Advanced Non-small Lung Cancer Research Articles

Abstract 2803: Identification of microbiome and predictive immune biomarkers in patients with advanced non-small lung cancer treated with pembrolizumab with or without chemotherapy

Abstract Background: Recent studies have shown that gut microbiota modulates antitumor immunity, and affect clinical efficacy of immune checkpoint inhibitors, including anti-programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. We aimed to explore the metagenomic profiles of previously untreated, treatment naïve, stage IV non-small cell lung cancer (NSCLC) treated with pembrolizumab, an anti-PD1 agent with or without platinum-based chemotherapy and identify distinct ecological niche between responder and non-responder groups. Methods: We performed metagenome sequencing, whole exome sequencing (WES), and RNA sequencing (RNA-seq) on 50 patients with stage IV NSCLC, including adenocarcinoma (N=31) and squamous cell carcinoma (N=22). We employed Dirichlet Multinomial Mixtures (DMM) community typing to cluster microbial community profiling data at the genus level and analyzed the changes in microbial composition and diversity between enterotype 1 (E1, N=27) and enterotype 2 (E2, N=23). Mutation landscape including genomic alterations in relation to immune response was analyzed between responders and non-responders using WES data. Differentially expressed genes (DEGs), Gene Set Enrichment Analysis (GSEA), and immune deconvolution analysis were carried out using RNA-seq data to analyze molecular profiling of two enterotypes between the responder (N=15) and non-responder (N=35) groups. Results: The two enterotypes exhibited distinct microbial abundances and alpha diversity indices. Abundances of members of Bacteroidaceae (P=0.011) and Oscillospiraceae (P<0.001) were higher in E2 members, and enrichment of Lactobacillaceae (P=0.006) and Bifidobacteriaceae (P=0.041) were higher in E1. Compared to E1, the number of observed bacterial species (P<0.001) and Shannon index (P<0.001) was significantly higher in E2, indicating a healthier gut environment. The proportion of responders was higher in E2 than in E1 cluster. Comparison between responders and non-responder groups within each enterotype revealed that Lactobacillaceae showed an association with the response in E2 cluster. Mutation landscape revealed TP53 mutation as the most common mutation, more frequently observed in the E2 (100%) than in the E1 (56%) cluster. Conclusion: We explored the association between the gut microbiome and clinical response to pembrolizumab with or without combination with chemotherapy and found that E2 cluster enriched with Lactobacillaceae is associated with treatment response. Further analysis with larger cohort is ongoing. Citation Format: Jii Bum (Joy) Lee, Su-Jin Choi, Gang-Taik Lee, Junwon Yang, Hyun-Seok Oh, Arim Min, Bo-Eun Kwon, Seong-san Kang, Sujeong Baek, Dong Kwon Kim, Jae Hwan Kim, Sun Min Lim, Min Hee Hong, Kyoung-Ho Pyo, Byoung Chul Cho. Identification of microbiome and predictive immune biomarkers in patients with advanced non-small lung cancer treated with pembrolizumab with or without chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2803.

The role of chemoradiotherapy and immunotherapy in stage III NSCLC.

Locally advanced non-small lung cancer encompasses a diverse range of tumors. In the last few years, the treatment of stage III unresectable non-small lung cancer has evolved significantly. The PACIFIC trial opened a new therapeutic era in the treatment of locally advanced NSCLC, establishing durvalumab consolidation therapy as the new standard of care worldwide. A careful evaluation of this type of lung cancer and a discussion of the management of these patients within a multidisciplinary team represents a crucial step in defining the best treatment strategy for each patient. For unresectable stage III NSCLC, definitive concurrent chemoradiotherapy (CCRT) was historically recommended as a treatment with a 5-year survival rate ranging from 20% to 30%. The PACIFIC study conducted in 2017 compared the use of chemoradiotherapy and maintenance therapy with the anti-PD-L1 monoclonal antibody durvalumab to a placebo in patients with locally advanced NSCLC who had not experienced disease progression. The study was prospective, randomized, and phase III. The administration of this medication in patients with locally advanced non-small cell lung cancer (NSCLC) has demonstrated a notable improvement in overall survival. Multiple clinical trials are currently exploring various immune checkpoint inhibition regimens to enhance the treatment efficacy in patients with stage III cancer. Our goal is to offer an up-to-date summary of the planned clinical trials for treatment options, focusing on the significant obstacles and prospects in the post-PACIFIC era.

Extended ICI treatment after first-line chemoimmunotherapy could predict the clinical benefit of ramucirumab plus docetaxel in advanced non-small lung cancer: Post hoc analysis from NEJ051 (REACTIVE study).

The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC). Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC.

Treatment for Advanced Non-Small Lung Cancer (NSCLC) with Mutated EGFR in Low- and Middle-Income Countries (LMICs).

Treatment for Advanced Non-Small Lung Cancer (NSCLC) with Mutated EGFR in Low- and Middle-Income Countries (LMICs).

EP08.02-13 Association of the Benefit of Durvalumab Consolidation Therapy and Driver Mutation Status for Locally Advanced Non-small Lung Cancer

EP08.02-13 Association of the Benefit of Durvalumab Consolidation Therapy and Driver Mutation Status for Locally Advanced Non-small Lung Cancer

Chinese expert consensus on immunotherapy for advanced non-small lung cancer with oncogenic driver mutations (2023 edition)

Non-small cell lung cancer (NSCLC) with oncogenic driver mutations was previously deemed " forbidden territory" for immunotherapy. With the growing understanding of the impact of target drugs on the immune microenvironment and the continuous generation of clinical evidence, immunotherapy is expected to bring new hope for the NSCLC with oncogenic driver mutations. This consensus is updated based on the Chinese expert consensus on immunotherapy for advanced non-small lung cancer with oncogenic driver mutations (2022 edition), and developed by the consensus expert panel through symposiums, combining the latest medical evidence and clinical practice. After thorough discussion, the expert panel reached new consensuses on 3 clinical questions: in patients with ALK fusion who are progressing on tyrosine kinase inhibitor(TKI) therapy, immune checkpoint inhibitors (ICIs)-based treatment is not recommended; ICIs-based treatment is recommended for patients with HER-2 mutations; ICIs-based treatment is recommended for NSCLC patients with MET exon 14 skipping after resistance to the targeted therapy. At the same time, with the continuous accumulation of clinical evidence, the recommendation levels of the three consensus opinions were adjusted in this update: the recommendation of ICIs combined with anti-angiogenesis therapy for patients with extensive progression after EGFR-TKIs resistance was adjusted to the level of strong; the ICIs recommendations for patients with advanced KRAS mutant and BRAF mutant NSCLC were adjusted to the level of consistent and strong, respectively. This updated consensus, combined with the latest evidence and clinical experience widely recognized by the expert panel in the immunotherapy of driver gene mutation advanced NSCLC, aims to provide standardized guidance for the clinical practice in China.

The Relationship of CYFRA 21-1 to the Metastatic Process of Advanced Non- Small Cell Lung Carcinoma

Lung cancer is a leading cause of death worldwide. Globally, lung cancer is estimated to cause 2.2 million new cases and 1.8 million deaths in 2020. About 85% of total lung cancer cases are estimated to be Non-Small Cell Carcinoma Lung Cancer (NSCLC). Lung cancer itself has several tumor markers because the type of cancer depends on its cell origin where Cytokeratin19 fragment (CYFRA 21-1) is used for squamous cell carcinoma type lung cancer. This study aims to assess the sensitivity of CYFRA 21-1 tumor biomarker examination in advanced non-small cell carcinoma lung cancer. This study was a cross-sectional study in lung cancer patients at Wahidin Sudirohusodo Hospital in the period January- March 2023. Each research subject collected bronchial lavage and serum samples, then tested CYFRA 21-1 levels using the ELISA method. The results showed that in subjects with JPBSK, most diagnoses were made based on the bronchial lavage method (72.7%), diagnosed at an advanced stage (88.5%) with a cytology/histology type of squamous cell carcinoma (43.2%). The research data showed that the serum level of CYFRA 21-1 in NSCLC patients was higher than non-cancer patients (p=0.015). It can be concluded that serum CYFRA 21-1 levels increased significantly in NSCLC subjects when compared to non-cancer. Keywords: NSCLC, CYFRA 21-1, Bronchial Rinses, Serum

Pembrolizumab Every 6 Weeks Versus Every 3 Weeks in Advanced Non-Small Cell Lung Cancer.

The survival benefits and adverse effects of pembrolizumab 2 mg/kg intravenously (IV) every 3 weeks (Q3W) in advanced non-small lung cancer (NSCLC) are well documented in the literature. Based on pharmacokinetic models, a pembrolizumab 4 mg/kg IV every 6 weeks (Q6W) dosing regimen is also approved in some countries. To date, there is no direct comparison in the literature between these 2 regimens in advanced NSCLC. This retrospective study included 80 patients with advanced NSCLC who received pembrolizumab monotherapy 4 mg/kg Q6W between March 1, 2020 and December 31, 2021 and 80 patients with advanced NSCLC who received pembrolizumab monotherapy 2 mg/kg Q3W between January 1, 2017 and January 15, 2019 at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The primary outcomes of this study were to compare overall survival (OS), progression-free survival (PFS) as well as the occurrence and severity of immune-mediated adverse events (AEs) in patients with advanced NSCLC who received pembrolizumab Q6W vs Q3W. Data cutoff date was December 15, 2022. Median follow-up was 14.5 ± 8.6 months in the Q6W group and 18.3 ± 19.6 months in the Q3W group. Median PFS was 6.9 months (CI 95% 5.0-10.7) in the Q6W group vs 8.9 months (CI 95% 5.6-14.1) in the Q3W group (adjusted HR 1.27 (CI 95% 0.85-1.89), P = .25). Median OS was not reached in the Q6W group vs 20.5 months (CI 95% 13.7-29.8) in the Q3W group (adjusted HR 0.80 (CI 95% 0.50-1.29), P = .36). Immune-mediated AEs of grade ≥ 3 occurred in 18% of patients in the Q6W group and in 19% of those in the Q3W group. In this unicentric retrospective study, the pembrolizumab Q6W dosing regimen was comparable to the Q3W in terms of OS, PFS, and toxicity.

Post-therapeutic circulating tumor cell-associated white blood cell clusters predict poor survival in patients with advanced driver gene-negative non-small cell lung cancer

PurposeThis study aimed to investigate the clinical utility of diverse aneuploid circulating tumor cell (CTC) subtypes and particularly CTC-associated white blood cell (CTC-WBC) clusters in predicting treatment response, prognosis and real-time monitoring disease progression in advanced driver gene-negative non-small lung cancer (NSCLC) patients.Materials and methodsA total of 74 eligible patients were prospectively enrolled and serial blood samples were collected at pre-treatment(t0), after two cycles of therapy (t1) and at post-four-to-six treatment cycles (t2). Co-detection of diverse subtypes of aneuploid CTCs and CTC-WBC clusters was conducted in advanced NSCLC patients receiving first-line treatment.ResultsAt baseline, CTCs were detected in 69 (93.24%) patients and CTC-WBC clusters were detected in 23 (31.08%) patients. Patients with CTCs < 5/6ml or with CTC-WBC clusters undetectable exhibited a better treatment response than patients with pre-therapeutic aneuploid CTCs ≥ 5/6ml or harboring CTC-WBC clusters (p = 0.034 and p = 0.012, respectively). Before treatment, patients bearing tetraploid CTCs ≥ 1/6ml showed significantly inferior progression-free survival (PFS) [hazard ratio (HR):2.420, 95% confidence interval (CI): 1.426–4.106; p = 0.001] and overall survival (OS) compared to patients with tetraploid CTCs < 1/6ml (HR:1.907, 95%CI: 1.119–3.251; p = 0.018). A longitudinal study demonstrated that post-therapeutic patients harboring CTC-WBC clusters displayed the reduced PFS and OS compared with those without CTC-WBC clusters, and subgroup analysis showed that the presence of CTC-WBC clusters indicated a worse prognosis in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. After adjusting for multiple significant factors, post-therapeutic CTC-WBC clusters were the only independent predictor of both PFS (HR:2.872, 95% CI: 1.539–5.368; p = 0.001) and OS (HR:2.162, 95% CI: 1.168–4.003; p = 0.014).ConclusionsIn addition to CTCs, longitudinal detection of CTC-WBC clusters provided a feasible tool to indicate initial treatment response, dynamically monitor disease progression and predict survival in driver gene-negative advanced NSCLC patients.

Abstract 3499: Inhibition of SOS1 by MRTX0902 augments the anti-tumor response of the targeted EGFR inhibitor osimertinib in NSCLC

Abstract Osimertinib is a third generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recommended as a first line therapy in patients with advanced non-small lung cancer (NSCLC) characterized by EGFR activating mutations (exon 19 deletions and exon 21 L858R) and the resistance associated exon 20 T790M mutation, which is present in approximately 40-55% of patients following treatment with first generation EGFR-targeting inhibitors. Unfortunately, osimertinib monotherapy inevitably leads to both EGFR-dependent and EGFR-independent resistance mechanisms that reactivate RTK/MAPK pathway signaling. Thus, exploration of new combination strategies that target RTK/MAPK-mediated bypass of EGFR dependence may circumvent or delay therapeutic resistance are a key research focus. Preclinically, it has been shown that EGFR-mutant NSCLC cell lines are sensitive to inhibition of an upstream node of the MAPK pathway, the Son of Sevenless homolog 1 (SOS1) protein, which functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases. MRTX0902 is a selective and potent SOS1 inhibitor currently in Phase 1 clinical trials and functions by disrupting the KRAS/SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS, ultimately leading to downregulation of KRAS-MAPK pathway signaling. Here we demonstrate that dual inhibition of SOS1 and mutant EGFR by osimertinib results in greater anchorage-independent (3D) cell death and further downregulation of MAPK and PI3K/AKT pathway signaling compared to single agent osimertinib treatment. In our current study, we characterized the anti-tumor effects of SOS1 inhibition by MRTX0902 as a monotherapy and in combination with osimertinib in EGFR mutant models of NSCLC. While single agent MRTX0902 treatment effectively inhibited EGFR mutant cell survival, combination treatment of MRTX0902 with osimertinib resulted in (1) deeper and sustained inhibition of MAPK and PI3K/AKT pathway signaling, (2) enhanced inhibition of 3D cell viability and increased apoptosis, and (3) increased anti-tumor efficacy compared to osimertinib monotherapy in EGFR mutant CDX models in vivo. These studies uncover the potential clinical application of combined vertical inhibition of RTK/MAPK pathway signaling by osimertinib and MRTX0902 and ultimately aide in the understanding of EGFR and RAS biology in targeted cancer therapy. Citation Format: Shilpi Khare, Niranjan Sudhakar, Jade Laguer, David M. Briere, Larry Yan, Allan Hebbert, Andrew Calinisan, Lars D. Engstrom, Fadia Qiryaqos, Peter Olson, James G. Christensen, Jacob R. Haling. Inhibition of SOS1 by MRTX0902 augments the anti-tumor response of the targeted EGFR inhibitor osimertinib in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3499.

Abstract 4866: Pharmacological mechanisms of osimertinib in advanced non-small lung cancer bearing the deletion exon 19 of EGFR In an original chicken chorioallantoic membrane (CAM) Model

Abstract Introduction: NSCLC accounts for about 80-85% of all lung cancers. Approximately 10-50% of patients with NSCLC harbor EGFR activating mutations, such as in-frame deletions in exon 19 (Ex19del). Currently, for patients with advanced NSCLC, testing for sensitizing mutations in EGFR is mandatory prior to the administration of anti-EGFR inhibitors such as Osimertinib. The CAM xenograft offers a rich environment in nutrients and embryonic growth factors, favorable for aggressive tumor development, with its highly vascularized membrane and natural immunodeficiency at engraftment (at EDD9). Methods: HCC827 Ex19del cells have been engrafted in ovo, and treated with various doses of osimertinib for seven days (4 treatments). The xenografts were collected and immunohistopathological, transcriptional and genetic analyses were carried out. Based on human transcriptional data, supervised multivariate discrimination between conditions and ontology analysis was performed through GSEA. Results: The xenograft growth was inversely dependent on the exposure dose of osimertinib, with a reduction in tumor weight of 58% for 10 µM (corresponding to 8.3 µg/Kg, T1/2 =4hr). The histological analysis showed epithelial tumor cells composed of solid sheets. The quantity of tumor cells was significantly lower in the treated group, with an area of tumor necrosis. The immunohistochemistry of tumor cells confirmed the human pulmonary epithelial origin, with TTF1 positive in treated and control groups. As expected, the ontology analysis of transcriptomic findings highlighted a downregulation of the EGFR pathway and its downstream effectors. Furthermore, the transcriptomic responses associated with chemotaxis, immune cell recruitment, and angiogenesis were dampened in the presence of osimertinib. This suggests that therapeutic efficacy was not uniquely guided through cell-autonomous mechanisms, but also takes place at the tissue level. We confirmed this in an independent experiment of in ovo HCC827 engraftment, showing a statically significant reduction of 15% in the number of vessels surrounding the xenograft in the osimertinib-treated condition. This demonstrates the advantage of using the in ovo model to decipher the regulations associated with therapeutics in a complex tissue context. Conclusions: For the first time, we have observed that osimertinib modulates angiogenesis and chemotaxis, which apparently reduces immune system recruitment and immune checkpoint responses. The ontologic analysis of transcriptomic findings in the CAM model strongly support the clinical observations of the pharmacological tumoral response to targeted therapy. The fact that immune infiltration was reduced in osimertinib-treated tumors may partially explain the lower response to immunotherapy regimens in osimertinib resistance contexts. Citation Format: David Barthelemy, Arnaud Vigneron, Xavier Rousset, Jerome Guitton, Emmanuel Grolleau, Margaux Raffin, Julie Balandier, Gaelle Lescuyer, Florence Geiguer, Sebastien Couraud, Jean Vaillet, Nazim Benzerdjeb, Lea Payen-Gay. Pharmacological mechanisms of osimertinib in advanced non-small lung cancer bearing the deletion exon 19 of EGFR In an original chicken chorioallantoic membrane (CAM) Model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4866.

Chinese expert consensus on immunotherapy for advanced non-small lung cancer with oncogenic driver mutations (2022 edition)

Non-small cell lung cancer (NSCLC) with oncogenic driver mutations was previously deemed " forbidden territory" for immunotherapy. With the growing understanding of the impact of target drugs on the immune microenvironment and the continuous generation of clinical evidence, immunotherapy is expected to bring new hope for the NSCLC patients with oncogenic driver mutations. An expert panel of medical oncology, respiratory medicine and pathology organized by the Society of Cancer Precision Medicine of Chinese Anti-Cancer Association and Expert Group on Lung Cancer of Chinese Medical Journal conducted an in-depth discussion on current evidence of immune microenvironment and clinical studies and formulated a Chinese expert consensus on immunotherapy for advanced NSCLC with oncogenic driver mutations by combining with clinical experience. This expert consensus aims to provide guidance for Chinese clinicians on immunotherapy in NSCLC with oncogenic driver mutations.

Is immunotherapy at reduced dose and radiotherapy for older patients with locally advanced non-small lung cancer feasible?-a narrative review by the international geriatric radiotherapy group.

Background and ObjectiveThe standard of care for locally advanced non-small cell lung cancer (NSCLC) is either surgery followed by adjuvant chemotherapy with or without radiotherapy or concurrent chemotherapy and radiotherapy. However, older patients (70 years old or above) with multiple co-morbidities may not be able to tolerate the combined treatment due to its toxicity. Since lung cancer prevalence increases significantly with age, a new algorithm needs to be investigated to allow curative treatment for those with locally advanced disease.MethodsA literature search of the literature was conducted through PubMed and Google Scholar using search terms such as locally advanced NSCLC, older cancer patients, immunotherapy with check point inhibitors (CPI), and image-guided radiotherapy (IGRT). s were screened, full articles fitting the article topic were reviewed, and duplicated and non-English articles were excluded.Key Content and FindingsRecently, CPI has been introduced and proven effective for selected patients with increased program death ligand 1 (PD-L1) expression (50% or above). A reduced dose for CPI (RDCPI) may be as effective as a full dose and may decrease treatment cost. New radiation technique such as IGRT may also minimize radiotherapy complication through normal lung and cardiac sparing.ConclusionsIGRT and RDCPI may be an innovative option for older patients with locally advanced NSCLC and high PD-L1 expression and needs to be investigated in future prospective studies.

EP05.01-013 Increased C-reactive Protein after Chemoradiotherapy and Immunotherapy in Locally Advanced Non-small Lung Cancer Indicates Worse Survival

Adjuvant durvalumab after chemoradiotherapy (ChRT) in PD-L1 positive tumours is standard radical treatment for fit patients with locally advanced non-small cell lung cancer (LA-NSCLC). Many studies showed that immune response based on neutrophil-to-lymphocyte ratio (NLR), serum C-reactive protein (CRP) values and the use of antibiotic treatment before and during immunotherapy (IT) can predict survival in metastatic NSCLC patients, but rare data are published for LA-NSCLC.

Ground-glass opacity showed response to immunotherapy in cancer patients.

e14605 Background: Ground glass opacities (GGO) are lesions with hazy density on CT. Immune checkpoint inhibitors (ICIs) achieved a significant improvement in the treatment of early and advanced non-small lung cancer (NSCLC). It is unclear whether ICI therapy show efficacy on GGO lesions. Methods: As the largest diameter of most lesions was less than 10mm, the definition of evaluable lesion we expanded the lower limit of the diameter to 4 mm. We retrospectively assessed cancer patients with GGOs who underwent at least two courses of immunotherapy between January 2016 and June 2021 in Second Xiangya hospital, China. Also, we evaluated GGOs that had been examined by low-dose thin-slice CT more than twice. Wilcoxon test was used to evaluate the length and diameter changes of GGO. We assessed the correlation between CT imaging features of GGO and the efficacy of immunotherapy through univariate and multivariate logistic regression. Results: Among eligible patients (n = 51), 35 were lung cancer patients and 16 were other tumor patients. Confirmed 95 GGOs were included. 68 GGOs were from lung cancer patients and 27 GGOs were from patients with other types of cancer (such as esophageal carcinoma, oral squamous cell carcinoma and hepatocarcinoma etc.). The diameter of GGO decreased significantly after immunotherapy (7.56 vs 4.31, P = 0.000). The same results were observed in lung cancer patients (7.98mm vs 4.92mm, P = 0.000) and in non-lung cancer patients (6.90mm vs 3.35mm, P = 0.001). The volume of GGO shirked significantly after immunotherapy in cancer patients (297.35mm3 vs 125.46mm3, P = 0.000) lung cancer patients (401.41 mm3 vs 164.91 mm3, P = 0.007) and non-lung cancer patients (137.93mm3 vs 65.04mm3, P = 0.000). Conclusions: GGO can response to immunotherapy, which indicates immunotherapy maybe potentially helpful for patients with multiple GGO lesions such as multiple primary lung cancer (MPLC) patients.

Multi-Omics Approaches for the Prediction of Clinical Endpoints after Immunotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review.

Immune checkpoint inhibitors (ICI) have revolutionized the management of locally advanced and advanced non-small lung cancer (NSCLC). With an improvement in the overall survival (OS) as both first- and second-line treatments, ICIs, and especially programmed-death 1 (PD-1) and programmed-death ligands 1 (PD-L1), changed the landscape of thoracic oncology. The PD-L1 level of expression is commonly accepted as the most used biomarker, with both prognostic and predictive values. However, even in a low expression level of PD-L1, response rates remain significant while a significant number of patients will experience hyperprogression or adverse events. The dentification of such subtypes is thus of paramount importance. While several studies focused mainly on the prediction of the PD-L1 expression status, others aimed directly at the development of prediction/prognostic models. The response to ICIs depends on a complex physiopathological cascade, intricating multiple mechanisms from the molecular to the macroscopic level. With the high-throughput extraction of features, omics approaches aim for the most comprehensive assessment of each patient. In this article, we will review the place of the different biomarkers (clinical, biological, genomics, transcriptomics, proteomics and radiomics), their clinical implementation and discuss the most recent trends projecting on the future steps in prediction modeling in NSCLC patients treated with ICI.

Association Between Smoking History and Overall Survival in Patients Receiving Pembrolizumab for First-Line Treatment of Advanced Non–Small Cell Lung Cancer

There is a need to tailor treatments to patients who are most likely to derive the greatest benefit from them to improve patient outcomes and enhance cost-effectiveness of cancer therapies. To compare overall survival (OS) between patients with a current or former history of smoking with patients who never smoked and initiated pembrolizumab monotherapy as first-line (1L) treatment for advanced non-small lung cancer (NSCLC). This retrospective cohort study compared patients diagnosed with advanced NSCLC aged 18 or higher selected from a nationwide real-world database originating from more than 280 US cancer clinics. The study inclusion period was from January 1, 2011, to October 1, 2019. Smoking status at the time of NSCLC diagnosis. OS measured from initiation of 1L pembrolizumab monotherapy. In this retrospective cohort study, a total of 1166 patients (median [IQR] age, 72.9 [15.3] years; 581 [49.8%] men and 585 [50.2%] women) were assessed in the primary analysis, including 91 patients [7.8%] with no history of smoking (ie, never-smokers) and 1075 patients [92.2%] who currently or formerly smoked (ie, ever-smokers). Compared with ever-smokers, never-smokers were older (median age [IQR] of 78.2 [12.0] vs 72.7 [15.5] years), more likely to be female (61 [67.0%] vs 524 [48.7%]) and to have been diagnosed with nonsquamous tumor histology (70 [76.9%] vs 738 [68.7%]). After adjustment for baseline covariates, ever-smokers who initiated 1L pembrolizumab had significantly prolonged OS compared to never-smokers (median OS: 12.8 [10.9-14.6] vs 6.5 [3.3-13.8] months; hazard ratio (HR): 0.69 [95% CI, 0.50-0.95]). This trend was observed across all sensitivity analyses for the 1L pembrolizumab cohort, but not for initiators of 1L platinum chemotherapy, for which ever-smokers showed significantly shorter OS compared with never-smokers (HR, 1.2 [95% CI, 1.07-1.33]). In patients with advanced NSCLC who received 1L pembrolizumab monotherapy in routine clinical practices in the US, patients who reported a current or former history of smoking at the time of diagnosis had consistently longer OS than never-smokers. This finding suggests that in never-smoking advanced NSCLC, 1L pembrolizumab monotherapy may not be the optimal therapy selection, and genomic testing for potential genomically matched therapies should be prioritized over pembrolizumab in never-smokers.

Novel targeted therapies for advanced non-small lung cancer

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for almost 80%–85% of all lung cancer cases. Unfortunately, more than half of the patients will be diagnosed with advanced disease at the time of presentation, which makes their disease incurable. Historically, the 5 year overall survival for advanced NSCLC was 5%. However, there has been a significant increase in our understanding of the genetic basis of NSCLC, which has led to development of both immunotherapy and targeted therapy agents. This has improved the 5 year overall survival to become within the range of 15%–50% depending on certain mutations and biomarkers. Over the last decade the United States Food and Drug Administration (FDA) has approved almost 20 new targeted therapies and clinical trials are still undergoing to evaluate more novel agents. In this review, we will present recent updates on novel targeted therapies.

P10.09 Efficacy and Toxicity of EGFR-TKI in Frail NSCLC with EGFR Mutation: A Retrospective Analysis in a Single Institution

EGFR-TKI is the standard treatment of care for sensitizing EGFR mutation-positive advanced non-small lung cancer (NSCLC) patients. However, the treatment strategy of first-line EGFR-TKI for frail patients has not been well established yet. In current NCCN guideline, osimertinib is preferred as first-line therapy for sensitizing EGFR mutation-positive patients regardless of their age and ECOG performance status (PS), while Japan Lung Cancer Society guideline 2020 recommends first generation EGFR-TKIs for the patients with PS 2-4.

Efficacy of weekly paclitaxel-bevacizumab combination in advanced nonsquamous non-small cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study.

e21086 Background: With the growing role of immunotherapy (ICI) as first-line setting for advanced NSCLC, strategies must be redefined after failure. The combination paclitaxel-bevacizumab showed in the ULTIMATE trial a significant superiority versus docetaxel as second or third-line treatment. Limited restropective studies has demonstrated unexpected efficacy of chemotherapy after prior progression on ICI. This combination could be use as salvage treatment following ICI. Methods: This multi-centric retrospective study identifies patients treated with the combination paclitaxel-bevacizumab in metastatic non-squamous NSCLC as second-line therapy or beyond. Main objectives were to describe safety and efficacy of this combination, with a special attention to the sub-group treated just after ICI. Results: From January 2010 to February 2020, 314 patients started the paclitaxel-bevacizumab combination : 55% male, with a median age of 60 years, 27% with a performance status ≥2, 45% with brain metastases. A majority of patients were treated in second (20%) and third-line (39%), and 28% were treated just after ICI failure (88/314). Objective response rate (ORR) was 40% and disease control rate was 77 %. Median progression-free survival (PFS) and overall survival (OS) were 5,7 months [IQ,3,2–9,6] and 10,8 months [IQ,5,3–19,6] respectively. All grades adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued a monotherapy alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compare to those not previously treated with ICI (ICI-) : 7,0 months [IQ,4,2–11,0] vs 5,2 months [IQ,2,9–8,8] p (log-rank) = 0,01. There was not statistically significant difference in term of OS between this two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment (ICI+) and performance status. Conclusions: This study confirms an acceptable toxicity profile associated with interesting efficacy of the combination paclitaxel-bevacizumab as second-line treatment or beyond for non–squamous NSCLC patients, particularly after progression with ICI.