Immunotherapy In Advanced Non-small Cell Lung Cancer Research Articles

Triple-induction treatment for locally advanced non-small cell lung cancer: a case report of pathological complete response

BackgroundIn patients with resectable stage III non-small cell lung cancer (NSCLC), induction chemoimmunotherapy followed by surgical resection has shown unprecedented rates of pathological response and event-free survival. However, a triple-induction including radiochemotherapy and immunotherapy followed by surgical resection has not been routinely established in clinical practice.Case presentationWe report the case of a 47-year-old patient with stage IIIA NSCLC who was treated in a combined concept including induction concurrent radiochemotherapy, followed by 4 cycles of pembrolizumab and subsequent intrapericardial left-sided pneumonectomy. Histological analysis revealed a pathological complete response.ConclusionsThe case demonstrates that the combination of neoadjuvant chemo-, radio- and immunotherapy in advanced NSCLC may lead to a relevant down-staging and may enable a R0-resection of a borderline resectable tumor. However, the combination of four different treatment modalities requires resilience and a good performance status. A triple induction treatment may be a promising option for selected patients with locally advanced NSCLC and good performance status.

Prediction performance comparison of biomarkers for response to immune checkpoint inhibitors in advanced non-small cell lung cancer.

The aim of the present study was to compare the predictive accuracy of PD-L1 immunohistochemistry (IHC), tissue or blood tumor mutation burden (tTMB, bTMB), gene expression profile (GEP), driver gene mutation, and combined biomarkers for immunotherapy response of advanced non-small cell lung cancer (NSCLC). In part 1, clinical trials involved with predictive biomarker exploration for immunotherapy in advanced NSCLC were included. The area under the curve (AUC) of the summary receiver operating characteristic (SROC), sensitivity, specificity, likelihood ratio and predictive value of the biomarkers were evaluated. In part 2, public datasets of immune checkpoint inhibitor (ICI)-treated NSCLC involved with biomarkers were curated (N = 871). Odds ratio (OR) of the positive versus negative biomarker group for objective response rate (ORR) was measured. In part 1, the AUC of combined biomarkers (0.75) was higher than PD-L1 (0.64), tTMB (0.64), bTMB (0.68), GEP (0.67), and driver gene mutation (0.51). Combined biomarkers also had higher specificity, positive likelihood ratio and positive predictive value than single biomarkers. In part 2, the OR of combined biomarkers of PD-L1 plus TMB (PD-L1 cutoff 1%, 0.14; cutoff 50% 0.13) was lower than that of PD-L1 (cutoff 1%, 0.33; cutoff 50% 0.24), tTMB (0.28), bTMB (0.48), EGFR mutation (0.17) and KRAS mutation (0.47), for distinguishing ORR of patients after immunotherapy. Furthermore, positive PD-L1, tTMB-high, wild-type EGFR, and positive PD-L1 plus TMB were associated with prolonged progression-free survival (PFS). Combined biomarkers have superior predictive accuracy than single biomarkers for immunotherapy response of NSCLC. Further investigation is warranted to select optimal biomarkers for various clinical settings.

Abstract 2531: rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms

Abstract Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small-cell lung cancer (NSCLC). So far, testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aimed to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of identified SNP candidate. rs822336 SNP efficiently predicted response to anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients as compared to rs2282055 and rs4143815 SNPs. rs822336 SNP mapped on promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines. The induction of PD-L1 expression by rs822336 SNP was predicted by allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially modulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. In addition, binding microarray validated the allele- specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. Lastly, the induction of PD-L1 expression by rs822336 genotype differentially affected the susceptibility to anti-PD-1 monoclonal antibody nivolumab of human NSCLC cell lines co-cultured with HLA class I antigen matched PBMC. These results have clinical relevance since identified rs822336 SNP and the induction of PD-L1 expression as novel biomarkers for predicting ICI-based immunotherapy in NSCLC patients. Citation Format: Giovanna Polcaro, Luigi Liguori, Valentina Manzo, Annalisa Chianese, Giuliana Donadio, Alessandro Caputo, Giosuè Scognamiglio, Federica Dell'Annunziata, Maddalena Langella, Graziamaria Corbi, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Margot De Marco, Jessica Dal Col, Valentina Pagliara, Pio Zeppa, Amelia Filippelli, Gianluigi Franci, Fabrizio Dal Piaz, Valeria Conti, Stefano Pepe, Francesco Sabbatino. rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms [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 2531.

Subsequent surgical treatment or maintenance immunotherapy in stage III lung cancer patients achieving a favorable response following neoadjuvant immunotherapy: A matched retrospective cohort study from the surgical perspective.

Current treatment strategies for advanced non-small cell lung cancer (NSCLC) are highly individualized and subject to ongoing debates. In the era of immunotherapy, surgery assumes a critical role. The aim of this study was to investigate if subsequent surgical intervention, following a favorable response to immunotherapy and chemotherapy, could yield a more favorable prognosis for patients with advanced stage III NSCLC compared to the continuation of immunotherapy and chemotherapy. We included patients whose tumors exhibited a favorable response (including partial response [PR] and complete response [CR]) to immunotherapy and chemotherapy. These patients were categorized into two groups based on their subsequent treatment plans: surgical and nonsurgical (continuation of maintenance immunotherapy and chemotherapy). The efficacy and long-term prognosis of these groups were compared after matching them in a 1:1 ratio using propensity scores. In total, 186 patients (93 in each group) were included in this study after matching via propensity scores. The 1- and 3-year overall survival (OS) and progression-free survival (PFS) rates were 96.0%, 88.5%, and 93.1%, 80.7% in the surgical group, and 93.2%, 83.1%, and 57.7%, 50.4% in the nonsurgical group, respectively. Patients in the surgical group exhibited significantly superior PFS and OS compared to those in the nonsurgical group (p = 0.025 and p = 0.00086). Univariate and multivariate analyses confirmed ΔBMI, Δtumor size reduction, tumor response, earlier clinical stage (IIIb vs. IIIa), and surgery as independent protective factor for patient prognosis. We further selected 101 patients with CR (39 in the surgical group and 62 in the nonsurgical group) and found that patients in the surgical group were significantly better in both PFS and OS. Our subgroup analysis in postoperative patients demonstrated that different surgical strategies did not significantly affect the long-term prognosis of patients (PFS and OS) but could impact their perioperative experience. Patients with advanced stage III NSCLC, whose tumors achieved PR and CR after 2-4 cycles of immunotherapy combined with chemotherapy, experience a more promising prognosis with subsequent surgical intervention compared with the continued immunotherapy. Despite encountering formidable obstacles, such as protracted surgical procedures and associated trauma, we must rise to the challenge and unleash the power of surgery after immunotherapy in advanced NSCLC.

Predictive Value of NLR and PLR in Driver-Gene-Negative Advanced Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors: A Single Institutional Cohort Study.

To investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for the efficacy and prognosis of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors in driver-gene-negative advanced non-small-cell lung cancer (NSCLC). A retrospective analysis of 107 advanced NSCLC patients without gene mutations who received PD-1/PD-L1 inhibitors in our hospital from January 2020 to June 2022 was performed. NLR and PLR were collected before PD-1/PD-L1 inhibitors, the optimal cut-off values of NLR and PLR were determined according to the receiver operating characteristic (ROC) curve, and the effects of NLR and PLR on the efficacy of PD-1/PD-L1 inhibitors in advanced NSCLC patients were analyzed. A total of 107 patients were included in this study. Receiver operating characteristic analysis showed that the optimal cut-off values of NLR and PLR were 3.825, 179, respectively. Kaplan-Meier curve showed that low baseline levels NLR and PLR were associated with an improvement in both progression-free survival (PFS) (P < .001, < .001, respectively) and overall survival (OS) (P = .009, .006, respectively). In first-line treatment and non-first-line treatment, low baseline levels NLR and PLR were associated with an improvement in PFS. In multivariate analysis, low baseline NLR and PLR showed a strong association with both better PFS (P = .011, .027, respectively) and longer OS (P = .042, .039, respectively). Low baseline NLR and PLR levels are significantly associated with better response in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors, which may be indicators to predict the efficacy of immunotherapy in advanced NSCLC with driver-gene-negative.

Dynamic monitoring of serum tumor markers as prognostic factors in patients with advanced non-small-cell lung cancer treated with first-line immunotherapy: a multicenter retrospective study

Background: To date, no specific studies have reported the use of dynamic serum tumor markers (STMs) as prognostic factors in patients with advanced non-small-cell lung cancer (NSCLC) who receive first-line immunotherapy. Therefore, it is unclear whether STMs can be used as a prognostic factor for first-line immunotherapy in advanced NSCLC. Objectives: To elucidate the role of STMs in monitoring immunotherapy response in advanced NSCLC. Patients were treated with first-line programmed cell death-1/programmed cell death ligand-1 inhibitors at four Chinese centers. Design: This was a multicenter retrospective study. Methods: Blood samples were collected at baseline and after 6–8 weeks of treatment. Computed tomography scans were used to evaluate treatment efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Post-treatment drops in STMs [Serum carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125)] were decreased ⩾20% (Group C) over baseline was used as cutoff level for defining a marker response. If STMs were increased by ⩾20% after treatment, the therapeutic effect was limited (Group A). Patients with STM changes between a 20% increase or decrease were enrolled in Group B. In univariate and multivariate stepwise Cox regression analyses, STMs and RECIST responses were analyzed for their impact on progression-free survival (PFS) and overall survival (OS). Results: The analysis included 716 patients. By multivariate analysis, CEA, NSE, CYFRA21-1, CA19-9, and CA125 (Group A versus Group B and Group A versus Group C) were associated with significant differences in PFS. Similar results were observed in the OS analysis. Similar results were observed in the adenocarcinoma subgroup analyses. In squamous cell carcinoma subgroup analyses, there was no statistical difference in PFS ( p = 0.147) or OS ( p = 0.068) between Group A and Group B for CA125. Conclusion: The increase and decrease in serum levels of STMs might be reliable prognostic factors for immunotherapy efficacy in NSCLC patients.

Plasma GDF15 levels associated with circulating immune cells predict the efficacy of PD-1/PD-L1 inhibitor treatment and prognosis in patients with advanced non-small cell lung cancer

PurposeAlthough increased plasma growth differentiation factor-15 (GDF15) levels have been reported in patients with various cancers, the predictive role of PD-1/PD-L1 inhibitors in advanced cancers remains unknown. This study aimed to investigate GDF15 levels as a predictive marker in advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors and analyze their association with immune cell populations.MethodsThis study included 87 patients with advanced NSCLC receiving anti-PD-1/PD-L1 inhibitors between March 2018 and May 2020. Blood samples were obtained immediately before and months after PD-1/PD-L1 inhibitor administration.ResultsThe objective response rate (ORR) was significantly higher in the low GDF15 than in the high GDF15 group (39.2% vs. 15.3%, P = 0.013). The median progression-free survival (PFS) was significantly longer in the low GDF15 than in the high GDF15 group (13.2 [95% CI 7.6–18.9] vs. 7.2 [95% CI 4.8–9.6] months, P = 0.048). Moreover, plasma GDF15 levels negatively correlated with PD-1+/CD8+ T cells (r = − 0.399, P = 0.003) and positively with PD-1+/Treg cells (r = 0.507, P < 0.001) and PD-1+Treg/CD4+ T cells (r = 0.439, P < 0.001). The ORR was significantly higher in the group with decreased GDF15 from baseline than in the increased GDF15 group (37.2% vs. 10.0%, P = 0.026). The median PFS was significantly longer in the decreased GDF15 group (14.8 [95% CI 10.4–19.2] vs. 5.9 [95% CI 2.8–9.0] months, P = 0.002). Plasma GDF15 levels were associated with PD-1+CD8+ T cells and PD-1+ Treg cells.ConclusionPlasma GDF15 could be a potential biomarker for predicting the efficacy and survival benefit of immunotherapy in advanced NSCLC.

27-gene Immuno-Oncology (IO) Score is Associated With Efficacy of Checkpoint Immunotherapy in Advanced NSCLC: A Retrospective BC Cancer Study

BackgroundImmune checkpoint inhibitors (ICI) are standard of care in advanced non-small cell lung cancer (NSCLC). However, not all patients benefit, even among PD-L1 tumor proportional score (TPS) ≥50%, indicating an unmet need for additional biomarkers such as those assessing the tumor immune microenvironment (TIME). DetermaIO is a 27-gene assay that classifies TIME and has previously demonstrated association with ICI response. MethodsFFPE samples were selected from BC Cancer and West Clinic Cancer Center patients with performance status (PS) ≤2 who received at least 2 cycles of ICI monotherapy in the first (1L) or second line (2L). IO scores were generated and analyzed for association with PFS and OS. ResultsIn the entire cohort (N=147), IO score was significantly associated with OS (HR=0.68, 95%CI 0.47-0.99, P = .042) and PFS (HR=0.62, 95%CI 0.43-0.88, P = .0069). In 1L treated patients (PD-L1≥50%, N=78), IO score was significantly associated with PFS (HR=0.55, 95%CI 0.32-0.94, P = .028). In exploratory analyses, IO score was associated with benefit in 1L PS2 patients for OS (HR = 0.26, 95%CI 0.091-0.74, P = .012) and PFS (HR = 0.27, 95%CI 0.098-0.72, P = .0095) which was confirmed in PFS subgroup analysis in the independent West Cancer Center study (N=13 HR=0.14, 95%CI 0.027-0.76, P = .023). ConclusionThese data confirm the association of DetermaIO with ICI clinical benefit in NSCLC, and expand on previous studies by demonstrating that first line treated PD-L1≥50% patients can further be stratified by IO score to identify efficacy. Exploratory analysis suggested that the IO score identifies benefit in patients with poor PS.

Development of a Personalized Tumor Neoantigen Based Vaccine Formulation (FRAME-001) for Use in a Phase II Trial for the Treatment of Advanced Non-Small Cell Lung Cancer.

Stage III–IV non-small cell lung cancer (NSCLC) is a devastating disease characterized by a poor prognosis. NSCLC tumors carry genetic mutations, which can lead to the expression of altered protein sequences. Peptides originating from mutated proteins and bound to MHC molecules on the tumor cell surface are referred to as neoantigens, as they are tumor-specific and not expressed in normal cells. Due to their tumor specificity, neoantigens have a strong potential to induce an anti-tumor immune response and have been investigated for development of personalized therapeutic cancer vaccines. The current study describes the development of a clinical grade neoantigen vaccine formulation (FRAME-001) intended as immunotherapy in advanced NSCLC in combination with the immune checkpoint inhibitor pembrolizumab. The detection of aberrant tumor-specific transcripts as well as an algorithm to select immunogenic neoantigen peptides are described. Subsequently, selected neoantigen peptides were synthesized with a high throughput synthesis platform and aseptically formulated under good manufacturing practice (GMP) conditions into four aqueous peptides mixtures that each contained six neoantigen peptides. A validated stability-indicating analytical method was developed in which we considered the personalized nature of the formulation. An extensive stability study performed either at −25 °C or −80 °C showed that the formulation was stable for up to 32 weeks. The formulation was mixed with the vaccine adjuvant Montanide ISA 51 VG, which yielded the final vaccine emulsion. The stability of the vaccine emulsion was demonstrated using microscopic examination, differential light scattering, and the water-drop test. The presented data show that FRAME-001 is a feasible personalized vaccine formulation for the treatment of stage III–IV NSCLC. The presented data may give guidance in the development of novel personalized therapeutic vaccines since this formulation strategy could be used for any cancer indication.

Predicting the efficacy of first-line immunotherapy by combining cancer cachexia and tumor burden in advanced non-small cell lung cancer.

BackgroundCancer cachexia and tumor burden predict efficacies of programmed cell death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors and chemotherapy or pembrolizumab in non‐small cell lung cancer (NSCLC). There are no predictive models that simultaneously assess cancer cachexia and tumor burden.MethodsIn the present retrospective study, we reviewed the medical records of patients with advanced NSCLC who received cancer immunotherapy as first‐line systemic therapy. Clinical immune predictive scores were defined according to multivariate analysis of progression‐free survival (PFS) and overall survival (OS).ResultsA total of 157 patients were included in the present study (75 treated with PD‐1/PD‐L1 inhibitors + chemotherapy; 82, pembrolizumab monotherapy). Multivariate analysis for PFS revealed that PD‐L1 tumor proportion scores <50%, a total target lesion diameter ≥76 mm, and cancer cachexia were independently associated with poor PFS. Multivariate analysis for OS revealed that ≥4 metastases and cancer cachexia were significantly associated with poor OS. In the immune predictive model, the median PFS was 21.7 months in the low‐risk group (N = 41); 7.6 in the medium‐risk group (N = 64); and 3.0 in the high‐risk group (N = 47). The median OS were not reached, 22.4 and 9.1 months respectively. Our immune predictive model was significantly associated with PFS (p < 0.001) and OS (p < 0.001).ConclusionWe proposed the immune predictive model, including tumor burden and cancer cachexia, which may predict the efficacy and survival outcome of first‐line immunotherapy in advanced NSCLC.

Current status and future perspectives on immunotherapy in neoadjuvant therapy of resectable non-small cell lung cancer.

Resectable non-small cell lung cancer (NSCLC) is defined as stage I-II, and some locally advanced (stage III) tumor. Despite the associated relatively high recurrence rates after surgery, surgical treatment remains the standard treatment for patients with early-stage NSCLC. At present, neoadjuvant therapy is becoming an increasingly popular therapeutic strategy for resectable NSCLC. However, studies have reported that neoadjuvant chemotherapy only slightly improves recurrence rates, making it inadequate for extending patient survival. The significant survival benefits of immunotherapy in advanced NSCLC have greatly stimulated researchers' interests in applying immune checkpoint inhibitors (ICIs) for treating early-stage resectable NSCLC. A few recent phase II radomized clinical trials suggested that ICIs yield better major pathologic response (MPR) rates than neoadjuvant chemotherapy alone, demonstrating their potential as alternatives to the existing fixed therapy pattern for early-stage NSCLC. Most initial studies regarding neoadjuvant immunotherapy selected MPR and pathologic complete response (pCR) as primary or secondary endpoints, leading to a significant reduction in the time and cost of research and development compared with the use of overall survival time and median survival time as endpoints. Meanwhile, to confirm these benefits, more phase III clinical trials are being conducted, and there is a growing demand for research on related problems, including the screening of population, formulation of treatment strategies, duration and course of immunotherapy, influence of neoadjuvant immunotherapy on the safety of surgery, standardization of treatment effect evaluation and pathologic evaluation, and ways to effectively identify pseudoprogression and avoid resultant misjudgment in surgery and adjuvant therapy.

Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non-small cell lung cancer.

BackgroundThis study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non‐small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD‐1/PD‐L1 therapy) combined with chemotherapy or anti‐angiogenesis therapy.MethodsWe conducted a retrospective analysis of NSCLC patients who underwent next‐generation sequencing test (either 295‐gene panel NGS or 1021‐gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan–Meier survival analysis was used to compare progression‐free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status.ResultsWe enrolled 323 cases and 388 cases of NSCLC patients in the 295‐gene panel cohort and 1021‐gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti‐angiogenesis therapy had longer PFS than other participants (p < 0.05).ConclusionsThe combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.

Complete metabolic response in advanced non-small cell lung cancer patients with prolonged response to immune checkpoint inhibitor therapy.

9050 Background: Recently reported, extended follow-up data from KEYNOTE-024 or -010 indicates that non-small-cell lung cancer (NSCLC) patients can experience long-term benefit from immunotherapy irrespective of discontinuation (per protocol: 35 cycles ∼24 months) or type of response in computed tomography (CT). Similar results were observed in the pooled analysis of 5-year follow-up data from CheckMate-017 and -057. This raises the question, whether patients may safely discontinue immunotherapy after achieving durable response. However, recently published results from CheckMate-153 demonstrated inferior survival rates in patients ceasing immunotherapy after one year, therefore optimal treatment duration of immunotherapy in advanced NSCLC remains unknown. Protocols from published Phase-III trials implemented treatment for a period of approximately 24 months or until evidence of disease progression or unbearable toxicity. Therefore, the ideal duration of immunotherapy remains unclear, and finding markers of beneficial outcome is of great importance. Here, we determine the proportion of complete metabolic responses (CMR) in patients that have not progressed after 24 months of immunotherapy. Methods: This is a retrospective analysis of forty-five patients with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) imaging for assessment of residual metabolic activity after at least 24 months of immunotherapy. Lesion-uptake in FDG PET on or below background level (using mediastinum as reference) was considered as CMR. Time until best objective morphological response including disease stabilization was measured from start of immunotherapy until first stable CT-scan (i.e. no progression or further response compared to previous scan) using RECIST 1.1. Results: Out of 45 patients, 29 patients had a CMR (64%). CMR was observed more frequently in non-first line patients. Patients with CMR were younger (median 65.7 vs. 75.5, P = 0.03). Fourteen patients with CMR have discontinued therapy and have not progressed until time of analysis; however median follow-up was only 5.6 (range 0.8-17.0) months. Conclusions: After a minimum of 24 months of palliative immunotherapy for NSCLC, CMR occurred in almost two thirds of patients. Potentially, achievement of CMR might identify patients, for whom palliative immunotherapy may be safely discontinued.

Abstract 6098: Gut microbiome predicts response to immunotherapy in advanced NSCLC

Abstract Introduction: It has demonstrated that gut microbiome could affect the response to anti-programmed death 1 (PD-1) immunotherapy in the Western population. And one study has suggested that the diversity of gut microbiome was associated with responses to immunotherapy in China. However, there were some conflicts in these previous studies. This study is aimed to further explore the relationship between gut microbiome and clinical response in advanced non-small cell lung cancer (NSCLC) patients. Methods: From 30th/January/2018, advanced NSCLC patients with anti-PD-1 immunotherapy were enrolled. Fecal samples were collected prior to starting therapy and serially after immunotherapy. Total DNA was extracted and 16S ribosome RNA gene sequencing was applied to assess gut microbiome composition. Results: Clinical response rate was determined by radiography according to Response Evaluation Criteria in Solid Tumor Version 1.1. There were sixteen responders (referred to as R, thirteen with stable disease and three with partial response), and thirteen non-responders (NR), yielding a response rate of 55.2%. Firmicutes, Bacteroidetes, Actinobacteria and Proteobacoteria were the main microbial composition in baseline stool samples. Gut microbiome diversity at baseline was not statistically different between responders and non-responders. However, the relative abundance of Akkermansia genus at baseline was significantly enriched in R cohort (p=0.0363). The count of OTUs at progression increased significantly during the treatment. (p=0.012). Of note, Alloprevotellal and Capnocytophaga were overrepresented significantly at progression, indicating that they were associated with unfavorable clinical outcome. Conclusions: This study illustrated that the relationship between clinical outcomes and gut microbiome by dynamic monitoring. Akkermansia present at baseline feces was related with better clinical response to immunotherapy. The increase of some bacteria abundance, especially Alloprevotellal and Capnocytophaga, may predict disease progression during the immunotherapy. This study will continue to collect fecal samples and further verify these conclusions. Citation Format: Lu Yang, Huihui Yin, Yan Wang, Yuchen Jiao. Gut microbiome predicts response to immunotherapy in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6098.

Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy in EGFR/ALK wild-type advanced non-small cell lung cancer

BackgroundImmunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there...

P2.16-38 Efficacy and Safety of Target Therapy and Immunotherapy in Advanced NSCLC in Elderly: A Systematic Review of Real World Studies

Despite notable advances, treatment of advanced non small cell lung cancer (NSCLC) in the elderly remains a challenge. Target therapy and immunotherapy outcomes have been demonstrated in several randomized controlled trials (RCT), however real world setting may closely mirrors everyday clinical practice in elderly population, characterized by poor performance status, significant comorbidities, concomitant treatments, limited adherence and compliance. Systematic review was conducted to examine the published real-world studies evaluating efficacy and safety of target therapy and immunotherapy in elderly patients with advanced NSCLC. These real-world data were compared to those obtained in the phase II and III randomized controlled trials. Following PRISMA guidelines, in February 2019 we searched the MEDLINE, Web of Science, and Scopus databases in English language. Titles and abstracts were reviewed by 2 independent reviewers (FT; FV); disagreements were resolved by a third. All identified full papers were assessed independently by three researchers (FT, FV, and AV). Included studies were required to be RWS, and evaluate target therapy or immunotherapy in advanced NSCLC elderly patients. The Newcastle Ottawa Scale (NOS) was used for quality assessment of studies included in the systematic review. We found 235 studies through the database, 167 remained after duplicate removal and 24 full-text articles were assessed for eligibility (Figure 1). The systematic search of the literature identified 9 studies meeting the selection criteria to analyse in qualitative synthesis. These studies included a total of 1882 elderly patients mainly treated with first-generation EGFR tyrosine-kinase inhibitors (5 studies), osimertinib only in one study. Bevacizumab in association with chemotherapy was evaluated in two studied. Immunotherapy data was available only in one study. Clinical characteristics of each study population are analyzed. The first relevant aspect is the lack of data on Multidimensional Geriatric Assessment and Charlson Comorbidity Index, that should represent main instruments in clinical practice to personalize therapeutic approach. Heterogeneity of first-generation EGFR TKI efficacy among the studies could be influenced by genetic differences among ethnic groups. In general, the results showed that PFS of patients with advanced NSCLC treated with first-generation EGFR TKI in the real world setting were consistent with those observed in clinical trials, while an inferior survival was recorded. Collected toxicity data were limited. RWS represent a broad picture of the activity and tolerability of new drugs and can provide interesting observations and research ideas in several settings, particularly in elderly patients, integrating and defining data of the RCTs.

P1.04-61 Neutrophil-Lymphocyte Ratio: A Predictive Biomarker of Immunotherapy in Lung Cancer?

Identifying predictive biomarkers of immunotherapy in advanced non-small cell lung cancer (NSCLC) is essential to select the patients that could benefit more from this revolutionary therapy. Besides PD-L1 expression, neutrophil-lymphocyte ratio (NLR) has been explored as a potential predictor of clinically meaningful outcomes. Aim: Assess if NLR is an independent predictor of response to immunotherapy in advanced NSCLC. Retrospective study of patients with locally advanced or metastatic NSCLC treated with immunotherapy in the second or further lines setting in a Multidisciplinary Thoracic Tumor Unit between 2015 and 2018. Pre-treatment NLR was calculated from baseline peripheral blood cell counts. NLR was categorized as a binary variable: “low” (<5) or “high” (≥5). Cox regression models were used for overall survival (OS) and progression-free survival (PFS) analysis. From a total of 63 patients, 49 were treated with nivolumab and 14 with pembrolizumab. At the beginning of immunotherapy, baseline patient characteristics were: men: 79.4%; median age (IQR): 62 (56-70) years; ever smokers: 82.5%; ECOG PS 0-1: 82.5%; adenocarcinoma: 63.5%; squamous cell carcinoma: 31.7% and NSCLC-NOS: 4.8%; stage IV: 76.2%; PD-L1 expression <1%: 47.6%. Twenty-three patients (36.5%) received immunotherapy in the third or further lines of treatment. Median PFS and OS were 5 months (2-10) and 8 months (4-13), respectively. After adjusting for gender, age, tobacco habits, ECOG PS, histology and PD-L1 expression, "high" NLR was an independent predictive factor of worse PFS (HR 2.22; 95% CI 1.06-4.66; p 0.035) and OS (HR 2.74; 95% CI 1.19-6.30; p 0.017). In our cohort, patients with NLR≥5 had a higher risk of disease progression and death compared to those with NLR<5. NLR is an inexpensive and affordable biomarker that could help to predict response to immunotherapy. Further large prospective studies are needed to validate this biomarker and to establish the optimal cut-off level.

Bioinformatics Model of Serum Biomarkers to Prognosticate the Response to Programmed Death-1/Ligand-1 Targeted Immunotherapy in Metastatic Non–Small Cell Lung Cancer

Abstract Introduction Immune-checkpoint inhibitors revolutionized the therapeutic paradigm for metastatic non–small cell lung cancer (NSCLC). The average response, however, still hovers at 20%, demonstrating the urgent need for biomarkers predictive of response. High-throughput laboratory technology promises to serve as an insightful and robust tool to recognize and select patterns of biomarkers in serum. We applied machine learning on serum immune-checkpoint biomarkers for prognostication of response to immunotherapy in advanced NSCLC. Method Pretreatment sera from 106 advanced NSCLC cases who failed frontline chemotherapy were evaluated for 16 soluble immune-checkpoint molecules using the Human Immuno-Oncology Checkpoint Protein Panel (MilliporeSigma). This panel constituted BTLA, CD27, CD28, TIM-3, HVEM, CD40, GITR, GITRL, LAG-3, TLR-2, PD-1, PD-L1, CTLA-4, CD80, CD86, and ICOS. Primary data points were collected and calculated via a Luminex FLEXMAP 3D system (xPONENT v4.0.3 Luminex Corp). The minimum follow-up after treatment was 12 months. Response patterns were categorized based on their overall survival (OS) as long-term responders (&gt;12 months) or short-term responders (&lt;12 months). Values were analyzed with the clinical outcomes using “Survminer” and “survival” R packages to determine the log-rank-based cutoff values associated with overall survival. Finally, machine learning methods were implemented using “caret” and “rpart” R packages to fit a classification model to predict the response pattern. The model was trained and tested on random fractions of the cohort. Results BTLA4, HVEM, CD40, GITRL, LAG-3, PD-1, CD80, and CD86 serum levels significantly correlated with OS (all P values ≤.02 and HR of 0.27, 0.5, 4.59, 0.17, 0.12, 0.48, 3.64, and 0.37, respectively). The algorithm composing PD-1, LAG-3, CD86, and CTLA4 predicted the response pattern with PPV of 81%, specificity of 87%, and accuracy of 75%. Conclusion The serum immune-checkpoint predictive model might assist in the tissue and gene-based profiling of immune-checkpoints to predict the benefit from immunotherapy.

Checkpoint inhibitors in the decision-making algorithm of advanced non-small-cell lung cancer.

The checkpoint inhibitors opened a new era in the treatment of advanced non-small-cell lung cancer (NSCLC) initially by replacing second-line standard chemotherapy with docetaxel and subsequently by replacing platinum-based chemotherapy in the first line, albeit in patients selected for a high expression of PD-L1. The decision algorithm has therefore been radically modified for patients who do not have activating mutations. However, we are only at the beginning of a new era from which we expect in the near future the use of immunotherapy in most patients as a first line treatment in substitution or in combination with chemotherapy. These strategies are now the objective of recent studies that have shown a benefit with the combination of chemotherapy and immunotherapy in patients with non-squamous histotype compared to chemotherapy alone or a benefit in patients selected for high mutational burden (TMB) with anti-PD1 and anti-CTLA-4 compared to chemotherapy alone. However, there are many questions regarding immunotherapy that should be considered in clinical practice as: response evaluation, validation of predictive factors such as TMB potentially complementary to the expression of PD-L1, proper education of the patients and of the medical staff to prompt recognition and adequate management of toxicities. In this article we discuss the current decisional algorithm and future perspectives of treatment with immunotherapy in advanced NSCLC.

Treatment with PD-1 inhibitors in NSCLC beyond disease progression: Impact on symptoms and cost.

174 Background: Immunotherapy with PD-1 axis inhibitors has become standard of care in the treatment of patients with advanced non-small cell lung cancer (NSCLC), with improved survival and less toxicity than chemotherapy. Response patterns to PD-1 axis inhibitors can be unconventional, including pseudoprogression. Identifying disease progression using RECIST has been challenging. We explored treatment past progression (TPP) with PD-1 inhibitors and its impact on patient symptoms and costs. Methods: Retrospective analysis of consecutive patients with advanced NSCLC that received single agent PD-1 inhibitors at the Princess Margaret Cancer Centre (PMH) between 2013 and 2017. Patient symptom burden was assessed by Edmonton Symptom Assessment Scale (ESAS) at outpatient clinic visits. Drug acquisition costs were calculated using hospital-based costs for the agents used and both actual and fixed dosing recommendations. Results: The study cohort included 89 patients with advanced NSCLC. Median age was 62, half were female and 75% had adenocarcinoma. Most, 70%, developed disease progression during treatment, 19% stopped due to toxicity. Twenty-one patients received TPP (23% of entire cohort, 34% of those with progression). Demographic characteristics except age and baseline symptom scores were similar between groups. Younger patients (p = 0.046), those with lower symptom burden upon RECIST progression (mean ESAS 14.7 vs. 27.2 non-TPP, p = 0.013) and greater symptom improvement from baseline (mean ESAS change -11.7 vs. -2.3 non-TPP, p = 0.11) were more likely to receive TPP. During TPP, only 1 patient achieved tumor response. TPP represented 29% of total treatment costs. This did not vary significantly between weight- based and fixed dosing. However, the costs of treatment of the entire cohort was 23% higher using fixed dosing compared to weight-based. Conclusions: : Treatment with immunotherapy beyond RECIST progression is common in advanced lung cancer, although patient benefit is rare. This can lead to substantial expenditure without clear value for most patients. Better methods for detecting early failure of immunotherapy in advanced NSCLC are needed, to allow patients to switch to more active treatment.