IIIA Non-small Cell Lung Cancer Research Articles

Importance of tumour volume and histology in trimodality treatment of patients with Stage IIIA non-small cell lung cancer-results from a retrospective analysis.

OBJECTIVESChemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a resectable tumour, good results have been achieved with trimodality treatment (TT). The objective of this bi-institutional analysis of outcomes in patients treated for Stage IIIA NSCLC was to identify particular factors supporting the role of surgery after CRT.METHODSIn a 2-centre retrospective cohort study, patients with Stage III NSCLC (seventh edition TNM) were identified and those patients with Stage IIIA who were treated with CRT or TT between January 2007 and December 2013 were selected. Patient characteristics as well as tumour parameters were evaluated in relation to outcome and whether or not these variables were predictive for the influence of treatment (TT or CRT) on outcome [overall survival (OS) or progression-free survival (PFS)]. Estimation of treatment effect on PFS and OS was performed using propensity-weighted cox regression analysis based on inverse probability weighting.RESULTSFrom a database of 725 Stage III NSCLC patients, 257 Stage IIIA NSCLC patients, treated with curative intent, were analysed; 186 (72%) with cIIIA-N2 and 71 (28%) with cT3N1/cT4N0 disease. One hundred and ninety-six (76.3%) patients were treated by CRT alone (high-dose radiation with daily low-dose cisplatin) and 61 (23.7%) by TT. The unweighted data showed that TT resulted in better PFS and OS. After weighting for factors predictive of treatment assignment, patients with a large gross tumour volume (>120 cc) had better PFS when treated with TT, and patients with an adenocarcinoma treated with TT had better OS, regardless of tumour volume.CONCLUSIONSPatients with Stage IIIA NSCLC and large tumour volume, as well as patients with adenocarcinoma, who were selected for TT, had favourable outcome compared to patients receiving CRT. This information can be used to assist multidisciplinary team decision-making and for stratifying patients in studies comparing TT and definitive CRT.

Impact of thymosin α1 as an immunomodulatory therapy on long-term survival of non-small cell lung cancer patients after R0 resection: a propensity score-matched analysis.

Background:There is limited information about thymosin α1 (Tα1) as adjuvant immunomodulatory therapy, either used alone or combined with other treatments, in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the effect of adjuvant Tα1 treatment on long-term survival in margin-free (R0)-resected stage IA–IIIA NSCLC patients.Methods:A total of 5746 patients with pathologic stage IA-IIIA NSCLC who underwent R0 resection were included. The patients were divided into the Tα1 group and the control group according to whether they received Tα1 or not. A propensity score matching (PSM) analysis was performed to reduce bias, resulting in 1027 pairs of patients.Results:After PSM, the baseline clinicopathological characteristics were similar between the two groups. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly higher in the Tα1 group compared with the control group. The multivariable analysis showed that Tα1 treatment was independently associated with an improved prognosis. A longer duration of Tα1 treatment was associated with improved OS and DFS. The subgroup analyses showed that Tα1 therapy could improve the DFS and/or OS in all subgroups of age, sex, Charlson Comorbidity Index (CCI), smoking status, and pathological tumor-node-metastasis (TNM) stage, especially for patients with non-squamous cell NSCLC and without targeted therapy.Conclusion:Tα1 as adjuvant immunomodulatory therapy can significantly improve DFS and OS in patients with NSCLC after R0 resection, except for patients with squamous cell carcinoma and those receiving targeted therapy. The duration of Tα1 treatment is recommended to be >24 months.

Role of immunotherapy in stage IIIA non-small cell lung cancer: a narrative review

: Non-small cell lung cancer (NSCLC) is one of the main leading causes of death by cancer worldwide. Approximately one third of cases are diagnosed at stage III, whose therapeutic strategy based on multimodal treatment has reached a plateau of effectiveness. Treatment with anti-PD-1/PD-L1 [anti-PD-(L)1] antibodies have been stablished in advanced stages due to their improved clinical benefit and acceptable profile of related adverse events. Lately, numerous clinical trials have been designed with diverse approaches to introduce immunotherapy into stages IIIA. The objective of this review is to discuss the different strategies that are being taken in the ongoing clinical trials, taking into account the peculiarities of stage IIIA and the tumor microenvironment. PubMed, major international conferences and clinicaltrials.gov databases were searched from January 1, 1990, to May 11, 2020 using the terms NSCLC, stage III, resectable, unresectable, immunotherapy, checkpoint inhibition, neoadjuvant and adjuvant. In this review we describe, in the context of stage IIIA disease, the impact of anti-PD-(L)1 and conventional therapies on the tumor microenvironment. Moreover, we describe the role of immunotherapy, through the heterogeneous landscape of stage IIIA NSCLC, summarizing ongoing clinical trials in incidental, potentially resectable, and unresectable tumors. We finally discuss the potential of PD-L1, tumor mutation burden (TMB), and T-cell receptor (TCR) repertoire analysis as predictive biomarkers in stage IIIA NSCLC. Initial results seem to favor neoadjuvant over adjuvant treatment, with chemoimmunotherapy combination standing out. Ongoing trials will answer whether immunotherapy can transform stage IIIA from lethal to a curable disease. Additionally, higher pathological response rates observed, open the possibility to establishing it as survival surrogate, speeding up the potential immunotherapy implementation in stage IIIA NSCLC.

Neoadjuvant camrelizumab, nab-paclitaxel, and carboplatin in patients with stage IB-IIIA non-small cell lung cancer (NANE-LC): a study protocol of prospective, single-arm, multicenter, phase II study.

BackgroundPrevious studies have shown that neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy in patients with stage IB–IIIA non-small cell lung cancer (NSCLC) significantly improved the major pathological response (MPR) and the pathological complete response (pCR) rates. However, high-level evidence-based medical data confirming this effect are still lacking. In addition, there is an urgent need to develop an appropriate strategy to predict the benefit for patients receiving ICIs. In this study, we describe an ongoing study on the effect of neoadjuvant therapy with camrelizumab, nab-paclitaxel, and carboplatin on stage IB–IIIA NSCLC patients. The aim of this study is to establish a multiomics artificial intelligence system for predicting neoadjuvant therapy efficacy and assisting decision-making.MethodsThis prospective, single-arm, multicenter, phase II trial will enroll a total of 40 patients who will undergo surgery after three cycles of neoadjuvant therapy with camrelizumab, nab-paclitaxel, and carboplatin. The MPR rate is the primary endpoint, while the rates of pCR, complete resection, objective response, disease-free survival (DFS), adverse events (AEs), and quality of life (QOL) are secondary endpoints. Exploratory endpoints will serve to establish a multiomics artificial intelligence system for neoadjuvant therapy effect prediction and decision-making assistance based on radiomics, metabolism, genetic, and clinic-pathological characteristics and to explore the mechanisms of drug resistance.DiscussionThe efficacy of ICIs is influenced by many factors, including patient’s driver genes and smoking status. Thus, further subgroup analysis is needed. This study will indicate if our new multiomics artificial intelligence system constitutes a valid strategy for neoadjuvant therapy effect prediction and decision-making assistance in the context of neoadjuvant camrelizumab, nab-paclitaxel, and carboplatin treatment for patients with stage IB–IIIA NSCLC.Trial RegistrationThis trial has been registered at ClinicalTrials.gov (identification number: NCT04541251).

Adjuvant trials suggest changes to non-small cell lung cancer treatment paradigm: Results from clinical trials presented at the 2021 annual meeting of the American Society of Clinical Oncology may point to new ways to improve individualized therapy.

At the 2021 annual meeting of the American Society of Clinical Oncology, positive data from several phase 3 clinical trials indicated an earlier role for novel therapeutic treatments for patients with metastatic disease. The studies suggest that adjuvant therapy with newer agents may increase disease-free survival in a range of tumor types and benefit select subsets of patients with a higher risk of recurrence after primary treatment. The results of 4 clinical trials in total were presented; they investigated adjuvant treatment versus placebo or best supportive care in resected renal cell carcinoma, locally advanced cervical cancer, early-stage non–small cell lung cancer (NSCLC), and BRCA1/2-mutant, HER2-negative early breast cancer.1 Among the trials that were presented, data from the OlympiA trial (ClinicalTrials.gov identifier NCT02032823) regarding the use of olaparib (Lynparza), a poly(adenosine diphosphate ribose) polymerase inhibitor, revealed that the invasive (3-year) diseasefree survival rate improved to 85.9% (in contrast to 77.1% with a placebo) for patients with HER2-negative breast cancer and a BRCA1/2 mutation present (hazard ratio [HR] 0.58; 99.5% CI, 0.41-0.82; P < 0.0001). These patients were considered to have a high risk of recurrence after initial local treatment and neoadjuvant/adjuvant therapy.1, 2 The KEYNOTE-564 trial (ClinicalTrials.gov identifier NCT03142334) showed an estimated disease-free survival rate of 77.3% with the use of pembrolizumab (Keytruda), a PD-1 inhibitor (in contrast to 68.1% with a placebo), in patients with clear cell renal cell carcinoma. The patients studied were categorized as intermediate high risk or high risk for recurrence after nephrectomy. A trend suggesting a 96.6% overall survival benefit with pembrolizumab versus a placebo (93.5%) was also noted by investigators.1, 3 Negative trial data from patients with advanced cervical cancer and a high rate of potential relapse were also discussed during the plenary session. Data from the OUTBACK trial (ACTRN12610000732088) illustrated similar progressionfree survival rates (63% vs 61%; 95% CI, -5 to +9; P = 0.61) without improved overall survival (72% vs 71%; 95% CI, -6 to +7; P = 0.91) at 5 years for patients with advanced cervical cancer who were given adjuvant chemotherapy after the administration of cisplatin-based chemoradiation.1, 4 IMpower010 (ClinicalTrials.gov identifier NCT02486718), a randomized, global, open-label trial of atezolizumab (Tecentriq), an anti–PD-L1, versus best supportive care after adjuvant treatment, studied patients with resected stage IB to IIIA NSCLC. A total of 1280 patients were enrolled; they received 4 cycles of cisplatin with vinorelbine, docetaxel, pemetrexed, or gemcitabine. Patients were randomized to receive 16 cycles of atezolizumab every 3 weeks or best supportive care. Those enrolled in the atezolizumab arm were given a median of 16 doses with periodic radiologic imaging; cycles in both phases lasted for 21 days.5 The primary results of the IMpower010 study illustrated a disease-free survival benefit with adjuvant atezolizumab after adjuvant chemotherapy in the PD-L1 TC ≥1% stage II-IIIA (stratified HR 0.66; P = 0.0039) and all randomized stage II-IIIA populations (stratified HR 0.79; P = 0.0205). Although adverse events of any grade occurred in 92.7% of the patients in the atezolizumab arm, the discontinuation rate in this population was 18.2%, and the safety profile was similar to that of prior use of atezolizumab as a monotherapy. Specific adverse events were not detailed in the published abstract results.5 Suresh S. Ramalingam, MD, of the Winship Cancer Institute at Emory University in Atlanta, Georgia, gave a virtual interview to CancerNetwork (https://www.cancernetwork.com/) related to the American Society of Clinical Oncology plenary session. “The notion that we could use immune checkpoint inhibitors in early-stage disease to improve overall outcomes is very exciting and an important step forward in the management of early-stage lung cancer.” —Suresh S. Ramalingam, MD Conversely, tailoring treatment interventions in the adjuvant setting may also dictate that some patients will do best by avoiding more toxic treatments. Placing an emphasis on improved outcomes for patients who face a possibly increased residual risk after their initial treatment highlights the importance of the comprehensive selection and strategy of therapy in the adjuvant care setting.

Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non-small cell lung cancer.

Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for dynamically monitoring tumors. However, published data on perioperative ctDNA in patients with operable non-small cell lung cancer (NSCLC) are currently limited. This prospective study recruited 123 patients with resectable stage I to IIIA NSCLC. Preoperative and postoperative plasma samples and tumor tissue samples were subjected to next-generation sequencing with a panel of 425 cancer-related genes. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3 to 6 months for up to 3 years. After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 29 of 117 patients (24.8%) and was associated with inferior recurrence-free survival (RFS; hazard ratio [HR], 2.42; 95% CI, 1.11-5.27; P = .022) and inferior overall survival (OS; HR, 5.54; 95% CI, 1.01-30.35; P = .026). Similarly, ctDNA was detected in 12 of 116 first postsurgical samples (10.3%) and was associated with shorter RFS (HR, 3.04; 95% CI, 1.22-7.58; P = .012). During surveillance after surgery, longitudinal ctDNA-positive patients (37 of 119; 31.1%) had significantly shorter RFS (HR, 3.46; 95% CI, 1.59-7.55; P < .001) and significantly shorter OS (HR, 9.99; 95% CI, 1.17-85.78; P = .010) in comparison with longitudinal ctDNA-negative patients. Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 8.71 months. These results suggest that perioperative ctDNA analyses can predict recurrence and survival, and serial ctDNA analyses can identify disease recurrence/metastasis earlier than routine radiologic imaging in patients with resectable NSCLC. The utility of serial circulating tumor DNA (ctDNA) monitoring for predicting disease recurrence and survival for early-stage non-small cell lung cancer (NSCLC) has not been well characterized. The detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence and long-term patient outcomes for resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than routine radiologic imaging. ctDNA analyses can detect minimal residual disease for resectable NSCLC and thus can facilitate early intervention.

MA09.02 SAKK 16/14 - T-Cell Receptor Repertoire Metrics Predict Response to Neoadjuvant Durvalumab in Patients With Stage IIIA(N2) NSCLC

T-cell receptor (TCR) repertoire assessment in blood and tissue has emerged as a novel predictive marker for response to immune checkpoint inhibitor therapy in advanced stage cancers. However, its relevance and predictive significance in the setting of resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) has yet to be demonstrated. Here, we performed TCR sequencing in patients from the phase 2 trial SAKK 16/14 undergoing neoadjuvant chemotherapy with three cycles of cisplatin/docetaxel followed by treatment with the PD-L1 antibody durvalumab. A total of 127 peripheral blood samples and 67 formalin-fixed paraffin-embedded (FFPE) tissue samples were processed from 67 patients before and after neoadjuvant sequential chemo-immunotherapy treatment in the trial SAKK 16/14. Total RNA was extracted from peripheral blood and FFPE samples and used for TCR sequencing with the Oncomine TCR Beta-LR and SR Assays, respectively. TCR evenness, Shannon diversity, and TCR richness were calculated and correlated with the primary endpoint event-free survival (EFS) after 1 year, major pathological response (MPR), and nodal clearance. Tumor mutational burden (TMB) was assessed in tissue samples from extracted genomic DNA using the FoundationOne test or the Oncomine Comprehensive Assay Plus. Association between TCR metrics and clinical outcome data were analyzed using Mann-Whitney-Wilcox test. Analysis was performed using R (R Core Team, 2014). TCR repertoire could be assessed in a total of 97 peripheral blood (47 pre- and 50 post-treatment) and 64 FFPE (15 pre- and 49 post-treatment) samples. In pre-treatment peripheral blood samples, TCR evenness (p=0.032) was associated with 1 year EFS. In FFPE post-treatment samples, 1 year EFS as well as MPR were significantly associated with increased TCR richness (p=0.0168 and 0.0134) and Shannon diversity (p=0.0278 and p=0.0334). Furthermore, nodal clearance was significantly associated with TCR richness and Shannon diversity in post-treatment tissue samples (p=0.0015, p=0.0087). In contrast, TMB was not associated with EFS, MPR or nodal clearance (p=0.91, p=0.47, p=0.52). Our results show that TCR repertoire measured in peripheral blood samples and tumor tissue may provide a useful tool for predicting risk of recurrence after neoadjuvant sequential chemo-immunotherapy with durvalumab in patients with resectable stage IIIA(N2) NSCLC.

Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial

Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients. IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting). Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%). IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC. F Hoffmann-La Roche and Genentech.

Surgical perspective in neoadjuvant chemoimmunotherapy for stage II-III non-small cell lung cancer.

BackgroundThere are many studies on neoadjuvant immunotherapy for locally advanced non‐small cell lung cancer (NSCLC) patients. Expert consensus recommends neoadjuvant immunotherapy for patients with resectable stage IB–IIIA NSCLC. However, there are few clinical studies or cases to verify this.MethodsData were collected from all NSCLC patients who underwent surgical resection after neoadjuvant chemoimmunotherapy admitted to the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital between September 2020 and April 2021. Data collected included patient information, relevant examination results, intraoperative parameters, postoperative complications, pathological changes, and 90‐day mortality.ResultsIn total, 25 patients achieved R0 resection. Eleven (44%) patients completed surgery by thoracotomy, and three (12%) procedures were changed from minimally invasive procedures due to dense adhesions of hilar lymph nodes, which rendered it difficult to dissect the blood vessels. Thirteen (52%) patients achieved a major pathological response (MPR) with eight (32%) of these patients having a pathological complete response (pCR). Twenty‐two (88%) patients showed radiological regression, and three (12%) patients had stable disease. The median drainage time was 8.50 (3–27) days. Thirteen (52%) postoperative complications were observed, but none were above grade 3.ConclusionsIn this study, neoadjuvant chemoimmunotherapy was found to reduce tumor volume, cause pathological downstaging, and raise the surgical resection rate of patients with locally advanced NSCLC, and achieve a 100% R0 resection rate. There was an acceptable rate of postoperative complications. Thus, neoadjuvant chemoimmunotherapy is safe and practical.

Sarcopenia on preoperative chest computed tomography predicts cancer-specific and all-cause mortality following pneumonectomy for lung cancer: A multicenter analysis.

BackgroundMortality risk prediction in patients undergoing pneumonectomy for non‐small cell lung cancer (NSCLC) remains imperfect. Here, we aimed to assess whether sarcopenia on routine chest computed tomography (CT) independently predicts worse cancer‐specific (CSS) and overall survival (OS) following pneumonectomy for NSCLC.MethodsWe included consecutive adults undergoing standard or carinal pneumonectomy for NSCLC at Massachusetts General Hospital and Heidelberg University from 2010 to 2018. We measured muscle cross‐sectional area (CSA) on CT at thoracic vertebral levels T8, T10, and T12 within 90 days prior to surgery. Sarcopenia was defined as T10 muscle CSA less than two standard deviations below the mean in healthy controls. We adjusted time‐to‐event analyses for age, body mass index, Charlson Comorbidity Index, forced expiratory volume in 1 second in % predicted, induction therapy, sex, smoking status, tumor stage, side of pneumonectomy, and institution.ResultsThree hundred and sixty‐seven patients (67.4% male, median age 62 years, 16.9% early‐stage) underwent predominantly standard pneumonectomy (89.6%) for stage IIIA NSCLC (45.5%) and squamous cell histology (58%). Sarcopenia was present in 104 of 367 patients (28.3%). Ninety‐day all‐cause mortality was 7.1% (26/367). After a median follow‐up of 20.5 months (IQR, 9.2–46.9), 183 of 367 patients (49.9%) had died. One hundred and thirty‐three (72.7%) of these deaths were due to lung cancer. Sarcopenia was associated with shorter CSS (HR 1.7, p = 0.008) and OS (HR 1.7, p = 0.003).ConclusionsThis transatlantic multicenter study confirms that sarcopenia on preoperative chest CT is an independent risk factor for CSS and OS following pneumonectomy for NSCLC.

Hypervascularized bronchial arteries as a risk factor for intraoperative bleeding and prolonged surgery.

BackgroundThe present study investigated whether highly vascularized bronchial arteries affect the intraoperative blood loss and the operative time of video-assisted thoracic surgery (VATS) lobectomy for patients with non-small cell lung cancer.MethodsWe retrospectively collected data on consecutive pathological stage I to IIIA non-small cell lung cancer patients who underwent VATS lobectomy with systematic lymph node dissection between January 2017 and December 2019. Patients were divided into the following two groups according to bronchial artery diameters on preoperative enhanced contrast computed tomography (CT) findings: ≤2 and >2 mm groups.ResultsAmong the 175 patients enrolled, risk factors for intraoperative blood loss >50 mL were being male (P=0.005), a history of smoking (P=0.01), percent forced expiratory volume in 1 s (FEV1.0%) <70% (P=0.012), squamous cell carcinoma (P=0.049), and a bronchial artery diameter >2.0 mm (P<0.001) in the unadjusted analysis, and a bronchial artery diameter >2.0 mm (P<0.001) in the multivariable analysis. Risk factors for an operative time >200 min were being male (P<0.001), a history of smoking (P=0.007), FEV1.0% <70% (P=0.011), squamous cell carcinoma (P=0.046), a bronchial artery diameter >2.0 mm (P<0.001), and experience of surgeon <10 years (P=0.011) in the unadjusted analysis, and being male (P=0.047), a bronchial artery diameter >2.0 mm (P=0.024), and experience of surgeon <10 years (P=0.047) in the multivariable analysis.ConclusionsBronchial artery diameter was the most important risk factor of intraoperative bleeding and prolonged operative time during VATS lobectomy.

Abstract 2606: A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer

Abstract Background: 80% of non-small cell lung cancer (NSCLC) cases are diagnosed at stages IIIB-IV and have a dismal prognosis with a median life expectancy that does not exceed 2 years. In contrast, patients diagnosed at early and locally advanced stages (I-IIIA) can undergo surgery and have the potential to be totally cured. Imaging technologies often detect lung nodules of unknown significance that pose a diagnostic challenge; some patients with benign nodules are submitted to unnecessary surgical interventions while others with small tumors are just kept in observation, risking a significant delay for treatment. A diagnostic test that could differentiate between benign and malignant masses would be of great help in this setting. Methods: Circulating-free RNA (cfRNA) was isolated from the plasma of healthy individuals (N=21), early(I-II) stage (N=22) and stage IIIA (N=12) NSCLC patients, using an automatic extraction method(Qiasymphony, Qiagen). Purified cfRNA was quantified using Qubit, retrotranscribed and pre-amplified (14cycles) using the Low RNA Input Amplification kit (NanoString Technologies). Gene expression analysis was performed on the nCounter platform using the PanCancer IO360TM (NanoString Technologies), which can detect 770 transcripts related to tumor biology, micro-environment and the immune system. Results: Gene expression analysis revealed differential patterns for some cf-mRNAs from localized stage NSCLC patients versus healthy controls. A bioinformatics recursive feature elimination algorithm selected a 16-gene mRNA signature that was able to distinguish between localized NSCLC and control samples with an area under the ROC curve of 0.91 to 0.95. Furthermore, the signature scores derived from the algorithm were significantly different between the two cohorts. Conclusions: We have found an 16-gene signature that can differentiate between cfRNA of localized stages NSCLC patients and control individuals. Our results warrant validation studies in larger cohorts. Citation Format: Ana Giménez Capitán, Jillian Bracht, Nicolas Potie, María González-Cao, Santiago Viteri, Alejandro Martínez-Bueno, Carlos Cabrera-Gálvez, Pablo Rubinstein, Clara Mayo-de-las-Casas, Joselyn Valarezo, Chung-Ying Huang, Carlos Pedraz, Richard Boykind, Sarah Warren, Rafael Rosell, Miguel Ángel Molina-Vilaa, Andrés Aguilar-Hernández. A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2606.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BackgroundImmunotherapy is being tested in early‐stage non‐small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment‐related changes to find biomarkers associated to CPR.MethodsBlood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed.ResultsNeoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p‐value <.05. CPR patients had significantly higher levels of CD4+PD‐1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+CD56–CTLA‐4+ cells, CD14++CD16+CTLA‐4+ cells, CTLA‐4 expression on T CD56 cells and lower levels of b‐NGF, NT‐3, and VEGF‐D in plasma compared to non‐CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4‐1BB, MCSF, and PARC and lower levels of MPIF‐1 and Flt‐3L in plasma compared to non‐CPR.ConclusionsPatients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non‐CPR responses.

Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis

We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28–6.64 for PS, and 2.36 and 1.15–4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients.

Racial Disparity and Social Determinants in Receiving Timely Surgery Among Stage I-IIIA Non-small Cell Lung Cancer Patients in a U.S. Southern State.

Delayed surgery is associated with worse lung cancer outcomes. Social determinants can influence health disparities. This study aimed to examine the potential racial disparity and the effects from social determinants on receipt of timely surgery among lung cancer patients in Louisiana, a southern state in the U.S. White and black stage I–IIIA non-small cell lung cancer patients diagnosed in Louisiana between 2004 and 2016, receiving surgical lobectomy or a more extensive surgery, were selected. Diagnosis-to-surgery interval >6 weeks were considered as delayed surgery. Social determinants included marital status, insurance, census tract level poverty, and census tract level urbanicity. Multivariable logistic regression and generalized multiple mediation analysis were conducted. A total of 3,616 white (78.9%) and black (21.1%) patients were identified. The median time interval from diagnosis to surgery was 27 days in whites and 42 days in blacks (P < 0.0001). About 28.7% of white and 48.4% of black patients received delayed surgery (P < 0.0001). Black patients had almost two-fold odds of receiving delayed surgery than white patients (adjusted odds ratio: 1.91; 95% confidence interval: 1.59–2.30). Social determinants explained about 26% of the racial disparity in receiving delayed surgery. Having social support, private insurance, and living in census tracts with lower poverty level were associated with improved access to timely surgery. The census tract level poverty level a stronger effect on delayed surgery in black patients than in white patients. Tailored interventions to improve the timely treatment in NSCLC patients, especially black patients, are needed in the future.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

8500 Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Efficacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received ≥1 dose of atezo or who had ≥1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC ≥1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclusions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC ≥1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. [Table: see text]

Cause of death among patients with non-small cell lung cancer treated with postoperative radiation therapy (PORT).

e20555 Background: The indications for post-operative radiation therapy (PORT) in locally advanced non-small cell lung cancer (NSCLC) remain undefined and a major concern is the perceived risk of increased mortality from cardiopulmonary causes. The purpose of this study was to quantify the rate of cardiopulmonary death in patients with resected NSCLC receiving PORT using a large national database. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database for lung cancer, patients with Stage IIIA or Stage IIIB NSCLC according to the 6th AJCC edition treated with surgery followed by PORT, who also received chemotherapy were identified. Cause of death was categorized as due to lung cancer, other cancer, cardiac, pulmonary, or other and reported as a percentage of total deaths at one and 2 years. Kaplan-Meier survival analysis was done to compare overall survival between Stage IIIA and IIIB patients. Results: From 2004 to 2015, 4387 patients with stage IIIA and IIIB meeting the eligibility criteria were identified. The median age at diagnosis was 65 years old, most patients were male (53%), Caucasian (83%), had adenocarcinoma (54.8%), stage IIIA disease (69%), and N2 disease (78%). The median overall survival for Stage IIIA and IIIB patients was 39 months and 27 months respectively (p &lt; 0.001). Among the 2586 patients that died during the study period, the most common COD was lung cancer (81.3%). Cardiac and pulmonary COD occurred in 86 patients (3.3% of deaths) and 84 patients (3.2% of deaths) respectively, whereas 158 patients (6.1%) died from other cancers and 154 (5.9%) from other causes. There were 77 deaths from cardiopulmonary cause at 2 years (1.7% of patients and 2.9% of deaths). Cardiopulmonary COD was more common in patients with stage IIIB compared to IIIA disease (4.9% vs 3.3% of deaths, p &lt; 0.001). Lung cancer was the most common COD both at 1 and 2 years (85%) whereas cardiopulmonary was the COD in 5.2% of patients at 1 year and 5.1% at 2 years. Conclusions: This analysis showed a low cardiopulmonary mortality from PORT in the first 2 years. The role for adjuvant radiotherapy remains undefined and treatment decisions for patients with resected stage III NSCLC should be guided by co-morbidities and the competing risk for death from lung cancer.

Phase II trial of toripalimab plus chemotherapy as neoadjuvant treatment in resectable stage III non-small cell lung cancer (NeoTPD01 Study).

8541 Background: Multi-modality treatment provides modest survival benefits for locally advanced non-small-cell lung cancer (NSCLC) patients. Preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC. The current study aimed to investigate the activity and safety of the PD-1 inhibitor, toripalimab, with chemotherapy given as neoadjuvant treatment for resectable stage III NSCLC in Asian population. Methods: Eligible patients recruited were aged 18 years or older with histologically confirmed AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC who deemed surgically resectable. Patients received 3 cycles of neoadjuvant treatment with intravenous toripalimab (240 mg), carboplatin (area under curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for others) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks following the first day of the last cycle of treatment. The primary endpoint was major pathological response (MPR; ≤10% viable tumor cells). Secondary endpoints included pathological complete response (pCR), R0 resection rate, disease-free survival and safety. Paired primary tumor +/- lymph node and blood samples at baseline and surgery were obtained for exploratory study. This study is registered with ClinicalTrials.gov, NCT04304248. Results: Between August 2019 and July 2020, 33 patients (median age: 61, IQR: 56-66; female: 6, 18.2%) were enrolled and received neoadjuvant treatment. 18 (54.5%) patients had squamous cell lung cancer, and 13 (39.4%) had T3-4N2 stage IIIB disease. Two patients refused surgery and one had progressive disease after treatment. 30 (91.9%) patients underwent resection (median interval between neoadjuvant treatment and surgery: 36.5 days, IQR 30-42.5) and all except one achieved R0 resection (29/30, 96.7%). 20 patients (20/30, 66.7%) had an MPR, including 15 patients (15/30, 50.0%) had a pCR in the per-protocol population. Surgical complications included three arrhythmias, one prolonged air leak, and one chylothorax. 24 patients (80.0%) had pathological downstaging following treatment, and complete lymph node clearances (ypN0) were seen in 70.0% (21/30) of patients. The most common grade 3-4 treatment-related adverse events in the intention-to-treat population were anemia (2, [6.0%]). Severe treatment-related adverse event included one (3.0%) patient with grade 3 peripheral neuropathy (Guillain-Barré syndrome) and resulted in surgery cancellation. At the time of data cutoff (Feb 7, 2021), the median duration of follow-up was 4.13 months, and there were no treatment-related deaths. Conclusions: Toripalimab plus platinum-based doublet yields a high MPR rate, manageable treatment-related toxicity, and feasible surgical resection in resectable stage III NSCLC. Ongoing analysis of biomarker will be available at the meeting. Clinical trial information: NCT04304248.

Modeling the cost-effectiveness of adjuvant osimertinib in resected EGFR-mutant non-small cell lung cancer patients.

8527 Background: Adjuvant Osimertinib (Osi) was recently approved for resected EGFR-mutant non-small cell lung cancer (NSCLC) based on disease free survival (DFS) benefits from the ADAURA trial. Prior studies of adjuvant EGFR inhibitors yielding DFS benefits have lacked an overall survival (OS) benefit, leading to debate over early clinical implementation given the associated drug costs. This study aims to evaluate the cost-effectiveness (CE) of Osi in this setting. Methods: We constructed Markov models using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of the use of 3 years of adjuvant Osi versus placebo in the ADAURA patient population of stage IB to IIIA NSCLC patients over a 10-year time horizon. All patients entering the progressive disease (PD) state were assigned for re-treatment with Osi. Cost and utility values were derived from Medicare reimbursement data and literature (Table). A CE threshold of 3 times the GDP per capita was used. Deterministic sensitivity analyses were performed to assess the impact of a range of OS benefit, as the impact of adjuvant Osi on OS has not yet been reported. Results: The incremental cost-effectiveness ratio (ICER) for adjuvant Osi was $317,119.90 per QALY gained. Initial costs of Osi are higher in the first 3 years, but become lower than the placebo group in year 4 onward, with similar costs after year 7. Costs due to PD are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2,388, $379,047, and $502,937, respectively in the placebo group, compared to $505,775, $255,638, and $800,697, respectively in the Osi group. QALYs were higher in the Osi arm throughout. Sensitivity analysis using incremental OS gains reaches the CE threshold of $195,000 between 25-30% OS benefit of Osi over placebo. A 50% discount to the Osi annual cost yielded an ICER of $115,419. Conclusions: 3 years of adjuvant Osi is more cost-effective than placebo if one is willing to pay $317,119 more per QALY gained, with most costs accruing in the first 3 years as drug cost. This strategy became cost-effective with an OS benefit between 25-30% over placebo. Discount to Osi annual costs improves the ICER significantly. True cost-effectiveness of adjuvant Osi will require further study due to immaturity of ADAURA OS data and model limitations.[Table: see text]

Prognostic Value of the Tumor Immune Microenvironment for Early-stage, Non-Small Cell Lung Cancer.

The role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed. Stage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma. There were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death. This study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.