Therapy For Advanced Non-small Cell Lung Cancer Research Articles

Rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC

Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). 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 aim 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 the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

Circulating Tumour Cells: Detection and Application in Advanced Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide. Tissue biopsy is the current gold standard for the diagnosis and molecular profiling of NSCLC. However, this approach presents some limitations due to inadequate tissue sampling, and intra- and intertumour heterogenicity. Liquid biopsy is a noninvasive method to determine cancer-related biomarkers in peripheral blood, and can be repeated at multiple timepoints. One of the most studied approaches to liquid biopsies is represented by circulating tumour cells (CTCs). Several studies have evaluated the prognostic and predictive role of CTCs in advanced NSCLC. Despite the limitations of these studies, the results of the majority of studies seem to be concordant regarding the correlation between high CTC count and poor prognosis in patients with NSCLC. Similarly, the decrease of CTC count during treatment may represent an important predictive marker of sensitivity to therapy in advanced NSCLC. Furthermore, molecular characterization of CTCs can be used to provide information on tumour biology, and on the mechanisms involved in resistance to targeted treatment. This review will discuss the current status of the clinical utility of CTCs in patients with advanced NSCLC, highlighting their potential application to prognosis and to treatment decision making.

Peripheral myeloid cells as prognostic markers in patients (pts) with non-small cell lung cancer (NSCLC) treated with cemiplimab: Pooled analysis of EMPOWER-Lung 1 and EMPOWER-Lung 3 phase 3 trials.

9028 Background: Circulating innate and adaptive immune cells can modulate clinical responses to immune checkpoint inhibition in pts with cancer; however, there are no clear validated baseline clinical tests to guide clinicians, outside of programmed cell death-ligand 1 (PD-L1) IHC tests on limited biopsy specimens. High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in NSCLC, but data are limited on the potential contribution of other immune cells such as monocytes and eosinophils in modulating systemic immune response. Further, previous correlative studies have not established clinically actionable immune cell cut-off values. Methods: We used multiple quantitative analytic methods including multivariable Cox regression and conditional decision trees to assess the prognostic importance of NLR and peripheral myeloid cells, including monocytes and eosinophils, in pts with NSCLC treated with cemiplimab in Phase 3 trials EMPOWER-Lung 1 (NCT03088540) and EMPOWER-Lung 3 (NCT03409614). In EMPOWER-Lung 1, pts with PD-L1 ≥50% were randomized 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-based chemotherapy (chemo). EMPOWER-Lung 3 was a 2-part study. In Part 1, pts with PD-L1 < 50% were randomized 1:1:1 to chemo, cemiplimab 350 mg Q3W + chemo, or cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W + chemo. In Part 2, pts were randomized 2:1 to receive cemiplimab 350 mg or placebo Q3W + chemo. Results: Overall, 691 pts in EMPOWER-Lung 1 and 769 pts in EMPOWER-Lung 3 were included in this analysis. The results showed significant association between multiple factors including NLR and overall survival (OS) and progression-free survival (PFS). For pts with NLR > 3.98 vs ≤3.98, median OS (95% CI) was 10 (9–13) vs 20 (17–24) months (HR: 2.04; 95% CI: 1.60–2.61; P< 0.001) and median PFS (95% CI) was 4 (4–6) vs 6 (6–7) months (HR: 1.80; 95% CI: 1.50–2.18; P< 0.001), respectively, accounting for known prognostic factors. In multivariable analyses, monocytes (OS HR: 1.72; 95% CI: 1.29–2.30; P< 0.001; PFS HR: 1.37; 95% CI: 1.08–1.75; P= 0.010) and log eosinophils (OS HR: 0.90; 95% CI: 0.85–0.97; P= 0.003; PFS HR: 0.93; 95% CI: 0.88–0.98; P= 0.004) were significantly associated with OS and PFS in both studies. (Neutrophil + monocyte)/lymphocyte ratio was the top predictor of both OS and PFS in decision tree analysis. Peripheral blood cell count correlations were not affected by tumor PD-L1 levels (ρ < 0.15 for all markers). Conclusions: This is a large and comprehensive prognostic analysis of data from two prospective Phase 3 clinical trials in advanced NSCLC. Clinically actionable peripheral blood cell count parameters, incorporating putative immunosuppressive myeloid cells (neutrophils and monocytes) and protective lymphocytes and eosinophils, may help predict response to anti–PD-1 therapy in advanced NSCLC. Clinical trial information: NCT03088540 , NCT03409614 .

Cell adhesion molecules and immunotherapy in advanced non-small cell lung cancer: Current process and potential application.

Advanced non-small cell lung cancer (NSCLC) is a severe disease and still has high mortality rate after conventional treatment (e.g., surgical resection, chemotherapy, radiotherapy and targeted therapy). In NSCLC patients, cancer cells can induce immunosuppression, growth and metastasis by modulating cell adhesion molecules of both cancer cells and immune cells. Therefore, immunotherapy is increasingly concerned due to its promising anti-tumor effect and broader indication, which targets cell adhesion molecules to reverse the process. Among these therapies, immune checkpoint inhibitors (mainly anti-PD-(L)1 and anti-CTLA-4) are most successful and have been adapted as first or second line therapy in advanced NSCLC. However, drug resistance and immune-related adverse reactions restrict its further application. Further understanding of mechanism, adequate biomarkers and novel therapies are necessary to improve therapeutic effect and alleviate adverse effect.

Maximum Somatic Allele Frequency-Adjusted Blood-Based Tumor Mutational Burden Predicts the Efficacy of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer.

Recent studies exhibited the unstable prediction ability of blood-based tumor mutational burden (bTMB) when predicting the response of immune checkpoint inhibitors (ICIs) therapy in patients with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) abundance, usually represented by maximum somatic allele frequency (MSAF), was one possible confounding factor influencing bTMB ability in ICIs response prediction. MSAF-adjusted bTMB (Ma-bTMB) was established and validated in patients with advanced NSCLC among Geneplus Cancer Genome Database (GCGD, n = 1679), Zhuo (n = 35), Wang (n = 45), POPLAR (NCT01903993, n = 211) and OAK (NCT02008227, n = 642) cohorts. MSAF demonstrated a modest positive correlation with bTMB and a negative one with survival benefit. Improved survival outcomes of ICIs therapy have been observed among patients with high-Ma-bTMB compared to those with low-Ma-bTMB in Zhuo and Wang cohorts. In addition, compared to low-Ma-bTMB, high-Ma-bTMB was associated with more positive clinical benefits from ICIs therapy than chemotherapy both in POPLAR and OAK cohorts. Further exploration suggested that Ma-bTMB could precisely identify more potential ICIs beneficiaries compared to bTMB and LAF-bTMB, complementary to PD-L1 expression. We developed Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker effectively differentiates beneficiaries of ICIs therapy in advanced NSCLC, warranting future clinical trials.

343P Immunotherapy as first-line treatment in metastatic non-small cell lung cancer: A single center experience

Immunotherapy has revolutionized treatment in metastatic non small cell lung cancer (NSCLC) without driver mutation.In our study we evaluated the efficacy of pembrolizumab in combination with chemotherapy as first line therapy in advanced NSCLC.

Application of Immune Checkpoint Inhibitors in EGFR Mutant Advanced Non-small Cell Lung Cancer

近年来，免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）极大地提高了无驱动基因突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的生存率。与野生型肿瘤相比，表皮生长因子受体（epidermal growth factor receptor, EGFR）突变的肿瘤在程序性细胞死亡配体1（programmed cell death ligand 1, PD-L1）、肿瘤突变负荷（tumor mutational burden, TMB）等免疫微环境特征上具有更大的异质性。ICIs是否适用于EGFR突变的NSCLC患者一直存在争议。临床研究显示免疫单药对于EGFR突变的NSCLC患者无显著疗效，ICIs联合化疗和抗血管生成药物则显示了良好的生存获益。本文就EGFR突变晚期NSCLC患者ICIs单药或联合治疗的临床研究及相关机制进行综述。

EP08.02-158 Final Analyses of ALTER-L018: A Randomized Phase II Trial of Anlotinib Plus Docetaxel vs Docetaxel as 2nd-line Therapy for EGFR-negative NSCLC

Docetaxel is one of the standard 2nd-line treatments for advanced non-small cell lung cancer (NSCLC), but the effect is limited. The combination of docetaxel and ramucirumab/nintedanib has demonstrated antitumor activity as 2nd-line therapy in advanced NSCLC. Anlotinib, an oral multi-target angiogenesis, can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial (ALTER0303). We conducted ALTER-L018 to evaluate improvement of the efficacy and safety of anlotinib plus docetaxel in EGFR-negative advanced NSCLC.

EP16.02-006 Evaluation of Carcinoembryonic Antigen (CEA) as Predictive Marker in Patients with Metastatic Non-small Cell Lung Cancer

Serum carcinoembryonic antigen (CEA) has been evaluated in several studies as a prognostic marker in patients with non-small cell lung cancer (NSCLC). Studies evaluating its predictive role in terms of response to systemic therapy in advanced NSCLC particularly in the Indian population are scarce.

Increased adherence to molecular profiling recommendations in non–small cell lung cancer through use of prior authorization and peer review.

9129 Background: National oncology guidelines advocate for broad molecular profiling to detect potentially actionable driver mutations prior to initiation of first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). Results of genomic tests can confirm the presence of specific cancer tumor mutations that are best treated with more targeted therapies. Recent studies have shown that up to 30% of lung cancer patients may not receive the most effective treatment due to a lack of guideline-concordant genomic testing. We analyzed data from our prior authorization medical oncology program to determine adherence to national guidelines recommendations, and then developed a program to improve adherence to broad molecular profiling utilizing our proprietary prior authorization algorithms and our proactive peer consultation model. Methods: eviCore healthcare uses the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to support its proprietary program for medical oncology drug management, and requires attestation on the results of NCCN recommended genomic/molecular test results in advanced NSCLC during prior authorization of systemic therapy. In November 2019, we implemented a next-generation sequencing (NGS) testing results requirement for metastatic non-squamous NSCLC patients prior to first-line therapy approval. If testing had not been completed, a peer to peer consultation was performed to advocate for testing prior to initiation of chemoimmunotherapy regimens. The rate of appropriate tumor testing is defined by provider attestation of test results prior to initiation of therapy. We define the control period (pre- implementation) as October 2018 through September 2019 ( n = 667). The measurement period (post-implementation) is January 2020 through December 2020 ( n = 390). Results: From pre to post there was a 35% increase in testing adherence (p < 0.001). After the testing requirement was implemented, the appropriate tumor testing rate increased to 99% by the second half of 2020, compared to the control period (62%). Additionally, after the testing requirement began, pembrolizumab utilization for advanced stage NSCLC decreased by a net 4.2% per month. This decrease in pembrolizumab utilization likely reflected patients being matched to more appropriate targeted therapy based on genomic testing results. Conclusions: We demonstrate that by combining medical oncology prior authorization with focused peer consultation, adherence to national society recommendations for broad molecular profiling prior to initiating first line therapy in advanced NSCLC can be significantly improved. By improving testing adherence, the most effective and appropriate therapy can be matched to the patient.

Tumor glycolytic profiling through 18F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC.

A significant proportion of patients with non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICIs). Since metabolic reprogramming with increased glycolysis is a hallmark of cancer and is involved in immune evasion, we used 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) to evaluate the baseline glycolytic parameters of patients with advanced NSCLC submitted to ICIs, and assessed their predictive value. 18F-FDG PET/CT results in the 3 months before ICIs treatment were included. Maximum standardized uptake values, whole metabolic tumor volume (wMTV), and whole-body total lesion glycolysis (wTLG) were evaluated. Cutoff values for high or low glycolytic categories were determined using receiver-operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were evaluated. Patients with a complete response and a matching group with resistance to ICIs underwent immunohistochemistry analysis. An unsupervised k-means clustering model integrating programmed cell death ligand 1 (PD-L1) expression, glycolytic parameters, and ICIs therapy was performed. In all, 98 patients were included. Lower baseline 18F-FDG PET/CT parameters were associated with responses to ICIs. Patients with low wMTV or wTLG had improved PFS and OS. High wTLG, strong tumor expression of glucose transporter-1, and lack of responses were significantly associated. Patients with low glycolytic parameters benefited from ICIs, regardless of chemotherapy. Conversely, those with high parameters benefited from the addition of chemotherapy. Patients with higher wTLG and lower PD-L1 were associated with progression and worse survival to ICIs monotherapy. Glycolytic metabolic profiles established through baseline 18F-FDG PET/CT are useful biomarkers for evaluating ICI therapy in advanced NSCLC.

LMD-06. A NSCLC patient with leptomeningeal metastasis harboring rare EGFR mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report

Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, He developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript’s submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patients with LM carrying EGFR G719S and L861Q. Aslo, it is recommended to consider performing leptomeningeal biopsy for precision treatment in NSCLC paiernts with leptomeningeal metastasis.

Targeted ctDNA sequencing analysis reveals concurrent genomic alterations and its impact on TKI and immune checkpoint inhibitor therapy in advanced NSCLC from Asian population.

3042 Background: For advanced non-small cell lung cancer (NSCLC), liquid biopsy followed by targeted DNA sequencing is used in the clinical setting for driver-gene identification in circulating tumor DNA (ctDNA), tumor evolution and treatment monitoring. To understand the complexity and diversity of genetic alterations in advanced NSCLC, we examined the genetic landscape of late-stage NSCLC from an Asian population and its association with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) treatment. Methods: Plasma cell-free DNA (cfDNA) from 142 Asian patients with advanced NSCLC underwent real-world testing in a CAP-accredited and CLIA-certified central laboratory. We analyzed genetic alterations in cfDNA using an amplicon-based next-generation sequencing assay that covers 61 NSCLC related genes. 88 patients (62%) had received one or more lines of treatment. A similar cohort from Caucasian NSCLC was used for comparison (Blakely et al. Nat Genet 2017). Systematic co-mutation analysis, functional annotation and pathway enrichment analysis were performed. Results: The top 10 mutated genes in the Asian cohort were EGFR (66.2%), TP53 (48.6%), KRAS (11.3%), BRCA2 (7%), CTNNB1 (6.3%), PIK3CA (6.3%), SMAD4 (5.6%), BRCA1 (4.9%), MET (3.5%) and RB1 (3.5%). EGFR mutations occurred at hotspots in exons 18 – 21, with exon19 deletion, L858R, T790M, C797S, and G719A being the top-ranking alleles, similar to the Caucasian NSCLC cohort. Concurrent KRAS and EGFR mutations were higher in Asian cohort (8.5%) than in Caucasian cohort (0.56%). A rare PD-L1 structural variant (1.1%), reported to be related to immune evasion in other cancers (Kataoka et al. Nature 2016), was detected in the EGFR-mutated subgroup. Within the first line TKI-treated group, responders (CR+PR) harbored more alterations than non-responders (p < 0.017). Among ICI-treated NSCLC patients (anti-PD-1/PD-L1 mono- or polytherapy), responders from 1st line or 2nd line ICI treatment harbored fewer mutations than non-responders, but the distribution of mutational allele frequency (MAF) in responders was shifted to the right (more clonal than subclonal mutations). Functional annotation suggests that concurrent mutated genes and copy number alterations in advanced EGFR-mutant NSCLC were enriched in cell cycle, DNA repair, PI3K-AKT signaling pathways. Conclusions: We characterized the ctDNA-derived genetic landscape of advanced NSCLC from an Asian population and dissected mutated genes with the outcome of TKI or ICI treatment. We also report a rare PD-L1 structural variant in the EGFR mutated subgroup, which could be associated with immune evasion. Our analyses support the occurrence of clonal and subclonal driver co-alterations in EGFR-driven NSCLC, underlining the clinical utility of ctDNA detection for NSCLC diagnosis and treatment selection.

A multicenter, randomized, phase II trial of anlotinib plus docetaxel versus docetaxel in EGFR-negative NSCLC patients after progression on first-line platinum-base chemotherapy: ALTER-L018.

e21186 Background: Docetaxel is one of the standard second-line treatments for advanced non-small cell lung cancer (NSCLC), but the effect is limited. The combination of docetaxel and antiangiogenic drug (ramucirumab/nintedanib) has demonstrated antitumor activity as second-line therapy in advanced NSCLC. Anlotinib, an oral multi-target angiogenesis TKI targeting the VEGFR, FGFR, PDGFR and c-Kit, can prolong both PFS and OS of refractory advanced NSCLC patients in phase III trial (ALTER0303). We conducted ALTER-L018 to evaluate improvement of the efficacy and safety of anlotinib plus docetaxel in EGFR-negative refractory advanced NSCLC. Methods: ALTER-L018 (NCT03624309) is an ongoing, open-label, multicenter, randomized, controlled comparative, phase II trial, which was performed at 10 sites in China. Eligible EGFR-negative NSCLC patients (pts), who has been assessed progression after first-line platinum-based chemotherapy (combined with or without Immune checkpoint inhibitors), were randomly assigned (in a 1:1 ratio) to group A (anlotinib: 12mg QD from day 1 to 14 of a 21-day cycle +docetaxel: 75mg/m2 Q3W) and group B (docetaxel: 75mg/m2 Q3W). The primary end point was PFS, and secondary end points included OS, ORR, DCR and safety. Results: Between Jan 14, 2019, and Feb 7, 2021, 73 patients (pts.) were enrolled and 8 pts. were excluded from the safety and efficacy analysis set (n = 65) due to inclusion violations. 65 pts characteristics (28 pts in group A / 37 pts in group B): median age: 55(40-71)/57(39-74); male: 82% / 78%; non-squamous NSCLC: 75% / 65%; Immunotherapy in the front line: 18% / 22%. Median PFS were 4.03 months (95%CI: 2.98-5.08) in group A and 1.7 months (95%CI: 0.45-2.95) in group B (HR 0.40; 95% CI :0.21-0.77; p = 0.004); In group A and B, ORR and DCR were 32.14% versus 8.11%(p = 0.042), 82.12% versus 54.05%(p = 0.29), respectively. The adverse events that possibly or definitely related to therapy occurred in 26 (93%) of pts. experienced total of 52 grade 1-2 adverse events in group A, and in 25 (68%) of pts. experienced total of 25 grade 1-2 adverse events in group B. The most common grade ≥3 TRAE were leukopenia (5, 18%), neutropenia (5, 18%) and thrombocytopenia (3, 11%) in group A, and leukopenia (3, 8%), neutropenia (2, 5%) and thrombocytopenia (1, 3%) in group B. Conclusions: This combination of anlotinib and docetaxel showed clinical benefit in EGFR-negative NSCLC patients in terms of PFS, ORR, and with manageable safety profile. It is a viable option for relapsed NSCLC, who has been assessed progression on first-line platinum-base chemotherapy combined with/without Immune checkpoint inhibitors, or who can’t tolerate Immunotherapy. Clinical trial information: NCT03624309.

Smoking history and the efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer: a systematic review and meta-analysis.

BackgroundSome studies imply a strong correlation between smoking history and the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). Hence, a systematic review and meta-analysis was conducted to comprehensively investigate this correlation.MethodsThree online databases including PubMed, Embase and Cochrane Library were searched. s and presentations from European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) were also reviewed. The deadline of search was Nov 9, 2019. Randomized clinical trials (RCT) of ICIs that reported hazard ratio (HR) for overall survival (OS) or progressive-free survival (PFS) by the smoking status of NSCLC patients were eligible for our study. We focused on publications issued in English. A random effects model was implemented in the synthesis, and a two-step interaction test was used to investigate the difference of ICIs efficacy among patients with different smoking histories.ResultsTwelve RCTs involving 6,497 NACLC patients [5,569 (85.72%) current/former smokers and 928 (114.28%) never smokers] were eligible for our systematic review and meta-analysis. The pooled HRs [95% confidential interval (CI)] of OS and PFS were 0.74 (0.67, 0.81) and 0.72 (0.59, 0.88) respectively for current/former smokers in the experimental group with ICIs versus those in the control group. The pooled HRs (95% CI) of OS and PFS were 0.81 (0.60, 1.08) and 0.92 (0.55, 1.54) respectively for never smokers in the experimental group with ICIs compared with those in the control group. The difference of ICIs efficacy in terms of OS between current/former and never smokers was insignificant [interaction HR (95% CI), 0.77 (0.69, 0.86), I2=25.4%, P_hetero=0.21].ConclusionsThe efficacy of ICIs in patients with smoking history is seemingly superior over patients without smoking history, but insignificantly. The difference can be explained by several factors such as insufficient sample size of non-smokers, and confounding factors. We suggest that smoking history cannot be recognized as a predictor of immune therapy in advanced NSCLC.

Abstract 5489: The cost of delaying therapy for advanced non-small cell lung cancer (NSCLC): a population kinetics assessment

Abstract Background: Systemic therapy prolongs overall survival (OS) in advanced NSCLC. The best outcome requires the best therapy choice. To choose the best therapy requires baseline diagnostic tests, staging and molecular profiling, but patients are at risk of deteriorating and dying while awaiting testing prior to therapy initiation. OS follows first order kinetics. We used population kinetics assessments to estimate % of patients dying while awaiting therapy initiation. Method: For 1st line studies in advanced NSCLC that included a placebo or best supportive care (BSC) arm we digitized published OS curves, used GraphPad Prism 7 for exponential decay nonlinear regression analysis, calculated OS half-life (t1/2) and assessed data fit to 1 and 2 phase decay models. The proportion of patients “x” surviving after a time of interest tn was calculated by the Excel formula x =EXP(-tn*0.693/t1/2) where * indicates multiplication and 0.693 is the natural logarithm of 2. Results: We identified 7 trials and a meta-analysis. Across studies, the median OS t1/2 with 1st line placebo/BSC was 19.3 weeks. Hence, by 1, 2, 3 and 4 weeks after study entry 4%, 7%, 10% and 13% of patients, respectively, would have died (ie, 4% of the remaining patients with each passing week). This is in keeping with most OS curves showing rapid decline from the outset. OS curves fit 2 phase decay models in 5 studies, indicating a distinct short survival subgroup (on average, 89% of patients in these trials) and a longer surviving subgroup (potentially from having initiated systemic therapy when progression was detected). The short survival subgroup had a median OS t1/2 across studies of 11.3 weeks. The earliest deaths would be expected to occur predominantly in this short survival subgroup, in which 5%, 9%, 13% and 17% had died by 1, 2, 3 and 4 weeks respectively. Conclusions: Since OS follows first order kinetics, OS decline was probably following approximately the same rate prior to patient inclusion on these trials. In addition, since patients may deteriorate rapidly, others may have become too sick to consider therapy even if still alive. Rapid deterioration and short OS help explain why less than 25% of Ontario patients make it on to systemic therapy for advanced NSCLC despite the therapy being government funded. Since diagnostic, staging and molecular profiling procedures are needed before optimal therapy can start, these procedures must happen rapidly. It also illustrates why we must make screening procedures for clinical trial inclusion much faster. Otherwise patients are at risk of deteriorating rapidly or dying while awaiting eligibility assessment. It is also important to not delay initiation of systemic therapy for procedures such as radiotherapy for asymptomatic brain metastases. Any inefficiency that delays systemic therapy initiation may worsen patient outcome. Citation Format: David J. Stewart, Donna Maziak, Marcio Gomes, Michael Fung-Kee-Fung, Carole Dennie, Harman Sekhon, Bryan Lo, John-Peter Bradford, Sara Moore, Neil Reaume. The cost of delaying therapy for advanced non-small cell lung cancer (NSCLC): a population kinetics assessment [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 5489.

Immunotherapy as a second-line or later treatment modality for advanced non-small cell lung cancer: A review of safety and efficacy.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of these cases. Surgical resection is the most common conventional treatment of lung cancer. For patients with advanced NSCLC, platinum-based chemotherapy remains the cornerstone of treatment. Although platinum-based chemotherapy demonstrated improved outcomes, the need for the second-line/later therapies is evident. A review was conducted to assess the safety and efficacy of immunotherapies as the second-line/later therapy of advanced NSCLC. Clinical trial data was collected via PubMed and Clinicaltrials.gov. Recent studies were selected based on prespecified inclusion/exclusion criteria. Data on the safety and efficacy of the immunotherapy was subsequently compiled from relevant trials. Monoclonal antibodies targeting PD-1/PD-L1 showed the most promising results as the second-line/later treatment modalities. Immunizations did not produce as robust of an immune response in participants; however, they warrant further research to determine their place in therapy.

PD-1 inhibitor plus chemotherapy as 2nd/subsequent line therapy had similar clinical outcome with PD-1/PD-L1 inhibitor monotherapy in advanced NSCLC.

e21600 Background: PD-1/PD-L1 inhibitor monotherapy has been approved as second line therapy in advanced non-small-cell lung cancer (NSCLC). The study aims to compare clinical outcome of PD-1 inhibitor plus chemotherapy with PD-1/PD-L1 inhibitor monotherapy as 2nd/subsequent line therapy in advanced NSCLC. Methods: The clinical data of NSCLC patients who received PD-1/PD-L1 inhibitor as 2nd/subsequent line therapy were retrospectively collected in our study. According to the therapy modality, patients were assigned to PD-1/PD-L1 inhibitor monotherapy group and PD-1 inhibitor plus chemotherapy group. Disease control rates (DCRs), progression free survival (PFS) and overall survival (OS) were evaluated between the 2 groups. The prognostic role of derived neutrophils-to-lymphocyte ratio (dNLR) on the outcomes was also evaluated at the same time. Results: From April 2017 to October 2019, a total of 84 patients were enrolled in the current study. Twenty-six patients were allocated to the PD-1/PD-L1 inhibitor monotherapy group and fifty-eight patients were allocated to PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were detailed as follow: liposome paclitaxel (n = 15), nab-paclitaxel(n = 12), docetaxel(n = 9), pemetrexed(n = 6), and others(n = 16). Disease control rates (DCRs) and overall survival (OS) were not significantly different between the two groups. Progression free survival (PFS) in the PD-1/PD-L1 inhibitor monotherapy was longer(median PFS: NR vs 4.4 months, p = 0.02). Univariate and multivariate analyses suggested that derived neutrophils-to-lymphocyte ratio (dNLR) was independent prognostic factor of OS and gender was independent prognostic factor of PFS. In the second-line therapy subgroup of 38 patients, OS and PFS were not significantly different in the two groups. In the subgroup of 46 patients of over 2nd line, PD-1/PD-L1 inhibitor monotherapy group had longer PFS (median PFS: NR vs 4.0 months, p = 0.01).The incidence of any grade adverse events (AEs) was no significant difference in the two groups. One patient in the PD-1 inhibitor plus chemotherapy group died of immune-related pneumonitis. Conclusions: The addition of chemotherapy to PD-1 inhibitor as 2nd/subsequent line therapy had similar clinical outcomes compared with PD-1/PD-L1 inhibitor monotherapy of advanced NSCLC patients.

Predictive value of the Lung Immune Prognostic Index (LIPI) in locally advanced non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) in the multicenter retrospective study.

e21076 Background: PD-L1 inhibitor, durvalumab has been approved since the PACIFIC study showed its efficacy as consolidation therapy after CCRT for locally advanced NSCLC. But predictive factor for the efficacy of CCRT on this post PACIFIC era have not been known. LIPI has been proposed as a new biomarker for the anti-PD-1 therapy of advanced NSCLC. In this study, we investigated the usefulness of LIPI as a predictive marker in multicenter cohort of patients with locally advanced NSCLC who received CCRT as initial treatment. Methods: 219 patients with available baseline LIPI were reviewed. The progression free survival (PFS) was estimated by the Kaplan-Meier method, and LIPI were calculated at baseline. Kaplan-Meier estimates of PFS and recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox and logistic regression models, respectively, adjusted for age, sex, ECOG-PS, smoking, histology, TNM stage, chemotherapy regimens, Body mass index (BMI), PD-L1 status, EGFR or ALK mutation, and baseline LIPI. Results: 62.5% (n = 137) of the patients had a good (0 factors) LIPI, while 37.5% (n = 82) had intermediate (1 factor) and poor (2 factors) LIPI respectively. In multivariable analysis, good LIPI (0 factors) were significantly associated with longer PFS (HR = 0.46, 95% CI 0.28-0.75; P < 0.01) as did ECOG-PS0 (P < 0.01), ≤stageIIIA (P < 0.01), being treated with durvalumab after CRT (P = 0.04). There were no difference in the patient characteristics between good LIPI and intermediate/poor LIPI, significantly. Higher LIPI (1 or 2 factors) were strongly prognostic factor for recurrence after CCRT in multivariate analysis (P = 0.04), along with ECOG-PS1≤ (P < 0.01), stage IIIB≤ (P < 0.01). Conclusions: The good LIPI predictive value for PFS and disease control in patients treated with CCRT was confirmed. Although a strong statistical significance, we needs to be confirmed further with longer follow-up and prospective study.

A phase II study of atezolizumab for pretreated advanced/recurrent non-small cell lung cancer with idiopathic interstitial pneumonias: rationale and design for the TORG1936/AMBITIOUS study.

Background:Approximately 10% of patients with non-small cell lung cancer (NSCLC) are complicated with comorbid interstitial pneumonia (IP) with a poor prognosis. The pharmacotherapy for advanced lung cancer occasionally induces fatal acute exacerbation of pre-existing IP. Due to the lack of prospective studies, there is an urgent need to establish a safe and effective pharmacotherapy, especially for second-line or later settings. Atezolizumab, an anti-programmed cell death-ligand 1 antibody, is thought to be the safest candidate for second-line therapy among various immune checkpoint inhibitors. Moreover, compared with patients without IP, the patients with comorbid IP may have higher tumor mutation burden (TMB) or microsatellite instability (MSI), which are partly associated with a more favorable response to immune checkpoint inhibitors.Methods:The Thoracic Oncology Research Group 1936/AMBITIOUS study is an ongoing, multicenter, single-arm, phase II trial to assess the safety and efficacy of atezolizumab for pretreated advanced/recurrent patients with NSCLC complicated with idiopathic, chronic fibrotic IP with a forced vital capacity of >70%. The patients will receive atezolizumab (1200 mg, day 1) every 3 weeks until the discontinuation criteria are met. The primary end point of this study is the 1-year survival rate, and a sample size of 38 patients is set. As a translational research, we will perform the analysis of TMB, somatic mutations, and MSI for nucleic acids extracted from archival tumor samples.Discussion:Since there is no standard second-line or later therapy of advanced NSCLC with IP, the results of this study are expected to have a major impact on clinical practice.Trial registration:Japan Registry of Clinical Trials, jRCTs031190084, registered 26 August 2019 - retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084