Clinical impact of inflammatory and nutrition index based on metabolic tumor activity in non­small cell lung cancer treated with immunotherapy.

The aim of the present study was to explore the relationship between tumor metabolic glycolysis and inflammatory or nutritional status in patients with advanced non-small cell lung cancer (NSCLC) who received programmed death-1 (PD-1) blockade. A total of 186 patients were registered in the present study. All of patients underwent 18F-FDG PET imaging before initial PD-1 blockade, and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed as indicators of 18F-FDG uptake. As inflammatory and nutritional index, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ration (PLR), systemic immune inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI) and Glasgow prognostic score (GPS) were evaluated based on previous assessment. 18F-FDG uptake by MTV and TLG significantly correlated with the scores of NLR, PLR, SII, PNI and ALI, in addition to the level of albumin, lactate dehydrogenase, C-reactive protein, white blood cells, neutrophils, lymphocytes and body mass index. The count of NLR, PLR and SII was significantly higher in patients with <1 year overall survival (OS) compared with in those with ≥1 year OS, and that of PNI and ALI was significantly lower in those with <1 year OS compared with those with ≥1 year OS. High MTV under the high PLR, SII and low ALI were identified as significant factors for predicting the decreased PFS and OS after PD-1 blockade in a first-line setting. In second or more lines, high MTV was identified as a significant prognostic predictor regardless of the levels of PLR, SII, ALI and GPS. In conclusion, metabolic tumor glycolysis determined by MTV was identified as a predictor for the outcome of PD-1 blockade under the high inflammatory and low nutritional conditions, in particular, when treated with a first-line PD-1 blockade. A high MTV under high PLR and SII and low ALI in the first-line setting could be more predictive of ICI treatment than other combinations.

Clinical Utility of Inflammatory and Nutritious Index as Therapeutic Prediction of Nivolumab plus Ipilimumab in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Biomarkers for predicting the outcome of ipilimumab plus nivolumab (Nivo-Ipi) treatment in cancer patients have not been identified. Herein, we investigated the prognostic significance of inflammatory and nutritional markers in patients with advanced non-small cell lung cancer (NSCLC) receiving Nivo-Ipi. METHODS: Our study retrospectively analyzed 101 patients with advanced NSCLC who received Nivo-Ipi at a single institution. Inflammatory and nutritional indices were correlated with patient outcomes and included the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score (GPS). RESULTS: The NLR significantly correlated with the PLR, SII, PNI, ALI, and GPS. Regarding therapeutic efficacy, the NLR, SII, and PNI predicted a partial response, and all indices predicted progressive disease. In subgroup analyses, the SII, PNI, and ALI predicted the outcome of patients with adenocarcinoma, whereas only the PNI predicted the outcome of patients with non-adenocarcinoma. The PNI and SII were the most useful indices in patients with a programmed death ligand-1 expression level of <1% and ≥1%, respectively. CONCLUSION: The NLR, PLR, SII, PNI, ALI, and GPS were significantly associated with the outcome of Nivo-Ipi treatment in patients with NSCLC. The PNI was the most suitable marker regardless of histological type. The SII and PNI were the most promising markers for patients with and without PD-L1 expression, respectively.

Clinical significance of antinuclear antibody as prognostic marker for first-line pembrolizumab in advanced non-small cell lung cancer.

BACKGROUND: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade. METHODS: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed. RESULTS: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA. CONCLUSIONS: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy.

Predictive significance of circulating tumor DNA against patients with T790M-positive EGFR-mutant NSCLC receiving osimertinib.

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Clinicopathological impact of VEGFR2 and VEGF-C in patients with EGFR-major mutant NSCLC receiving osimertinib.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been identified as one of the resistant mechanisms to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the relationship between the efficacy of osimertinib and protein expression of VEGF family members in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations remains unclear. METHODS: A total of 76 patients with advanced NSCLC with EGFR major mutations (del19 or L858R) receiving first-line osimertinib were eligible as the osimertinib (Osi) group, whereas 43 patients receiving first- or second-generation EGFR-TKIs were compared with the control group. The expression of vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor C (VEGF-C) in the tumor specimens was analyzed using immunohistochemistry. RESULTS: VEGFR2 and VEGF-C were highly expressed in 65.8% and 51.3% of patients, respectively, in the Osi group, and 69.7% and 76.7%, respectively, in the control group. High VEGFR2 and VEGF-C levels were significantly associated with poor performance status (PS) and female sex, respectively. In the Osi group, patients with co-high expression of VEGFR2 and VEGF-C showed significantly worse progression-free survival (PFS) and overall survival (OS) than those without co-high expression. In del19, VEGFR2 was a significant predictor of PFS and OS and independent predictor of OS in multivariate analysis. In L858R, co-high expression of VEGFR2 and VEGF-C was identified as a significant predictor of PFS and OS and independent predictor of PFS. CONCLUSION: VEGFR2 and VEGF-C are highly expressed in EGFR-mutant NSCLC cells. Increased expression of VEGFR2 was identified as a significant prognostic factor in patients with EGFR del19 mutation who received osimertinib, whereas co-high expression of VEGFR2 and VEGF-C was a significant predictor for those with EGFR L858R mutation.

Comparative analysis of different response criteria at early phase after PD-1 blockade in non-small lung cancer.

PURPOSE: To compare different response criteria using computed tomography (CT) and positron emission tomography (PET) in measuring response and survival in the early phase after programmed death-1 (PD-1) blockade monotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 54 patients with advanced NSCLC who had 2-deoxy-2-[fluorine-18]-fluoro-D-glucose PET or CT at baseline, and 4 and 9 weeks after PD-1 blockade, were registered. Therapeutic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), the immune-modified RECIST (irRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the immune-modified PERCIST (iPERCIST), and the European Organization for Research and Treatment of Cancer (EORTC) criteria for dichotomous groups, such as responders vs. non-responders and controlled vs. uncontrolled diseases. Cohen's κ was used to evaluate the concordance among the different criteria. RESULTS: The concordance between CT and PET response criteria was fair or slight for responders vs. non-responders, but the agreement between iPERCIST and irRECIST was moderate for controlled vs. uncontrolled diseases. The agreement between EORTC and PERCIST or iPERCIST in detecting responders was higher in the application of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) than in the standardized uptake value corrected for lean body mass (SUL)peak. To distinguish controlled from uncontrolled disease, RECIST, irRECIST, and PET criteria (PERCIST, iPERCIST, and EORTC) defined by MTV or TLG were found to be significant predictors of progression-free survival. To distinguish responders from non-responders, iPERCIST by SULpeak or EORTC by TLG were identified as significant indicators. The EORTC criteria using TLG for the detection of responders or uncontrolled diseases had a significantly higher predictive value for response assessment. CONCLUSIONS: The EORTC criteria based on TLG for the early detection of responders and uncontrolled disease were effective as a response assessment at 4 weeks after the PD-1 blockade. When SULpeak was not used but MTV or TLG was, the agreement between EORTC and PERCIST or iPERCIST was almost perfect.

Prognostic significance of tumor infiltrating lymphocytes on first-line pembrolizumab efficacy in advanced non-small cell lung cancer.

AIM: Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting. METHODS: Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N = 93) or surgical resections (N = 14) before first-line pembrolizumab. RESULTS: A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%. CONCLUSION: Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS.

Establishing a whole blood CD4+ T cell immunity measurement to predict response to anti-PD-1.

BACKGROUND: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. METHODS: The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. RESULTS: This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments. CONCLUSIONS: The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.

Single-Cell Analysis Reveals a CD4+ T-cell Cluster That Correlates with PD-1 Blockade Efficacy.

CD4+ T-cell immunity helps clonal proliferation, migration, and cancer cell killing activity of CD8+ T cells and is essential in antitumor immune responses. To identify CD4+ T-cell clusters responsible for antitumor immunity, we simultaneously analyzed the naïve-effector state, Th polarization, and T-cell receptor clonotype based on single-cell RNA-sequencing data. Unsupervised clustering analysis uncovered the presence of a new CD4+ T-cell metacluster in the CD62Llow CD4+ T-cell subpopulation, which contained multicellular clonotypes associated with efficacy of programmed death-ligand 1 (PD-1) blockade therapy. The CD4+ T-cell metacluster consisted of CXCR3+CCR4-CCR6+ and CXCR3-CCR4-CCR6+ cells and was characterized by high expression of IL7 receptor and TCF7. The frequency of these cells in the peripheral blood significantly correlated with progression-free survival and overall survival of patients with lung cancer after PD-1 blockade therapy. In addition, the CD4+ metacluster in the peripheral blood correlated with CD4+ T-cell infiltration in the tumor microenvironment, whereas peripheral Th1 correlated with local CD8+ T-cell infiltration. Together, these findings suggest that CD62Llow CCR4-CCR6+ CD4+ T cells form a novel metacluster with predictive potential of the immune status and sensitivity to PD-1 blockade, which may pave the way for personalized antitumor immunotherapy strategies for patients. SIGNIFICANCE: The identification of a new CD4+ T-cell metacluster that corresponds with immune status could guide effective tumor treatment by predicting response to immunotherapy using peripheral blood samples from patients.

Potential of VEGFR2 expression as a predictive marker of PD­1 blockade in patients with advanced NSCLC.

Angiogenesis serves a crucial role in cancer progression. Vascular endothelial growth factor (VEGF) exhibits an immunosuppressive function in patients with cancer. However, it remains unclear whether expression of VEGF in tumor tissue can predict the outcome of programmed death­1 blockade in patients with advanced non­small cell lung cancer (NSCLC). A training (n=32) and validation (n=76) cohort of patients with advanced NSCLC who received first­line pembrolizumab were enrolled. Immunohistochemical staining for VEGF receptor 2 (VEGFR2) and tumor­infiltrating lymphocytes (TILs; CD4, CD8 and FOXP3) was performed in tumor specimens of both cohorts and association with clinical outcomes was assessed. The percentages of high VEGFR2 expression were 34.3% (11/32) in training cohort and 25.0% (19/76) in validation cohort. No statistically significant difference in objective response between high and low VEGFR2 expression was observed for training (27.2 vs. 45.0%) and validation (31.2 vs. 35.7%) cohorts. The positive rate of intratumoral FOXP3 was significantly associated with high VEGFR2 expression for validation cohort, but not training cohort. In validation cohort, high VEGFR2 expression in patients with non­adenocarcinoma (non­AC) was significantly correlated with positive FOXP3 TILs in intratumoral and stromal sites, but not CD4 and CD8. High VEGFR2 expression in both cohorts indicated a significantly worse overall survival (OS) than low VEGFR2 expression. VEGFR2 was identified as an independent prognostic marker associated with worse OS. High VEGFR2 expression was a significant marker for predicting worse OS in patients treated with first­line pembrolizumab, particularly in those with non­AC.

Simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non-small cell lung cancer treated with intensity modulated radiotherapy.

BACKGROUND: In this study, we developed a simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiotherapy (IMRT). METHODS: Data of 28 patients with stage IIB to IIIC NSCLC were retrospectively analyzed. All patients were treated with IMRT and a simulated three-dimensional conformal radiotherapy (3D-CRT) plan created for them. Dose-volume parameters of lung were analyzed for their correlation with radiation pneumonitis (RP). RESULTS: Over a median follow-up of 14 months, grade 1 pneumonitis was diagnosed in 14 patients (50%), grade 2 pneumonitis in 11 (39%), and grade 3 pneumonitis in one (4%). Two patients did not develop pneumonitis. None of the patients developed grade 4 or 5 pneumonitis. Regarding dose-volume parameter ratios between IMRT and simulated 3D-CRT, receiver operating characteristic analysis showed that mean lung dose (MLD)IMRT /MLD3D-CRT had the largest area under curve (0.750). Cumulative 6-month incidences of grade 2 or greater RP were 78.4% versus 19.5% (MLDIMRT /MLD3D-CRT, ≥1.0 or less); this difference was significant (p < 0.05). CONCLUSIONS: We found that cutoff values for dose volume parameter ratios significantly predict grade 2 or greater RP. We believe that these parameter ratios could be useful in assisting evaluation of achievement degree of lung dose optimization in IMRT for LA-NSCLC.

Prognostic Potential of Metabolic Activity on 18 F-FDG Accumulation in Advanced NSCLC Receiving Combining Chemotherapy Plus PD-1 Blockade.

Combined chemotherapy plus programmed death-1 (PD-1) blockade is an established treatment against patients with advanced non-small cell lung cancer (NSCLC). However, a promising predictor besides programmed death ligand-1 expression remains uncertain. We examined the prognostic significance of baseline 18 F-FDG-positron emission tomography for predicting first-line combined chemotherapy plus PD-1 blockade in NSCLC patients. Forty-five patients with advanced NSCLC who received 18 F-FDG-positron emission tomography immediately before combined platinum-based chemotherapy with PD-1 blockade as first-line setting were eligible for this study, and assessment of maximum of standard uptake value (SUV max ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18 F-FDG uptake was performed. The objective response rate, median progression-free survival, and overall survival were 51.2%, 206 days, and 681 days, respectively. High SUV max , TLG, and MTV significantly correlated with age and performance status (PS), C-reactive protein (CRP), and PS, CRP, albumin, and baseline tumor size, respectively. Univariate analysis identified albumin, TLG and MTV as significant predictors of progression-free survival, and CRP, albumin, TLG and MTV as significant factors for predicting overall survival. High TLG was confirmed as an independent factor associated with poor prognosis in multivariate analysis. In particular, TLG is identified as the most powerful predictor in patients with good PS, adenocarcinoma, programmed death ligand-1≥1%, and low baseline tumor size. The tumor metabolic volume by MTV and TLG at pretreatment was clarified as a significant predictor for combined chemotherapy with PD-1 blockade, but not maximal glycolytic level by SUV max .

Prospective assessment using 18F-FDG PET/CT as a novel predictor for early response to PD-1 blockade in non-small-cell lung cancer.

Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

Metachronous lesions in the orbit, retroperitoneum, and pleura of mucosa-associated lymphoid tissue lymphoma: A case report.

BACKGROUND: Mucosa associated lymphoid tissue (MALT) lymphoma of the orbit is rare, often indolent, but can recur, and spread to extra-nodal sites. Pleural and retroperitoneum recurrences of MALT lymphoma are rare. CASE: A 65-year-old man was referred to our hospital due to right pleural effusion and difficulty in breathing. He had a medical history of having undergone surgery for MALT lymphoma of the left orbit. A chest computed tomography (CT) scan showed right pleural thickness, pleural effusion, and a retroperitoneal mass, spreading from the muscular layer to the subcutaneous layer. The thickened pleural lesion was surgically biopsied and diagnosed as a recurrence of MALT lymphoma. CONCLUSION: Pleural effusion should be carefully examined and monitored for the possibility of recurrence in MALT lymphoma patients.

Pretreatment body mass index predicts survival among patients administered nivolumab monotherapy for pretreated non-small cell lung cancer.

BACKGROUND: Biomarker assessments for nivolumab monotherapy efficacy in previously treated patients with non-small cell lung cancer (NSCLC) remain unclear. We evaluated whether body mass index (BMI) and Glasgow prognostic score (GPS) are useful for assessing the efficacy of nivolumab alone as a second-line treatment in patients with pretreated NSCLC. METHODS: Data of 99 patients treated with second-line nivolumab monotherapy for NSCLC between January 2016 and December 2019 were evaluated for prognostic values of BMI and GPS to assess their usefulness in predicting progression-free survival (PFS) and overall survival (OS). RESULTS: The Eastern Cooperative Oncology Group-performance status (PS) independently predicted the second-line nivolumab monotherapeutic effect; good PS (0-1) correlated with significantly longer PFS (4.3 vs. 1.9 months, log-rank; p = 0.0004) and OS (17.7 vs. 4.6 months, log-rank; p < 0.0001) than poor PS. BMI independently predicted survival, with high BMI (≥22.1 kg/m2 ) associated with significantly longer OS (19.1 vs. 8.5 months, log-rank; p = 0.0023) than low BMI (<22.1 kg/m2 ). However, GPS showed no significant difference for PFS or OS. CONCLUSION: Among patients with NSCLC treated with nivolumab monotherapy as second-line treatment, PS was significantly correlated with both PFS and OS and BMI with OS. Thus, BMI could be a useful predictor of survival in these patients.

Visual Assessment of 18F-FDG Uptake on PET to Predict Survival Benefit to PD-1 Blockade in Non-Small Cell Lung Cancer.

BACKGROUND: Programmed death 1 (PD-1) blockade is a standard treatment for patients with metastatic non-small cell lung cancer (NSCLC). Approximately 20% patients receiving PD-1 blockade monotherapy can survive for more than 5 years. However, there are limited data on the optimal biomarkers for predicting long-term outcomes. Therefore, this study aimed to evaluate the prognostic significance of 18F-FDG uptake in patients with NSCLC responding to PD-1 blockade. PATIENTS AND METHODS: Thirty-eight patients with advanced NSCLC who underwent 18F-FDG PET after confirmation of clinical response to PD-1 blockade monotherapy were retrospectively included in this study. Visual assessment using a 5-point scale score according to 18F-FDG uptake was performed, and the 18F-FDG uptake cutoff score for prolonged response to PD-1 blockade was defined as 3 (low score: 1, 2, or 3 and high score: 4 or 5). RESULTS: A significantly greater number of patients with low scores had a performance status of 0 or 1 than patients with high scores. Among the 38 patients, 20 (53%) had a low score and 18 (47%) had a high score. Progression-free survival and overall survival were significantly longer in patients with low scores than in patients with high scores. Low 18F-FDG uptake was an independent prognostic factor for predicting favorable progression-free survival and overall survival, as confirmed by multivariate analysis. CONCLUSIONS: Tumors with lower 18F-FDG uptake on PET than normal hepatic lesions exhibit the possibility of prolonged response to PD-1 blockade. Visual assessment on PET is easy for every clinician and is understandable to confirm aggressive tumor activity.

Combination of immune check inhibitor and immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis: A case report.

The present study selected two patients with lung cancer and epidermal growth factor receptor (EGFR) mutations who were treated with a programmed cell death protein 1 (PD-1) antibody and an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis. In the first case, a 67-year-old female was diagnosed with lung adenocarcinoma with an EGFR mutation (exon 19 deletion) and Stage IVB disease. Initial treatment with an EGFR mutation-targeted tyrosine kinase inhibitor (TKI), erlotinib, demonstrated a partial response. After disease progression this was followed by carboplatin and pemetrexed with bevacizumab, and re-challenged by erlotinib plus bevacizumab; however, the tumor eventually progressed. Subsequently, the patient was treated with immunomodulatory arabinomannan for 3 months. Immediately after, she was treated with nivolumab and showed a partial response. In the second case, a 57-year-old male with a history of smoking was diagnosed with stage IVB pulmonary adenocarcinoma with an EGFR mutation (exon 19 deletion). He was treated with afatinib, followed by osimertinib when a T790M mutation was identified later. After disease progressed with TKIs, cisplatin plus pemetrexed and re-challenge with erlotinib plus bevacizumab were administered subsequently. Nivolumab was administered for recurrent disease. Although he experienced tumor remission, regrowth of the tumors was observed. Under continuing nivolumab, he was treated by palliative irradiation treatments to the right pelvic bone metastasis and left adrenal metastasis with immunomodulatory arabinomannan. A chest computed tomography scan showed a reduction in the sizes of the primary site and pulmonary metastases, with a decreasing trend of carcinoma embryonic antigen. Overall, these cases may indicate that the immune adjuvant actions of immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis improves the effect of PD-1 antibody treatments.

Effect of Systemic Steroid Use for Immune-Related Adverse Events in Patients with Non-Small Cell Lung Cancer Receiving PD-1 Blockade Drugs.

OBJECTIVES: Programmed death-1(PD-1)/programmed death ligand-1 (PD-L1) antibodies have clinical benefits for cancer patients facing immune-related adverse events (irAEs). However, the effect of steroid use on the prognosis of patients with non-small cell lung cancer (NSCLC) receiving PD-1 blockade remains unclear. METHODS: NSCLC patients with complete response (CR)/partial response (PR) or stable disease (SD)/not evaluable (NE) status plus progression-free survival (PFS) of 180 days after PD-1 blockade from December 2015 to December 2018 were retrospectively registered in our study and were divided into two groups: those with and without systemic steroid use for irAEs. RESULTS: In total, 126 patients who had benefitted from PD-1 blockade were enrolled in our study; among them, 44 received systemic steroids for irAEs, and 82 had no adverse events or, if they did, did not receive systemic steroids. Among the 44 patients requiring steroids, interstitial lung disease (ILD), adrenal insufficiency, diarrhea, and liver dysfunction were observed in 19, 9, 4, and 4 patients, respectively. More side effects were observed in the group treated by steroids. The median PFS and overall survival (OS) in patients with and without systemic steroid use were 11.7 and 16.0 months (p < 0.037) and 35.0 and 41.0 months (p < 0.28), respectively. In univariate and multivariate analyses of survival, systemic steroid treatment for irAEs was significantly associated with PFS. The occurrence of ILD, adrenal insufficiency, and fever was significant in patients who used systemic steroids for irAEs. CONCLUSIONS: Patients administered systemic steroids for irAEs due to PD-1 blockade treatment exhibited shorter PFS than those who were not. Systemic steroids might affect survival after PD-1 blockade even for patients who once acquired its clinical benefit.

Feasibility of intensity modulated radiotherapy with involved field radiotherapy for Japanese patients with locally advanced non-small cell lung cancer.

The feasibility of intensity modulated radiotherapy (IMRT) with involved field radiotherapy (IFRT) for Japanese patients with locally advanced non-small cell lung cancer (LA-NSCLC) remains unclear. Here we reviewed our initial experience of IMRT with IFRT for Japanese patients with LA-NSCLC to evaluate the feasibility of the treatment. Twenty LA-NSCLC patients who were treated with IMRT with IFRT during November 2019 to October 2020 were retrospectively analyzed. All patients received 60 Gy in 30 fractions of IMRT and were administered concurrent platinum-based chemotherapy. The median patient age was 71 years old and the group included 15 men and 5 women. The patient group included 2 patients with stage IIB, 11 patients with stage IIIA, 5 patients with stage IIIB, and 2 patients with stage IIIC disease. Histological diagnosis was squamous cell carcinoma in 14 patients, adenocarcinoma in 5 patients, and non-small cell lung cancer in 1 patient. The median follow-up period was 8 months. The incidence of grade 3 or greater pneumonitis was 5%, and grade 3 or greater esophagitis was not observed. None of the patients developed regional lymph node, with only recurrence reported so far. These findings indicate that IMRT with IFRT for Japanese patients with LA-NSCLC is feasible in terms of acute toxicity. Further study with a larger number of patients and longer follow-up to clarify the effect of treatment on patient prognosis is required.

Efficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce. METHODS: This study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed. RESULTS: One hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39-84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups. CONCLUSION: The administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.