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Antinuclear antibodies (ANAs) predicting the safety and efficacy of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are still a matter of debate considering previous studies showed quite different results based on different ANA cut-off values. Thus, we investigated the associations between different ANA titers and the safety and efficacy of ICIs. Moreover, we also briefly discussed the effects of anti-thyroglobulin (ATG) and anti-thyroid peroxidase (ATPO) on the safety of ICIs.A total of 159 Chinese patients confirmed to have locally-advanced or metastatic NSCLC given ICIs or chemoimmunotherapy in Peking Union Medical College Hospital from January 2015 to December 2020 were analyzed retrospectively and were followed up until December 2020 or death or loss to follow-up. Patients' characteristics were retrieved from medical records. ANAs were detected by the indirect immunofluorescence assay, ATG and ATPO by the electrochemiluminescence immunoassay. The severity of immune-related adverse events (irAEs) was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) and the efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).The incidence of irAEs, median progression-free survival (mPFS) of the ANA negative and positive groups were 26.0%Preexisting ANAs may not correlate with the clinical benefit of immunotherapy in patients with NSCLC but may be associated with adverse skin reactions. Besides, ATG or ATPO has the potential to predict thyroid dysfunction.

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The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI.See articles by Tomita et al., p. 1236, and Peng et al., p. 1251

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Figure S6. Differential abundance analysis of antibiotic resistance genes and virulence factors between R and NR for WGS datasets.

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Purpose:While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.Experimental Design:We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach.Results:Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105).Conclusions:Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.

BACKGROUND: The baseline tumor size (BTS) is a prognostic factor for patients with non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitor monotherapy (ICI-mono). However, this relationship is not yet known in patients treated with ICI in combination with chemotherapy (ICI-chemo). METHODS: This single-center retrospective study evaluated 159 patients with advanced NSCLC who received first-line ICI-mono or ICI-chemo from January 2016 to April 2021. Their BTS values were estimated using the maximum BTS (max BTS) (maximum target lesions’ longest diameter) and total BTS (sum of target lesions’ longest diameters) in a radiological assessment according to the Response Evaluation Criteria for Solid Tumors. RESULTS: Based on a multivariable analysis, the large max BTS group had worse progression-free survival (PFS) in patients treated with ICI-mono (P=0.009), but it was not associated with worse PFS in patients treated with ICI-chemo (P=0.132). The group treated with ICI-mono had worse PFS compared to the group treated with ICI-chemo in patients with max BTS ≥50 mm (P=0.004), and the group treated with ICI-mono was not associated with worse PFS compared to the group treated with ICI-chemo in patients with max BTS

Background: The efficacy of osimertinib as a first-line treatment for patients with poor performance status (PS) remains unclear. Patients & methods: This multicenter retrospective study evaluated patients treated with osimertinib between 2018 and 2020, with PS 2–4. Results: Among 36 patients with PS 2, the median progression-free survival (PFS), 1-year PFS, median overall survival (OS) and 1-year OS were 14.5 months, 65.4%, 18.1 months and 72.7%, respectively. Among 20 patients with PS 3–4, the median PFS, 1-year PFS, median OS and 1-year OS were 3.0 months, 27.1%, 5.0 months and 46.1%, respectively. Conclusion: Osimertinib was not as efficacious as other EGFR-tyrosine kinase inhibitors.

BACKGROUND: Senescence marker protein 30 (SMP30), which plays a pivotal role as a suppressor protein in cell proliferation, among other regulatory actions, is a marker of aging that shows decreased expression during senescence. Decreased SMP30 has been identified in several human cancers, but its expression and role in human non-small cell lung cancer (NSCLC) remain unclear. METHODS: Using tumor tissue and matched adjacent normal tissue from 341 patients with resected NSCLC, we assessed SMP30 expression using immunohistochemical methods. The relationship between SMP30 expression and clinicopathologic characteristics was investigated by Kaplan-Meier survival analysis and multivariate analysis. Cell viability assay, colony formation assay, EdU incorporation assay and in vivo tumor xenograft models were also performed to investigate NSCLC cell proliferation using A549 and H1299 cell lines. Recombinant lentivirus-meditated in vivo gene overexpression and Western blot were performed to clarify the underlying molecular mechanism of SMP30 inhibiting NSCLC proliferation. RESULTS: SMP30 expression was frequently downregulated in NSCLC tissue, as compared with adjacent non-tumor tissue. Kaplan-Meier survival analyses revealed NSCLC patients with low SMP30 expression had a significantly worse overall survival (OS), with median OS of 18 vs. 67 months in high SMP30 expression group. SMP30 overexpression significantly inhibited A549 and H1299 cell proliferation both in vitro and in tumor xenografts and downregulated the expression of c-Myc and CyclinD1 protein. Moreover, Western blot analyses confirmed that SMP30 overexpression significantly inhibited the histone deacetylase 4 (HDAC4) level in NSCLC cells, and HDAC4 overexpression reversed SMP30-mediated NSCLC repression both in vitro and in vivo. CONCLUSIONS: SMP30 inhibited NSCLC proliferation by reducing HDAC4 expression, and SMP30 and HDAC4 may serve as new prognostic biomarkers and future therapeutic targets for NSCLC.

Cancer cachexia exerts a negative clinical influence on patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI). The prognostic impact of body weight change during ICI treatment remains unknown. The gut microbiota (GM) is a key contributor to the response to ICI therapy in cancer patients. However, the association between cancer cachexia and GM and their association with the response to ICIs remains unexplored. This study examined the association of cancer cachexia with GM composition and assessed the impact of GM on clinical outcomes in patients with NSCLC treated with ICIs. In this observational, prospective study, which included 113 Japanese patients with advanced NSCLC treated with ICIs, the prevalence of cachexia was 50.4% (57/113). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the cachexia group than in the non-cachexia group (4.3 vs. 11.6 months (p = 0.003) and 12.0 months vs. not reached (p = 0.02), respectively). A multivariable analysis revealed that baseline cachexia was independently associated with a shorter PFS. Moreover, a gain in body weight from the baseline (reversible cachexia) was associated with a significantly longer PFS and OS compared to irreversible cachexia. Microbiome profiling with 16S rRNA analysis revealed that the cachexia group presented an overrepresentation of the commensal bacteria, Escherichia-Shigella and Hungatella, while the non-cachexia group had a preponderance of Anaerostipes, Blautia, and Eubacterium ventriosum. Anaerostipes and E. ventriosum were associated with longer PFS and OS. Moreover, a cachexia status correlated with the systemic inflammatory marker-derived-neutrophil-to-lymphocytes ratio (dNLR) and Lung Immune Prognostic Index (LIPI) indexes. Our study demonstrates that cachexia and longitudinal bodyweight change have a prognostic impact on patients with advanced NSCLC treated with ICI therapy. Moreover, our study demonstrates that bacteria associated with ICI resistance are also linked to cachexia. Targeted microbiota interventions may represent a new type of treatment to overcome cachexia in patients with NSCLC.

The role of previous thoracic radiation therapy as a risk factor of immune-related pneumonitis is unclear. Furthermore, some patients develop radiation recall pneumonitis, which is characterized by a radiation pneumonitis-like imaging pattern with consolidation progressing within a previous radiation field. In this multicenter retrospective study, we analyzed the relationship of previous thoracic radiation therapy with immune-related pneumonitis and the characteristics of radiation recall pneumonitis. The medical records of patients with non-small-cell lung cancer who had received nivolumab between December 2015 and March 2017 at five institutions were retrospectively reviewed. Incidence, imaging patterns, clinical course, and risk factors of immune-related pneumonitis and radiation recall pneumonitis were evaluated. A total of 669 patients were evaluated, and the incidences of all-grade and grade 3 or higher immune-related pneumonitis were 8.8% and 2.6%, respectively. The incidences of immune-related pneumonitis were 13.2% (34/257) and 6.1% (25/412) in patients with and those without previous thoracic radiation therapy, respectively. A history of previous thoracic radiation therapy was associated with immune-related pneumonitis (odds ratio, 2.11; 95% confidence interval, 1.21-3.69 in multivariate analysis). Among the patients with previous thoracic radiation therapy, 6.2% (16/257) showed radiation recall pattern. This study found an increased risk of nivolumab-induced immune-related pneumonitis associated with a history of thoracic radiation therapy. Radiation recall pattern was one of the major patterns of immune-related pneumonitis among the patients with previous thoracic radiation therapy. Incidence, risk factors, and clinical outcome of radiation recall pneumonitis were elucidated.

BACKGROUND: Second-line treatment options for small cell lung cancer (SCLC) are limited. Preclinical research shows that inhibition of poly (ADP-ribose) polymerase (PARP) could upregulate programmed death-ligand 1 (PD-L1), and thus render cancer cells more sensitive to immune checkpoint inhibitors. This study investigated the tolerability, safety, and preliminary antitumor activity of fuzuloparib (a PARP inhibitor) plus SHR-1316 (a PD-L1 inhibitor) for relapsed SCLC. METHODS: Patients with SCLC who failed previous first-line platinum-based therapy were enrolled in this two-stage phase Ib trial. In stage 1, 2 dose levels were designed: fuzuloparib 100 mg or 150 mg twice daily plus SHR-1316 600 mg every 2 weeks, with 6 patients in each dose level. Based on the tolerability during the first 28-day cycle and the preliminary antitumor activity in stage 1, a recommended phase II dose (RP2D) was determined and introduced in the stage 2 expansion phase. The primary endpoints were safety and RP2D in stage 1 and objective response rate (ORR) in stage 2. RESULTS: A total of 23 patients were enrolled, with 16 receiving fuzuloparib 100 mg plus SHR-1316 and 7 receiving fuzuloparib 150 mg plus SHR-1316. At data cutoff on April 23, 2021, the median follow-up duration was 6.4 months (IQR, 3.0–9.7 months). All patients discontinued study treatment. One patient receiving fuzuloparib 150 mg plus SHR-1316 had clinically significant toxicities, and fuzuloparib 100 mg plus SHR-1316 was considered as the RP2D. In the RP2D cohort, the confirmed ORR was 6.3% (95% CI: 0.2–30.2%), and the disease control rate was 37.5% (95% CI: 15.2–64.6%). The median progression-free survival was 1.4 months (95% CI: 1.3–2.8 months), and the median overall survival was 5.6 months (95% CI: 3.0–16.7 months). Grade ≥3 treatment-related adverse events (TRAE) occurred in 8 patients (34.8%). No treatment-related death occurred, and no patients discontinued treatment due to TRAEs. CONCLUSIONS: Fuzuloparib combined with SHR-1316 failed to improve the outcomes in unselected patients with relapsed SCLC. Future studies with biomarker analysis are warranted to select patients most likely to benefit from this combination treatment. Fuzuloparib 100 and 150 mg plus SHR-1316 were both tolerable with no new signals observed.

Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations. Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach. Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105). Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.

The PACIFIC trial demonstrated that durvalumab therapy following chemoradiation (CRT) was associated with improved overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). It is unclear whether the results obtained as part of randomised controlled trials are a reflection of real-world (RW) data. Several questions remain unanswered with regard to RW durvalumab use, such as optimal time to durvalumab initiation, incidence of pneumonitis and response in PD-L1 subgroups.In this multicentre retrospective analysis, 147 patients with stage III NSCLC treated with CRT followed by durvalumab were compared with a historical cohort of 121 patients treated with CRT alone. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test in univariate analysis. Multivariate analysis was performed to evaluate the effect of standard prognostic factors for durvalumab use.Median OS was not reached in the durvalumab group, compared with 26.9 months in the historical group (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.37-0.85, p = 0.001). In the durvalumab group, our data suggest improved 12-month OS in patients with PD-L1 expression ≥50% (100% vs 86%, HR: 0.25, 95% CI: 0.11-0.58, p = 0.007). There was no difference in OS between patients with a PD-L1 expression of 1-49% and patients with PD-L1 expression1%. Delay in durvalumab initiation beyond 42 days did not impact OS. Incidence of pneumonitis was similar in the durvalumab and historical groups. In the durvalumab group, patients who experienced any-grade pneumonitis had a lower 12-month OS than patients without pneumonitis (85% vs 95%, respectively; HR: 3.3, 95% CI: 1.2-9.0, p = 0.006).This multicentre analysis suggests that PD-L1 expression ≥50% was associated with favourable OS in patients with stage III NSCLC treated with durvalumab after CRT, whereas the presence of pneumonitis represented a negative prognostic factor.

Lung cancer is the most common cause of cancer-related death globally. In addition, its incidence increases with age, with approximately half of all cases diagnosed in patients aged ≥70. Molecular targeted therapies and immunotherapies for advanced non-small-cell lung cancer have markedly improved outcomes over the past two decades. Despite the high incidence of lung cancer in older people, most trials excluded such patients from enrollment. Therefore, the optimal treatment strategies for older patients remain unclear. The present review summarizes the published literature and provides guidance on the treatment of older patients with lung cancer within three broad stages: (i) early-stage lung cancer, (ii) locally advanced lung cancer and (iii) metastatic lung cancer. We also discuss the use of the latest evidence for older patients.

Background Based on several phase III studies, immune checkpoint inhibitors (ICIs) are essential and promising drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICI, the efficacy and safety of rechallenging the same or another type of ICI inhibitor remain unclear. Moreover, clinical data about the efficacy of switching the administration of anti-programmed death-1 (PD-1) antibodies (e.g. nivolumab, pembrolizumab) and anti-programmed death-ligand 1 (PD-L1) antibodies (e.g. atezolizumab) as ICI rechallenge are limited. Thus, the current study aimed to evaluate the efficacy and safety of such treatment strategy in NSCLC patients. Methods We retrospectively reviewed the medical records of 17 patients with advanced or recurrent NSCLC who received both anti-PD-1 and anti-PD-L1 antibodies during their clinical courses. Results Among the 17 patients, one (5.9%) and nine (52.9%) achieved partial response and stable disease, respectively, after ICI rechallenge. The median progression-free survival of ICI rechallenge in these patients was 4.0 (range: 0.4-8.0) months, and the median overall survival from the start of the initial ICI was 31.0 (range: 7.6-46.8) months. Of the 10 patients who developed immune-related adverse events (irAEs) during the first ICI treatment, five presented with these events after the readministration of ICI. Among them, four experienced relapsed irAEs and two patients had pneumonitis, which is a grade 3 or higher irAE. Almost all irAEs during the rechallenge treatment were manageable. Conclusions Switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be a treatment option for some NSCLC patients. Key points • Significant findings of the study In this study, switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be an effective and safe treatment option for some patients with advanced or recurrent NSCLC. • What this study adds Switching the administration of ICI may increase the efficacy of readministration. However, the mechanism is unknown. Thus, further accumulation of cases is required, and extensive investigations must be conducted to elucidate the mechanism and benefits of such treatment.

Histologic transformation has been described as an acquired mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We herein report the case of a woman with stage IV lung adenocarcinoma harboring EGFR exon 19 deletions who was initially treated with EGFR-TKIs; several cytotoxic chemotherapeutic regimens were used when resistance developed. A lymph node re-biopsy revealed histologic transformation of the tumor to combined small-cell lung cancer and squamous cell carcinoma with retained EGFR exon 19 deletions. Following sequential chemotherapy appropriate for transformed histology, a clinical response was achieved.

Platinum-based chemotherapy is the de facto standard treatment for metastatic or unresectable thymic carcinoma. The optimal chemotherapy regimen has not yet been determined, including whether this should be combined with a second- or third-generation anti-cancer agent. We retrospectively evaluated the data of patients with metastatic or unresectable thymic carcinoma who were treated with a combination of cisplatin and irinotecan as first-line chemotherapy between 2002 and 2021 (trial registration UMIN000012175). The primary endpoint was response rate according to the RECIST criteria version 1.1. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and toxicity (adverse events). Some patients analyzed in this study were also included in the previous trial, which was terminated early. For this analysis, we included 18 patients with a median age of 56 years and an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients had clinical stage IVa or IVb thymic carcinoma according to the Masaoka-Koga staging system. The response rate was 44% and the disease control rate was 89%. The median PFS was 8.4 months (95% confidence interval (CI): 2.7–11.6 months) and the median OS was 45.6 months (95% CI: 15.7–69.1 months). Grade 3 or worse hematological toxicity was observed in 5 patients and grade 3 or worse non-hematological toxicity was observed in 3 patients. None of the patients developed febrile neutropenia, and no treatment-related deaths occurred. Thus, the combination of cisplatin and irinotecan as first-line chemotherapy for metastatic thymic carcinoma showed efficacy and acceptable toxicity.

Background First-line treatment of non–small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death–1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte–associated protein–4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC. Patients and Methods Chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events. Conclusion If the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.

Background Osimertinib is the standard of care for patients with non-small-cell lung cancer (NSCLC) patients harboring acquired EGFR T790M resistance mutation. However, the frequency of T790M resistance mutation acquisition and the efficacy of osimertinib in patients harboring uncommon EGFR mutations, which accounts for approximately 10% of EGFR mutations, remain unclear. Case presentation We present the case of a 72-year-old Japanese woman with recurrent NSCLC harboring uncommon EGFR mutations, who was subsequently found to have acquired the T790M resistance mutation and was treated with osimertinib. She died 9 days later because of worsening respiratory failure with disease progression. Conclusion The findings of the present case suggest that the T790M resistance mutation can occur even when the patient harbors an uncommon EGFR mutation after EGFR-tyrosine kinase inhibitor treatment, and the prognosis could be poor despite the presence of an acquired T790M resistance mutation.

9036 Background: Despite immune-checkpoint inhibitors (ICI) achieving high response rates in patients (pts) with advanced non-small cell lung cancer (NSCLC), immune-related adverse events (irAE) remain an important therapeutic hurdle. The gut microbiome represents a novel prognostic marker of ICI response and early clinical evidence suggests that the microbiome may also regulate the development of irAE. We aimed to assess the association between irAE and the gut microbiome composition in advanced NSCLC pts amenable to ICI. Methods: In this study, we enrolled 464 pts from two independent cohorts (Montreal and Tokyo) with advanced NSCLC treated with ICI monotherapy or combination with chemotherapy. Fecal samples were collected prior to ICI initiation. Metagenomics microbiome profiling and 16S rRNA microbiome sequencing were performed for 81 pts and 133 pts respectively. The irAE were classified as CTCEA grade 0-1 (G0-1 irAE) and grade > 2 (G2-5 irAE). Microbiome composition of both groups was represented using alpha diversity, beta diversity indexes and LEfSe relative abundances. Results: Median follow-up was 28.3 months (mos) and the incidence of G2-5 irAE was 25.1% in the Montreal cohort. For the Tokyo cohort, the median follow-up was 19.6 mos and 30.8% pts developed G2-5 irAE. First, in both cohorts, overall survival (OS) and progression-free survival (PFS) were significantly improved for pts with G2-5 irAE compared to G0-1 irAE (OS: HR: 1.71, p = 0.008 and PFS: HR: 1.65, p < 0.001) and (OS: HR: 2.34, p = 0.001, and PFS: HR = 2.34, p = 0.006) respectively. Second, metagenomics analysis of 81 pts demonstrated a numerical decrease of the alpha diversity in terms of observed species in the G2-5 irAE. Dorea sp CAG 31, Anaerosporobacter mobilis, Butyricicococcus, and Enterococcus faecium were overrepresented in pts with G2-5 irAE. Conversely, Gordonibacter was increased in G0-1 irAE. Next, 16S rRNA profiling from the Tokyo cohort revealed an enrichment of Dorea, Butyricicococcus, and Eubacterium ventriosum in G2-5 irAE . Finally, we observed an enrichment in Dorea and Butyricicococcus in the pts with PFS > 6 months, as observed in the G2-5 irAE group. Conclusions: IrAE correlated with clinical outcome and microbiome composition in two independent cohorts of pts with advanced NSCLC. These results prompt further research on the potential mechanism underling the role of the microbiome in the development of irAE.

9050 Background: Host-related inflammatory biomarkers and gut microbiome are two major prognostic factors for non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (ICI). In this study, we aimed to assess an association between the Lung Immune Prognostic Index (LIPI) and the microbiome composition on ICI outcomes in two independent cohorts of NSCLC pts. Methods: We included 205 patients with advanced NSCLC treated with ICI (monotherapy or in combination with chemotherapy) from two independent cohorts. Metagenomics microbiome profiling was performed on the Canadian discovery cohort of 72 pts while 16S rRNA microbiome sequencing was used in the Japanese validation cohort of 133 pts. The LIPI score was calculated using the dNLR (neutrophils/[leucocytes-neutrophils]) and lactate deshydrogenase (LDH). Pts were classified as Good (G: 0 high factor), Intermediate (I: 1 high factor) and Poor (P: 2 high factors). Median overall survival (OS) was estimated using the Kaplan-Meier method. Microbiome diversity indexes and bacterial relative abundances were compared according to LIPI groups. Results: Among the 72 pts included in the discovery cohort, the median follow-up of 20.6 months (mos). The LIPI was distributed as follows: G (n = 31, 43.1%), I (31, 43.1%), P (10, 13.8%) and baseline characteristics were well balanced between the 3 groups. When segregating pts according to LIPI, the OS was 25.6 mo, 19.8 mo, and 5.7 mo in the G, I (HR: 1.71, 95%CI: 0.80-3.65) and P (HR: 3.97, 95%CI: 1.60-9.82) groups, respectively (p = 0.003). The microbiome alpha diversity was lower in the P group compared with the G group (p = 0.03), and there was a trend towards different microbiome composition in beta diversity (p = 0.055) between both groups. Pts in the G group had a favorable microbiome (enriched in Ruminococcus and Anaerostipes), while pts from the P group had an unfavorable microbiome (enriched in Enterobacteriaceae and Clostridium symbiosum and lavalense). Next, in the validation cohort of 133 pts, LIPI was distributed as follows: G (n = 62, 46.6%), I (51, 38.3%), P (20, 15%). Pts with G LIPI had not reached their median OS compared to pts in the I [15.7 mo HR: 1.60 (0.88-2.94)] and P [8.8 mo groups, HR: 2.02 (0.98-4.19)], p = 0.03. Similar to the discovery cohort, at the genus level, G LIPI group had enrichment of Ruminococcus as well as Anaerostipes compared with pts in the P and I groups with an overrepresentation of Hungatella. Conclusions: Host-related inflammatory biomarkers, represented by the LIPI, seemed to be associated with microbiome and ICI outcomes in pts treated with NSCLC. This observation was validated in an external validation cohort. This link could be in relation to the presence of proinflammatory bacteria in pts with poor LIPI.

Background Several studies suggest the gut microbiome may be a novel, modifiable biomarker for clinical efficacy of immune checkpoint inhibitors (ICIs). Microbiome profiling of pre-treatment samples demonstrated that high alpha-diversity and enrichment of specific bacterial species are associated with improved tumor responses in melanoma, renal cell cancer (RCC), and non-small cell lung cancer (NSCLC). Despite these reports, the specific bacteria or communities helpful or harmful have been inconsistent across study populations, and further correlation with immune and mutational biomarkers are limited or lacking. We hypothesize that, by use of a larger sample size and a consistent computational approach, we would derive a clearer microbial profile that correlated with immunotherapeutic outcomes. Methods We re-analyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n=303 unique patients) of responder (R) and nonresponse (NR) using a consistent computational approaches (Resphera Insight and MetaPhlAn2). Using novel microbiota signatures, we identified Re-analysis Indices for R- and NR-associated bacteria and validated the result in three addition cohorts with available raw sequencing data in patients with melanoma, hepatocellular cancer (HCC), and NSCLC (n=105). Results Our results confirm signals reported in each study, though some bacteria reported initially were not statistically significant after correction for false discovery rate. Likely, in part, because our analysis allows for comparison of individual species across cohorts, we were able to identify new bacterial signatures, such as Oxalobacter formigenes, Roseburia hominis and Veillonella parvula, Clostridium hathewayi, enriched in R and NR respectively. When our Re-analysis Index was compared to an index assembled from the literature, we noted improvement occurred in a sensitivity and specificity analysis, especially in NR-associated signals. Moreover, we found that alpha-diversity was not consistently predictive of response or nonresponse to ICIs. Our Re-analysis Index also validated in melanoma patients and HCC but did not perform as well in the NSCLC cohort, suggesting the need for further refinement based on tumor type. Conclusions In summary, this bioinformatics platform improves on existing pipelines by standardizing critical preprocessing and downstream analysis tools, enabling comprehensive evaluations of taxonomic and functional signals across sequencing datasets. Notably, the NR-associated Re-analysis Index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (p

The necessity of regular blood tests with the administration of immune checkpoint inhibitors has not been investigated. This study examined the safety of omitting a blood test every 2 weeks for patients with lung cancer who were injected an immune checkpoint inhibitor. We conducted a retrospective review of the medical records of 201 patients diagnosed with lung cancer and administered with nivolumab or durvalumab between December 1, 2015, and February 30, 2020, in a single hospital. We extracted 16 patients who had treatments without blood testing every 2 weeks. Adverse events that resulted in discontinued treatment included two cases of interstitial pneumonia, one case of creatinine increase, and one infection. All four cases were detected by chest X-ray or their symptoms. Our results indicate that immune checkpoint inhibitor administration without a blood test every 2 weeks did not subject patients to more adverse side effects.

Objective Polypharmacy (PP) is a common problem among the older adults and has a potential effect on health-related problems. However, the significance of PP in older advanced non–small cell lung cancer (NSCLC) patients and those on oral molecular-targeted anticancer agents is unclear. Materials and methods This retrospective, nonrandomized study reviewed the records of 334 advanced NSCLC patients who underwent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. PP was defined as ≥ 5 concomitant medications. Potentially inappropriate medication (PIM) use was measured using the updated screening tool of older people's prescriptions (STOPP) ver. 2 criteria. We also estimated survival distributions using the Kaplan–Meier method, compared between–group differences using the log-rank test, explored potential predictors of survival using Cox regression, and performed cluster analysis to identify factors affecting multiple-medication use. Results The PP and PIM use prevalence was 38.4% and 31.9%, respectively. The median overall survival (OS) for PP(+) and PP(−) patients was 19.4 and 27.3 months, respectively. Multivariate analysis revealed a significant correlation between PP and OS. The frequency of unexpected hospitalization during EGFR-TKI treatment was higher in PP(+) patients compared to PP(−) patients (49.4% vs. 29.4%; odds ratio = 2.34). Conclusion PP is an independent prognostic factor in older advanced NSCLC patients taking EGFR-TKIs. PP can be used as a simple indicator of such patients' comorbidities and symptoms or as a predictive marker of unexpected hospitalization during treatment.

Baseline tumor size (BTS) and the presence of massive lesions are important for predicting the clinical course of cancer. However, their impact on survival and clinical response in patients with advanced NSCLC undergoing immune checkpoint inhibitor (ICI) treatment has been scarcely investigated. We retrospectively reviewed 294 patients who underwent ICI therapy for advanced or recurrent non-small-cell lung cancer (NSCLC) between January 2016 and July 2019. Of these 294 patients, 284 (96.6%) had at least one measurable lesion. Of these, 263 patients treated with ICI monotherapy were included in the analysis. The median total and maximum target lesion diameters were 96.5 mm and 49.1 mm, respectively. Median progression-free survival (PFS) with massive lesions (max BTS > 50 mm, group A) and without massive lesions (max BTS ≤ 50 mm, group B) was 2.5 months (95% CI 1.8–3.7) and 6.7 months (95% CI 5.1–9.7), respectively. Median overall survival (OS) for groups A and B was 9.5 months (95% CI 5.5–12.3) and 20.0 months (95% CI 13.3–32.0), respectively. The multivariate analysis revealed marked associations between the presence of massive lesions and both PFS and OS. The presence of massive lesions (max diameters > 50 mm) is an independent prognostic factor in advanced NSCLC treated with ICI monotherapy. Although overall response rates were similar between groups A and B, the disease control rate was significantly poorer for group A. Max BTS might be useful for predicting clinical outcomes for patients undergoing immunotherapy as a parameter reflecting their tumor burden.

The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI. See articles by Tomita et al., p. 1236, and Peng et al., p. 1251