CONCLUSIONS: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions.

Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice.

PURPOSE: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. METHODS: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). RESULTS: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. CONCLUSION: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.

Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System.

Patients with cancer are presumed to be at increased risk from COVID-19 infection-related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19-positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. SIGNIFICANCE: COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.This article is highlighted in the In This Issue feature, p. 890.

Survival Disparities in Black Patients With EGFR-mutated Non-small-cell Lung Cancer.

BACKGROUND: Little is known about the difference between black and non-black patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), particularly regarding survival. We thus characterized the EGFR expression profile, clinical characteristics, and survival outcome in these patients. PATIENT AND METHODS: We reviewed the cancer registry and patient charts at a New York-Bronx network (n = 2773) treating a large population of minority patients, for non-squamous NSCLC (n = 1986) diagnosed between 2009 and 2015. Survival was adjusted for smoking, gender, age, weight, and stage. RESULTS: The EGFR mutation rate was 15% (98/652) in tested patients (black, 14%; non-black, 16%). There was no significant difference between the 2 cohorts with respect to age at diagnosis, gender, presenting stages, and socioeconomic status. On the other hand, weight was noted to be heavier in black patients with EGFR-mutated NSCLC than their non-black counterparts (P = .012). After adjusting for gender, age, smoking status, weight, and stage, the multivariate analysis revealed no racial disparity in survival among patients with wild-type EGFR (P = .774); However, among patients with EGFR-mutated NSCLC, black patients had shorter survival in comparison with non-black patients (P = .001), with 2-year survival rates being 33% versus 61%, respectively. Such shorter survival was also observed among EGFR-inhibitor treated patients with common EGFR mutations (P = .040). CONCLUSIONS: To our knowledge, this is the first report of inferior survival among black patients with NSCLC with EGFR mutations, relative to non-black patients. The survival disparities suggest the need of more tailored management for this patient population.

Impact of Primary Care Access on Mortality of Lung Cancer Patients in an Underserved Community.

BACKGROUND: Lack of access to primary care physicians (PCPs) may be an important contributor to mortality differences attributed to race/ethnicity. This study examined the effects of primary care access on mortality of lung cancer patients in an underserved community. METHODS: Medical records of all newly diagnosed patients with primary lung cancer from 2012 to 2016 at a National Cancer Institute (NCI)-designated center in Bronx, New York were reviewed. Demographic data, PCP status, and residence in primary care shortage areas (PCSAs) were collected. Survival data from time of first imaging to death or the end of follow-up on January 1, 2018 were recorded. Survival analysis was performed using Kaplan-Meier and Cox hazards modeling. RESULTS: Among 1062 patients, 874 (82%) were PCSA residents, 314 (30%) were Hispanic, and 445 (42%) were African American. PCSA residents were likely Hispanics (P<0.001), African Americans (P<0.001), of lower income (P<0.001), and had advanced disease at diagnosis (P=0.01). Patients without established PCPs had more comorbidities (P=0.04), more advanced disease (P<0.001), and less in-network cancer treatment (P<0.001). PCSA residence (P=0.03, hazard ratio [HR]=1.27) and no established PCP (P<0.001, HR=1.50) were associated with increased mortality. In multivariable modeling, lack of established PCP remained a predictor of increased mortality (P=0.02, HR=1.25). DISCUSSION: Among newly diagnosed lung cancer patients, lack of established PCP is associated with increased mortality. Hispanics and African Americans increasingly resided in PCSAs, suggesting race/ethnicity mortality differences may be mediated by primary care shortage. Patients without PCPs had worse health outcomes. Effective health policy efforts to reduce mortality in lung cancer patients must include approaches to improve primary care access.

Nanoparticle albumin bound-paclitaxel for treatment of advanced non-small cell lung cancer: an evaluation of the clinical evidence.

INTRODUCTION: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a microtubule inhibitor, has demonstrated clinical efficacy in the treatment of advanced non-small cell lung cancer (NSCLC) either as monotherapy or in combination. Nab-paclitaxel was developed to reduce the toxicities associated with solvent-bound paclitaxel (sb-paclitaxel). Areas covered: This review first focuses on the clinical trials evaluating the efficacy and tolerability of nab-paclitaxel in NSCLC at different settings. The approval of nab-paclitaxel in combination with carboplatin at the front-line setting for advanced NSCLC was based on the key phase III study, which showed that nab-paclitaxel/carboplatin was associated with superior overall response rate and favorable toxicity profile compared to sb-paclitaxel/carboplatin. The review also addresses the nab-paclitaxel pharmacology, other combinations (e.g. immunotherapy with PD-1/PD-L1 inhibitors), potential biomarkers (e.g. caveolin-1), and special subgroups (e.g. the elderly, squamous histology). Expert opinion: Existing data has established the role of nab-paclitaxel in the management of advanced NSCLC. Emerging evidence, such as preliminary results from Keynote-407 and IMpower 131 studies, indicates that novel combinations of nab-paclitaxel/carboplatin and PD-1/PD-L1 inhibitors could further improve clinical benefits with manageable toxicity. Nevertheless, in order to better position nab-paclitaxel and to improve patient selection, future studies are warranted to further understand its mechanism of action, predictive biomarkers, and potential synergism with other agents.

Screening Patterns and Mortality Differences in Patients With Lung Cancer at an Urban Underserved Community.

BACKGROUND: The landmark National Lung Screening Trial demonstrated significant reduction in lung cancer-related mortality. However, European lung cancer screening (LCS) trials have not confirmed such benefit. We examined LCS patterns and determined the impact of LCS-led diagnosis on the mortality of newly diagnosed patients with lung cancer in an underserved community. PATIENTS AND METHODS: Medical records of patients diagnosed with primary lung cancer in 2013 through 2016 (n = 855) were reviewed for primary care provider (PCP) status and LCS eligibility and completion, determined using United States Preventative Services Task Force guidelines. Univariate analyses of patient characteristics were conducted between LCS-eligible patients based on screening completion. Survival analyses were conducted using Kaplan-Meier and multivariate Cox regression. RESULTS: In 2013 through 2016, 175 patients with primary lung cancer had an established PCP and were eligible for LCS. Among them, 19% (33/175) completed screening prior to diagnosis. LCS completion was associated with younger age (P = .02), active smoking status (P < .01), earlier stage at time of diagnosis (P < .01), follow-up in-network cancer treatment (P = .03), and surgical management (P < .01). LCS-eligible patients who underwent screening had improved all-cause mortality compared with those not screened (P < .01). Multivariate regression showed surgery (hazard ratio, 0.31; P = .04) significantly affected mortality. CONCLUSION: To our knowledge, this is the first study to assess LCS patterns and mortality differences on patients with screen-detected lung cancer in an urban underserved setting since the inception of United States Preventative Services Task Force guidelines. Patients with a LCS-led diagnosis had improved mortality, likely owing to cancer detection at earlier stages with curative treatment, which echoes the finding of prospective trials.

Mouse models in squamous cell lung cancer: impact for drug discovery.

INTRODUCTION: Squamous cell lung cancer (SQCLC) is the second most common subtype of non-small cell lung cancer (NSCLC) and has limited therapeutic options. Its development is likely a result of a multistep process in response to chronic tobacco exposure, involving sequential metaplasia, dysplasia and invasive carcinoma. Its complex genomic landscape has recently been revealed but no driver mutations have been validated that could lead to molecularly targeted therapy as have emerged in lung adenocarcinoma. Few preclinical murine models exist for testing and developing novel therapeutics in SQCLC. Areas covered: This review discusses the pathophysiology and molecular underpinnings of SQCLC that have limited the development of animal models. It then explores the advantages and limitations of a variety of existing mouse models and illustrates their potential application in drug discovery and chemoprevention. Expert opinion: There are several challenges in the development of mouse models for SQCLC, such as lack of validated driver genetic alterations, unclear cell of origin, and difficulty in reproducing the sophisticated tumor microenvironment of human disease. Nevertheless, several successful SQCLC murine models have emerged, especially Patient Derived Xenografts (PDXs) and Genetically Engineered Mouse Models (GEMMs). Continued efforts are needed to generate more SQCLC animal models to better understand its carcinogenesis and metastasis and to further test novel therapeutic strategies.

Leptomeningeal metastases in non-small-cell lung cancer.

Leptomeningeal metastasis is a complication of advanced non-small-cell lung cancer (NSCLC). Diagnosis and monitoring of leptomeningeal metastasis are challenging, and are based on neurological, radiographic, and cerebrospinal fluid findings. Substantial progress has been made in several key aspects of management of leptomeningeal metastasis, including improved characterisation of the genetic profiles, generation of clinically relevant animal models, advances in cerebrospinal fluid liquid biopsy with improved cytology and genotyping analysis, and the development of therapeutic agents with greater CNS penetration. This Review discusses cumulative data on multiple treatment modalities with a particular focus on recent advances in molecularly targeted therapies in subtypes of patients with leptomeningeal metastasis from NSCLC. Future research is needed to further understand the biology of leptomeningeal metastasis and the mechanisms of resistance to treatment.

Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1-Negative Human Lung Cancers.

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non-small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2.Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated.Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, whereas HHLA2 was positive in 61% and 64% of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1-negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells.Conclusions: The majority of PD-L1-negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1-negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors. Clin Cancer Res; 24(8); 1954-64. ©2018 AACR.

Positron Emission Tomography-Adjusted Intensity Modulated Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: To perform a prospective trial examining positron emission tomography (PET)-based, dose-painted intensity modulated radiation therapy (IMRT) in the setting of locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with stage IIB-III NSCLC were treated with 25 fractions of dose-painted IMRT. Tumors or lymph nodes with metabolic tumor volume exceeding 25 cm3 were deemed "high risk" and received 65 Gy. Smaller lesions were treated with 57 Gy or 52.5 Gy (after November 2014). Patients received concurrent weekly carboplatin (area under the curve = 2) and paclitaxel (45 mg/m2). The primary study endpoint was the absence of high residual metabolic activity (maximum standardized uptake value > 6) in treated lesions on PET 12 to 16 weeks after completion of IMRT. RESULTS: Thirty-five subjects with 116 hypermetabolic lesions were eligible for analysis. The primary endpoint was met for 24 of 30 patients (80%) who underwent posttreatment PET, satisfying our efficacy objective. With a median follow-up duration of 23.8 months for living patients, progression in a lesion targeted with radiation therapy has been observed in 5 patients (14%). Treating progression in other sites and death without progression as competing risks, 2-year cumulative incidence rates of local disease progression in high-risk lesions (n=24) and low-risk lesions (n=92) are 9% and 3%, respectively. The actuarial rate of overall survival at 2 years is 52%. CONCLUSIONS: Dose-painted IMRT based on pretreatment PET metrics with concurrent chemotherapy yields high rates of metabolic response and local disease control for locally advanced NSCLC. Future trials should test this approach to maximize the therapeutic ratio of thoracic radiation therapy.

Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC. METHODS: We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805. FINDINGS: Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment. INTERPRETATION: Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC. FUNDING: National Cancer Institute of the National Institutes of Health.

Investigational therapies for squamous cell lung cancer: from animal studies to phase II trials.

INTRODUCTION: It remains challenging to treat squamous cell lung cancer (SCC) with limited therapeutic options. However, recent breakthroughs in targeted therapies and immunotherapies have shed some light on the management of this deadly disease. Areas covered: The article first reviews the current treatment options for advanced SCC, especially recent FDA approved molecular agents (afatinib, ramucirumab and necitumumab) and immunotherapies (nivolumab, pembrolizumab and atezolimumab). We then provide an overview on investigational therapies with data ranging from preclinical to phase II studies, focusing on new cytotoxic agents, emerging molecularly targeted agents (including a PARP inhibitor for Homologous Recombinant Deficiency positive SCC) and novel immunotherapeutic strategies. Expert opinion summary: Identification of potential therapeutic targets, development of novel clinical trials and the rapid approvals of immune checkpoint inhibitors have shifted the management paradigm for squamous cell lung cancer. On the other hand, continued efforts are needed to identify the predictive biomarkers and to investigate novel mechanistically-driven mono- and combination therapies. We need to learn more about the biology behind immune checkpoint blockade and tumor genomics in SCC for better patient selection and future trial design.

18F-Fluorodeoxyglucose/Positron Emission Tomography Predicts Patterns of Failure After Definitive Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

BACKGROUND: We previously reported that pretreatment positron emission tomography (PET) identifies lesions at high risk for progression after concurrent chemoradiation therapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). Here we validate those findings and generate tumor control probability (TCP) models. METHODS: We identified patients treated with definitive, concurrent CRT for locally advanced NSCLC who underwent staging 18F-fluorodeoxyglucose/PET/computed tomography. Visible hypermetabolic lesions (primary tumors and lymph nodes) were delineated on each patient's pretreatment PET scan. Posttreatment imaging was reviewed to identify locations of disease progression. Competing risks analyses were performed to examine metabolic tumor volume (MTV) and radiation therapy dose as predictors of local disease progression. TCP modeling was performed to describe the likelihood of local disease control as a function of lesion size. RESULTS: Eighty-nine patients with 259 hypermetabolic lesions (83 primary tumors and 176 regional lymph nodes) met the inclusion criteria. Twenty-eight patients were included in our previous report, and the remaining 61 constituted our validation cohort. The median follow-up time was 22.7 months for living patients. In 20 patients, the first site of progression was a primary tumor or lymph node treated with radiation therapy. The median time to progression for those patients was 11.5 months. Data from our validation cohort confirmed that lesion MTV predicts local progression, with a 30-month cumulative incidence rate of 23% for lesions above 25 cc compared with 4% for lesions below 25 cc (P=.008). We found no evidence that radiation therapy dose was associated with local progression risk. TCP modeling yielded predicted 30-month local control rates of 98% for a 1-cc lesion, 94% for a 10-cc lesion, and 74% for a 50-cc lesion. CONCLUSION: Pretreatment FDG-PET identifies lesions at risk for progression after CRT for locally advanced NSCLC. Strategies to improve local control should be tested on high-risk lesions, and treatment deintensification for low-risk lesions should be explored.

HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status.

PURPOSE: Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC. EXPERIMENTAL DESIGN: We performed IHC with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinicopathologic characteristics of these patients. RESULTS: Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P = 0.01) and validation cohorts (89% vs. 69%, P = 0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared with squamous and large cell histology, non-Hispanic White versus Hispanics, and tumors with high tumor-infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma. CONCLUSIONS: HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy. Clin Cancer Res; 23(3); 825-32. ©2016 AACR.

Pax5 Re-expression in H460 Cells Treated with the Combination of Demethylating Agent and Histone Deacetylase Inhibitor is Associated with the Enhancement of P53 Binding to Pax5 Promoter Region.

BACKGROUND: The epigenetic combinations of DNA demethylating agents and histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits for non-small cell lung cancer (NSCLC) treatment, however, there are few studies uncovering the underlying molecular mechanism of the combinations. Our previous study showed that DNA demethylating agent Azacitidine (Aza) demethylated CpG sites in paired box gene 5 (pax5) promoter region, but did not induce pax5 mRNA or protein expression. METHODS: In this study we used epigenetic combination of Aza and HDAC inhibitor Vorinostat (SAHA) to treat NSCLC cells and to elucidate the underlying molecular mechanism. We treated pax5- silenced NSCLC H460 cells with Aza+SAHA combination at sub-toxic concentration and detected the re-expression of pax5 mNRA and protein. RESULTS: The results showed demethylation of CpG sites in pax5 promoter region by Aza treatment and increased DNA accessibility for protein binding by SAHA treatment. The combination of Aza+SAHA significantly increased p53 protein binding to DNA in pax5 promoter region (p<0.01). More efficient binding of the transcription factor p53 to pax5 promoter region is likely because SAHA increased accessibility of the chromatin conformation and Aza-demethylated DNA was more permissive, allowing transcription factors to bind. CONCLUSION: Our study not only explained an underlying mechanism, that pax5 re-expression was induced by Aza+SAHA combination in H460 cells via p53, but also demonstrated a pattern showing that the combination of demethylating agent and HDAC inhibitor can re-activate tumor suppressor gene (TSG) which is associated with the enhancement of transcription factors binding to the promoter region of the TSG.

Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non-small-cell Lung Cancer.

BACKGROUND: Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non-small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype. PATIENTS AND METHODS: Patients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m2 provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2-17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression-free survival (PFS), which would be considered promising for future study if median PFS was ≥ 4.5 months. RESULTS: Of 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty-nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed-alone groups, respectively. In patients with EGFR wild-type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed-alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6-month PFS (45% vs. 29%, P = .26), and 12-month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm. CONCLUSION: In patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.