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.

Efficacy and safety of amrubicin monotherapy after atezolizumab plus carboplatin and etoposide in patients with relapsed small-cell lung cancer.

This study examined the activity and safety of amrubicin monotherapy among relapsed small-cell lung cancer (SCLC) patients who had previously been treated with atezolizumab plus carboplatin and etoposide (AteCE). This retrospective study evaluated patients with relapsed SCLC who were treated with previously AteCE combination therapy followed by amrubicin monotherapy between August 2019 and May 2021. Clinical efficacy and toxicity were analyzed. Overall, 40 patients were included: 12 and 28 patients had sensitive and refractory relapse, respectively. The response rate was 32.5% (25.0% in the sensitive group and 35.7% in the refractory group). The median progression-free survival (PFS) and overall survival (OS) from the first amrubicin treatment was 3.4 months (95% CI: 1.9-4.9 months) and 9.9 months (95% CI: 4.5-11.5 months), respectively. There was no significant between-group difference in median PFS (3.6 months vs. 3.2 months, p = 0.42) or median OS (11.2 months vs. 7.3 months, p = 0.78). Grade ≥ 3 hematological adverse events occurred as follows: decreased white blood cells in 52.5% of patients; decreased neutrophil count in 57.5%; and febrile neutropenia in 10.0%. Grade 3 pneumonitis was observed in one patient. There were no treatment-related deaths. Amrubicin is feasible and effective for relapsed SCLC patients previously treated with AteCE therapy. Although immune checkpoint inhibitor treatment (ICI) does not improve the effect of amrubicin, the toxicity is not increased, suggesting that amrubicin remains effective even after ICI administration. Thus, amrubicin after AteCE could be the preferred standard chemotherapeutic choice in patients with relapsed SCLC.

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.

Efficacy and Safety of Anti-Programed Death-1 Blockade in Previously Treated Large-Cell Neuroendocrine Carcinoma.

BACKGROUND: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor with an aggressive clinical course. However, there is limited knowledge of its treatment strategy. This retrospective study aimed to assess the efficacy and safety of anti-programed death-1 (PD-1) blockade monotherapy in previously treated advanced LCNEC. METHODS: Eleven patients with previously treated advanced LCNEC who received immune checkpoint inhibitor monotherapy between January 2015 and November 2020 were retrospectively analyzed for efficacy and safety. RESULTS: Of a total of 11 patients (median [range] age, 66 [37-79] years; 8 men [73%] and 3 women [27%]), 8 patients had performance status (PS) 0-1 [73%] and 3 patients had PS 2 [27%]; 9 patients received 1 prior chemotherapy [82%] and 2 patients received 2 prior chemotherapies [18%]. The median follow-up duration was 4.6 months. Although PD-1 blockade was administered at median cycles of 3 (range, 1-12), overall response rate, median progression-free survival, and median overall survival were 9.1%, 2.7 months, and 4.6 months, respectively. Any adverse events were observed in 9 patients (82%), including 1 patient with grade 3 pneumonitis as a serious adverse event. CONCLUSION: Anti-PD-1 blockade monotherapy as a subsequent line for previously treated advanced LCNEC exhibited usefulness and tolerability and was identified as a valid treatment option.

Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP. CASE PRESENTATION: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high. CONCLUSIONS: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates.

The nontuberculous mycobacteria (NTM) cause miscellaneous disorders in humans, especially in the lungs, which present with a variety of radiological features. To date, knowledge of the pathogenic role of the Mycobacterium avium-intracellulare complex (MAC) in the human lung and the definitive criteria for initiating multidrug therapy are still lacking. However, there is little doubt that clarithromycin is the most efficacious drug among the various treatment regimens for lung NTM. In this study, with the use of a bridged nucleic acid (BNA) probe a detection system based on a real-time PCR (BNA-PCR) for the identification of the point mutations at position 2058 or 2059 in domain V of the 23S rRNA gene responsible for clarithromycin resistance was developed and has been assessed using MAC isolates from clinical samples. Out of 199 respiratory specimens, the drug susceptibility test demonstrated 12 strains resistant to clarithromycin, while the BNA-PCR showed 8 strains carrying the point mutation at position 2058 or 2059 of the 23S rRNA gene. This system revealed that there were mycobacterial strains resistant to clarithromycin which do not carry previously identified resistance genes. This paper documents a novel system for detecting clarithromycin-resistant strains and demonstrates that although these mutations are tacitly assumed to account for >90% of the reported resistant mutants, there is a significant fraction of resistant mutants that do not harbor these mutations. Therefore, unknown mechanisms affecting clarithromycin resistance remain to be elucidated.

Treatments and outcomes of advanced/recurrent non-small cell lung cancer harboring the EGFR T790M mutation: a retrospective observational study of 141 patients in Japan.

BACKGROUND: The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC. METHODS: We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities. RESULTS: Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4-36.7) and 9.1 (6.4-13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy ± bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations. CONCLUSIONS: This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy ± bevacizumab. Platinum-based doublet chemotherapy ± bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.

[Hange-Shashin-to for preventing diarrhea during afatinib therapy].

Afatinib is an epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI). In a randomized phase III study(Lux- Lung 3 study)employing patients harboring EGFR mutations, patients administered afatinib show a significantly longer progression free survival time(PFS)than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However, most of the patients(95.2%)treatedwith afatinib experiencedd iarrhea. In the present report, 16 patients with EGFR mutations were treatedby afatinib at our institution from May 2014 to December 2014. Twelve patients were administered a diarrhea prevention herbal medicine, Hange-shashin-to. Seven of 12 patients(58%)had no diarrhea during the 28 days of therapy. All 4 of the patients who did not receive Hange-shashin-to experienced diarrhea above Grade 1 within 6 days of starting therapy. The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin- to. In conclusion, preventive administration of Hange-shashin-to may reduce the occurrence of diarrhea during afatinib treatment.

Prior immune checkpoint inhibitors may enhance severe hypersensitivity related to selpercatinib in RET fusion gene-positive lung cancer.

Selpercatinib, a tyrosine kinase inhibitor approved for RET-fusion gene-positive lung cancer, can induce hypersensitivity, potentially exacerbated by prior immune checkpoint inhibitor (ICI) therapy. We present a case of severe toxicity following selpercatinib treatment in a 58-year-old female with lung adenocarcinoma, refractory to previous treatments including pembrolizumab. Symptoms included fever, rash, and multiorgan failure indicative of grade 4 hypersensitivity. Treatment involved platelet transfusion, heparin therapy, and prednisolone, leading to improvement upon selpercatinib cessation. This case highlights the importance of monitoring for hypersensitivity reactions in patients treated with selpercatinib, especially following prior ICI therapy.

Therapeutic Resistance in G-CSF Producing Lung Cancer With EGFR Mutation.

Background/Aim: Granulocyte colony-stimulating factor (G-CSF)-producing neoplasms are relatively rare; however, little is known on the clinical features of G-CSF-producing lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations. Case Report: A 66-year-old female was definitively diagnosed with G-CSF-producing lung cancer that was positive for EGFR mutations. She repeatedly received epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and afatinib. However, she developed resistance to these molecular-targeting drugs within 2 to 3 months after immediate shrinkage. Thus, the patient was treated with chemoimmunotherapy including bevacizumab, and demonstrated a slight survival benefit. Conclusion: Overall, G-CSF-producing lung cancers positive for EGFR mutations were resistant to different treatment modalities. Clinicians should be attentive to the potential resistance of G-CSF-producing EGFR mutant lung cancer to EGFR-TKI therapy.

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.

Metabolic Tumor Volume as Significant Predictor for Chemotherapy Containing PD-L1 Blocker in Extensive Stage Small Cell Lung Cancer.

BACKGROUND/AIM: Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker. PATIENTS AND METHODS: Forty-six patients with ES-SCLC who received 18F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated. RESULTS: PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUVmax, MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were significant predictors of OS. SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs. CONCLUSION: MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC.

[A case of lung paragonimiasis superinfection with hookworm presenting difficulty in discrimination].

A 40-year-old woman, who was born in Thailand and moved to Japan 20 years previously, was admitted to our university hospital because of eosinophilia and abnormal chest radiography findings over a 6-month period. The chest CT showed multiple cavitary nodules in the subpleural area and a tubular structure that extended from each cavity to the pleura. Immunological examination revealed an elevation of antibody titers against Ancylostoma duodenale, Paragonimiasis miyazakii and Paragonimiasis westermanii based on an ELISA assay. In addition, hookworm eggs were found in the stool. We firstly administered pyrantel pamoates, following which the eggs become undetectable. Nevertheless, eosinophilia and abnormal chest CT findings persisted. We diagnosed the patient as having a superinfection with paragonimiasis and hookworm, then administered praziquantel. Subsequently, the number of eosinophils returned to a normal level and the abnormal shadow in the chest CT images diminished without scarring. The final diagnosis was a superinfection of paragonimiasis and hookworm.

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.

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.

Intermittent administration of atezolizumab with combined carboplatin and etoposide therapy for patients with extensive­disease small cell lung cancer.

To the best of our knowledge, no published reports have examined the significance of additional immune checkpoint inhibitors in treating malignancies, including lung cancer. Therefore, the present study aimed to examine the efficacy and feasibility of adding atezolizumab to carboplatin and etoposide combination chemotherapy for small cell lung cancer with extensive disease (ED-SCLC). The present retrospective analysis examined 16 patients with ED-SCLC who received the addition of atezolizumab to carboplatin and etoposide therapy during treatment at four institutions between August 2019 and September 2020. The effectiveness of treatment was evaluated based on tumor response, survival time and adverse events. Within the study cohort, there were 14 males (87.5%) and 2 females (12.5%), with a median age of 73.5 years (range, 62-79 years); 7 patients had a performance status (PS) of 0-1 (43.8%) and 9 had a PS of 2-3 (56.3%). The median follow-up period was 12.1 months. The overall response rate, median progression-free survival time and median overall survival time were 75.0%, 5.3 and 13.0 months, respectively. Regarding the frequency of hematological adverse events, the occurrence of grade ≥3 adverse events was observed, including decreased neutrophil (56.3%), white blood cell (50.0%) and platelet (43.8%) counts, as well as febrile neutropenia (12.5%). Although 1 patient developed grade 3 pneumonitis as a serious adverse event, no treatment-related deaths were observed. Despite the aforementioned hematological toxicities, the addition of atezolizumab to carboplatin and etoposide therapy during treatment demonstrated favorable efficacy and acceptable toxicity in ED-SCLC. Thus, adding atezolizumab to carboplatin and etoposide combination chemotherapy may be a treatment option for ED-SCLC.

Real-world data of atezolizumab plus carboplatin and etoposide in elderly patients with extensive-disease small-cell lung cancer.

PURPOSE: The aim of this study was to assess the effectiveness and tolerability of atezolizumab plus carboplatin and etoposide combination chemotherapy in elderly patients with extensive-disease (ED) small-cell lung cancer (SCLC). METHODS: This retrospective study evaluated 65 SCLC patients who received atezolizumab, carboplatin, and etoposide for ED-SCLC in nine study institutions between August 2019 and September 2020. Clinical efficacy, assessed according to response rate and survival, and toxicity were compared between the elderly (n = 36 patients; median age: 74 years [range: 70-89 years]) and the non-elderly group (n = 29 patients; median age: 67 years [range: 43-69 years]). RESULTS: The response rate was 73.8% (80.5% in the elderly group and 65.5% in the non-elderly group). There was no significant difference in both the median progression-free survival (5.5 months vs. 4.9 months, p = 0.18) and the median overall survival (15.4 months vs. 15.9 months, p = 0.24) between the elderly group and the non-elderly group. The frequencies of grade ≥3 hematological adverse events in the elderly patients were as follows: decreased white blood cells, 36.1%; decreased neutrophil count, 61.1%; decreased platelet count, 8.3%; and febrile neutropenia, 8.3%. One treatment-related death due to lung infection occurred in the elderly group. CONCLUSION: Despite hematologic toxicities, especially decreased neutrophil count, atezolizumab, carboplatin, and etoposide combination chemotherapy demonstrates favorable effectiveness and acceptable toxicity in elderly patients. Thus, atezolizumab plus carboplatin and etoposide could be the preferred standard treatment modality for elderly patients with ED-SCLC.

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.

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.