Impact of Cachexia and First-Line Systemic Therapy for Previously Untreated Advanced Non-Small Cell Lung Cancer: NEJ050A.

BACKGROUND: Cancer cachexia complicates advanced non-small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first-line systemic therapy. METHODS: We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first-line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first-line systemic therapy. RESULTS: A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0-2 who were initiated on first-line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first-line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy-associated emesis affecting early appetite-related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: -3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (-1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression-free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003). CONCLUSIONS: Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite-related QOL trends vary based on the type of first-line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter.

Durvalumab after chemoradiotherapy for locoregional recurrence of completely resected non-small-cell lung cancer (NEJ056).

Locoregional recurrence of non-small-cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT-D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT-D group. After IPTW adjustment, the CRT-D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW-adjusted median progression-free survival was 25.4 and 11.5 months for the CRT-D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30-0.64); the median overall survival was not reached in either group favoring CRT-D (hazard ratio, 0.49; 95% confidence interval, 0.24-0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT-D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection.

A retrospective evaluation of therapeutic efficacy and safety of chemoradiotherapy in older patients (aged ≥ 75 years) with limited-disease small cell lung cancer: insights from two institutions and review of the literature.

BACKGROUND: The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC. PATIENTS AND METHODS: From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT. RESULTS: A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The median ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75-81) years and 79 (range: 76-92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1-5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference (p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively (p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group. CONCLUSIONS: Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group.

The Glasgow Prognostic Score as a Predictor of Survival after Chemoradiotherapy for Limited-Disease Small Cell Lung Cancer.

INTRODUCTION: Established biomarkers for predicting chemoradiotherapy efficacy for limited-disease small cell lung cancer (LD-SCLC) are lacking. The inflammation-based Glasgow Prognostic Score (GPS), comprising serum C-reactive protein (CRP) and albumin levels, can predict survival in advanced cancer. This study investigated whether metabolic and inflammatory markers, including the GPS, can predict the efficacy of chemoradiotherapy in patients with LD-SCLC. METHODS: We retrospectively analyzed 124 patients who underwent chemoradiotherapy for LD-SCLC at two institutions between April 2007 and June 2021, and assessed the prognostic significance of various metabolic and inflammatory markers. The GPS was calculated using the CRP and albumin concentrations, and categorized as follows: 0, CRP <1.0 mg/dL and albumin ≥3.5 mg/dL; 1, elevated CRP or decreased albumin; and 2, CRP ≥1.0 mg/dL and albumin<3.5 mg/dL. Differences in progression-free survival (PFS) and overall survival (OS) were examined using Kaplan-Meier curves and Cox proportional-hazard models. RESULTS: The overall response rate was 95.1% (95% confidence interval [CI]: 89.6-97.9%). The median PFS and OS from chemoradiotherapy initiation were 12.6 (95% CI: 9.9-15.4) and 29.0 (95% CI: 24.8-45.5) months, respectively. The GPS demonstrated independent predictive ability for the effectiveness of chemoradiotherapy, wherein favorable scores (GPS 0-1) were significantly correlated with superior PFS and OS compared to unfavorable scores (GPS 2: PFS: 14.8 vs. 6.7 months, p = 0.0001; OS: 35.4 vs. 11.0 months, p < 0.0001). CONCLUSION: This preliminary examination revealed that the GPS was significantly associated with PFS and OS in patients undergoing chemoradiotherapy for LD-SCLC, indicating its potential utility in assessing the therapeutic outcomes in LD-SCLC.

Risk and survival of patients with non-small cell lung cancer and pre-existing autoimmune disorders receiving immune checkpoint blockade therapy: Survival analysis with inverse probability weighting from a nationwide, multi-institutional, retrospective study (NEJ047).

BACKGROUND: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established. PATIENTS AND METHODS: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan. RESULTS: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006). CONCLUSIONS: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID.

D-dimer cut-off value for predicting venous thromboembolism at the initial diagnosis in Japanese patients with advanced lung cancer.

OBJECTIVE: Cancer is a well-known risk factor for venous thromboembolism. The D-dimer level is used to predict venous thromboembolism; however, reports on an appropriate D-dimer cut-off value in Japanese patients with advanced lung cancer are lacking. Therefore, this study aimed to calculate the D-dimer cut-off value for venous thromboembolism at the time of lung cancer diagnosis. METHODS: The Rising-venous thromboembolism/NEJ037 study was a multicenter, prospective observational study. Patients with lung cancer who were contraindicated for radical resection or radiation were enrolled and followed up for 2 years. In the present study (jRCT no. 061180025), a receiver operating characteristic curve for D-dimer levels was created using the dataset of the Rising-venous thromboembolism/NEJ037 study. RESULTS: The Rising-venous thromboembolism/NEJ037 study included a total of 1008 patients, of whom 976, whose D-dimer levels had been measured at the time of cancer diagnosis, were included in the present study. At the time of lung cancer diagnosis, 62 (6.3%) and 914 (93.7%) patients presented with and without venous thromboembolism, respectively. The D-dimer values ranged from 0.1 to 180.1 µg/ml and from 0.1 to 257.2 µg/ml in patients with and without venous thromboembolism, respectively. The receiver operating characteristic curve was discriminative with a cut-off value of 3.3 µg/ml and an area under the curve of 0.794 (sensitivity, 0.742; specificity, 0.782; 95% confidence interval, 0.725-0.863). CONCLUSIONS: This is the first study to calculate the D-dimer cut-off value in Japanese patients with advanced lung cancer. Patients with D-dimer levels ≥3.3 µg/ml at the time of initial diagnosis may have coexisting venous thromboembolism.

Immunotherapy With Radiotherapy for Brain Metastases in Patients With NSCLC: NEJ060.

Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

Clinical Outcome of Nivolumab Plus Ipilimumab in Patients with Locally Advanced Non-Small-Cell Lung Cancer with Relapse after Concurrent Chemoradiotherapy followed by Durvalumab.

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7-7.7) and 18.5 months (95% CI: 3.5-33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8-64.5) and 36.4% (95% CI: 19.0-53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.

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.

Immunotherapy or Chemoimmunotherapy in Older Adults With Advanced Non-Small Cell Lung Cancer.

Importance: Immune checkpoint inhibitor (ICI) plus chemotherapy combination treatment (ICI-chemotherapy) is now a standard treatment for non-small cell lung cancer (NSCLC) without targetable oncogene alterations, but there are few data on ICI-chemotherapy for patients 75 years and older. Objective: To inform the choice of first-line drugs in clinical practice and assess the safety and efficacy of ICI-chemotherapy combination treatment in older adult patients with previously untreated advanced NSCLC. Design, Setting, and Participants: This retrospective cohort study included 58 centers in Japan. The cohort consisted of patients 75 years and older with clinical stage IIIB, IIIC, IV, postoperative or radiotherapy recurrent NSCLC. Patients started first-line systemic therapy between December 2018 and March 2021. Those receiving first-line molecular targeted drugs were excluded. The data were analyzed from February 2022 to October 2022. Exposures: Systemic therapy. Main Outcomes and Measures: The main outcomes were overall survival (OS), progression-free survival (PFS), and safety. Results: A total of 1245 patients (median [range] age, 78 [75-95] years; 967 [78%] male) with NSCLC were included in the cohort. Programmed death ligand-1 (PD-L1) expression of less than 1% occurred in 268 tumors (22%); 1% to 49% in 387 tumors (31%); 50% and higher in 410 tumors (33%), and unknown expression in 180 tumors (14%). Median OS was 20.0 (95% CI, 17.1-23.6) months for the 354 patients receiving ICI-chemotherapy (28%); 19.8 (95% CI, 16.5-23.8) months for the 425 patients receiving ICI alone (34%); 12.8 (95% CI, 10.7-15.6) months for the 311 patients receiving platinum-doublet chemotherapy (25%); and 9.5 (95% CI, 7.4-13.4) months for the 155 patients receiving single-agent chemotherapy (12%). After propensity score matching, no differences in OS and PFS were found between the patients receiving ICI-chemotherapy vs ICI alone. Each group consisted of 118 patients. For PD-L1 expression of 1% and higher the OS hazard ratio (HR) was 0.98 (95% CI, 0.67-1.42; P = .90), and the PFS HR was 0.92 (95% CI, 0.67-1.25; P = .59). Significance was also not reached when separately analyzed for lower or higher PD-L1 expression (1%-49% or ≥50%). However, grade 3 or higher immune-related adverse events occurred in 86 patients (24.3%) treated with ICI-chemotherapy and 76 (17.9%) with ICI alone (P = .03). Conclusions and Relevance: In this study, ICI-chemotherapy combination treatment did not improve survival and increased the incidence of grade 3 and higher immune-related adverse events compared with ICI alone in patients 75 years and older. Based on these results, ICI alone may be recommended for older adult patients with PD-L1-positive NSCLC.

Prophylactic pegfilgrastim reduces febrile neutropenia in ramucirumab plus docetaxel after chemoimmunotherapy in advanced NSCLC: post hoc analysis from NEJ051.

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.

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.

Risk Factors for Bleeding Events in Japanese Patients with Advanced Lung Cancer: Data from the Rising-VTE/NEJ037 Study.

Despite the occurrence of various hemorrhagic events during advanced lung cancer treatment, few researchers have reported on their risk factors. Moreover, the development of cancer-related thromboembolism indicates anticoagulant use. However, adverse events such as bleeding should be monitored. In this study, we aimed to identify factors that influence the onset of hemorrhagic events in patients with lung cancer. The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study. A total of 1008 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Multivariate analysis using a Cox proportional hazard model was performed to compare the outcomes of the time to the onset of hemorrhagic events for 2 years after registration. Hemorrhagic events occurred in 115 patients (11.4%), with 35 (30.4%) experiencing major bleeding. Significant risk factors included venous thromboembolism (VTE) (hazard ratio [HR]: 4.003, p < 0.001) and an Eastern Cooperative Oncology Group Performance Status score of 1 (HR: 2.476, p < 0.001). Factors that significantly reduced hemorrhagic event risk were female sex (HR: 0.454, p = 0.002) and M1a status (HR: 0.542, p = 0.038). VTE is a risk factor for hemorrhagic events in patients with advanced lung cancer, and risks associated with anticoagulant therapy should be considered.

Extended ICI treatment after first-line chemoimmunotherapy could predict the clinical benefit of ramucirumab plus docetaxel in advanced non-small lung cancer: Post hoc analysis from NEJ051 (REACTIVE study).

BACKGROUND: The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. RESULTS: Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. CONCLUSION: Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC.

Analysis of non-alcoholic fatty liver disease during induction therapy for B-cell precursor acute lymphoblastic leukemia in children and adolescents.

BACKGROUND: A prospective evaluation of non-alcoholic fatty liver disease (NAFLD) during induction therapy for acute lymphoblastic leukemia (ALL) has not been performed. Herein, we prospectively investigated the frequency, risk factors, and outcomes of NAFLD during induction therapy in children and adolescents with B-cell precursor ALL (BCP-ALL). METHODS: This study enrolled 74 newly diagnosed BCP-ALL cases aged 1 year and older who were admitted to our department between January 2011 and December 2020. Median age was 6.6 years (1.3-17.5 years). Plain computed tomography (CT) of the upper abdomen was performed before induction therapy, and on days 15 and 29 after initiation of induction therapy. Patients with a liver/spleen CT ratio <0.9 were defined as having NAFLD. RESULTS: The frequency of NAFLD was 73%. Patients with NAFLD had a higher rate of hypertriglyceridemia. There was no significant difference in 5-year overall survival and event-free survival (EFS) between patients with and without NAFLD. However, after restricting the target age to 10 years and older, 5-year EFS was significantly higher in patients with NAFLD than in those without (88.5 vs. 42.9%, respectively, P = 0.037). Similarly, 5-year cumulative incidence of relapse (CIR) was significantly lower in patients with NAFLD than in those without it (5-year CIR, 6.3 vs. 57.1%, respectively, P = 0.013). CONCLUSION: Patients with NAFLD exhibit better outcomes including 5-year EFS and CIR. Further studies are necessary.

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.

A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study).

INTRODUCTION: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR-mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR-mutated NSCLC patients after TKI treatment. METHODS: Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. RESULTS: Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7-8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). CONCLUSIONS: Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR-mutated NSCLC patients.

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.