Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Treatment-related adverse events of combination chemoimmunotherapy versus chemotherapy alone in first-line treatment for non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials.

Background: Numerous meta-analyses have examined immunotherapy-induced adverse events (AEs) in non-small cell lung cancer (NSCLC). However, there is limited research comparing AEs from combination chemoimmunotherapy versus chemotherapy alone in the first-line NSCLC treatment, particularly regarding specific toxic symptoms and hematological toxicities associated with the addition of immune checkpoint inhibitors (ICIs). Methods: We conducted a meta-analysis of randomized clinical trials (RCTs) comparing ICIs + non-ICIs versus non-ICIs alone as first-line therapy in NSCLC, sourced from PubMed and Scopus databases. Our objective was to assess treatment-related AEs in both regimens, focusing on identifying the more prevalent toxic symptoms and hematological toxicities with ICI treatment. We calculated the relative risks (RRs) and 95% confidence intervals (CIs), and estimated the pooled RRs and 95% CIs using common- or random-effects models. Results: Our analysis included 10 trials with 6,008 patients. Combination chemoimmunotherapy significantly increased the risk of grade 3 or higher treatment-related AEs, treatment discontinuation, and deaths due to treatment-related AEs. Moreover, patients receiving combination chemoimmunotherapy had a significantly higher risk of certain toxic symptoms (all-grade: vomiting, diarrhea, and constipation; high-grade: fatigue and diarrhea) and pneumonitis (both all-grade and high-grade). Conclusions: These findings offer crucial insights into the toxicity profile of combination chemoimmunotherapy, serving as a valuable resource for clinicians managing lung cancer care.

MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC.

INTRODUCTION: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance. METHODS: H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity. RESULTS: We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs. CONCLUSIONS: Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.

Impact of Neoadjuvant Immune Checkpoint Inhibitors on Surgery and Perioperative Complications in Patients With Non-small-cell Lung Cancer: A Systematic Review.

Several clinical trials are currently underway to evaluate immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for patients with early-stage non-small-cell lung cancer (NSCLC), and their use in clinical practice is expected to increase in the future. Therefore, a proper assessment of surgical outcomes and perioperative complications after neoadjuvant ICIs is essential to establish recommendations and guidelines. We performed a systematic literature review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA), searching the PubMed and Scopus databases from the January 1, 2017, to the July 27, 2023, to identify potentially relevant published trials of neoadjuvant ICIs in patients with reseactable NSCLC with available information on surgical outcomes and perioperative complications. A total of 18 studies were included in the review. The rates of surgery cancellation ranged from 0% to 45.8%. Importantly, adverse events (AEs) were the least reported underlying cause, while disease progression caused from 0% to 75% of cancellations. Surgery delays ranged from 0% to 31.3% with AEs as the most frequently reported underlying cause. However, 6 out of 13 trials (46.2%) reported no surgery delays. Conversion rates from minimally invasive to open chest surgery were available for 7 trials and ranged from 0% to 53.8%. Thirty-day mortality rates ranged from 0% to 5.4%, with 11 out of 16 trials reporting 0%. A few reports described perioperative complications in detail. Considering the limited evidence available, we can preliminarily confirm that preoperative ICIs are safe and well tolerated even from the surgical perspective. Additional details on intraoperative findings from prospective controlled trials are needed to establish and disseminate guidelines and recommendations for thoracic surgeons.

Granzyme B (GZMB)-Positive Tumor-Infiltrating Lymphocytes in Lung Adenocarcinoma: Significance as a Prognostic Factor and Association with Immunosuppressive Proteins.

BACKGROUND: Granzyme B (GZMB) is a serine protease produced by cytotoxic lymphocytes that reflects the activity of anti-tumor immune responses in tumor-infiltrating lymphocytes (TILs); however, the prognostic significance of GZMB+ TILs in lung adenocarcinoma is poorly understood. METHODS: We analyzed 273 patients with pathological stage (pStage) I-IIIA lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We evaluated GZMB+ TIL counts by immunohistochemistry. We set the cut-off values at 12 cells/0.04 mm2 for GZMB+ TILs and divided the patients into GZMB-High (n = 171) and GZMB-Low (n = 102) groups. Then, we compared the clinicopathological characteristics of the two groups and clinical outcomes. Programmed cell death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumor cells was also evaluated, and combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 were performed. RESULTS: GZMB-Low was significantly associated with pStage II-III, PD-L1 positivity, and IDO1 positivity. Disease-free survival (DFS) and overall survival (OS) in the GZMB-Low group were significantly worse than in the GZMB-High group. In multivariable analysis, GZMB-Low was an independent prognostic factor for both DFS and OS. Furthermore, combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 showed that GZMB-Low with high expression of these immunosuppressive proteins had the worst prognosis. CONCLUSIONS: We analyzed GZMB+ TIL counts in lung adenocarcinoma and elucidated its prognostic significance and association with PD-L1 and IDO1. GZMB+ TIL counts might reflect the patient's immunity against cancer cells and could be a useful prognostic marker of lung adenocarcinoma.

Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small-cell lung cancer patients.

BACKGROUND: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy. MATERIALS AND METHODS: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17. RESULTS: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51-0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32-0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively). CONCLUSION: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

Combination Antiemetic Therapy for Chemotherapy-Induced Nausea and Vomiting in Patients with NSCLC Receiving Carboplatin-Based Chemotherapy.

Purpose: The incidence of delayed chemotherapy-induced nausea and vomiting (CINV) in patients with non-small cell lung cancer (NSCLC) receiving carboplatin (CBDCA)-based chemotherapy (CBDCA + pemetrexed or paclitaxel) has not been clearly described. Therefore, we attempted to evaluate whether delayed CINV could be controlled using a combination of three antiemetics and identify individual risk factors. Methods: We pooled data from two prospective observational studies, namely a nationwide survey of CINV and a prospective, observational study in Japan, to assess whether delayed CINV could be controlled using a combination of three antiemetics and identified individual risk factors via inverse probability treatment-weighted analysis. Results: In total, 240 patients were evaluable in this study (median age, 66 years; male, 173; female, 67). The three-antiemetic regimen controlled delayed nausea (31.6% vs 47.3%) and vomiting (5.1% vs 23.1%) better than two antiemetics. Younger age (<70 years; odds ratio [OR] = 2.233), motion sickness (OR = 3.472), drinking habits (OR = 1.972), receipt of the CBDCA + pemetrexed regimen (OR = 2.041), and the use of two antiemetics (OR = 1.926) were risk factors for delayed nausea. Female sex (OR = 3.372), drinking habits (OR = 2.272), receipt of the CBDCA+ pemetrexed regimen (OR = 2.314), and the use of two antiemetics (OR = 6.830) were risk factors for delayed vomiting. Conclusion: Female sex, younger age, and receipt of the CBDCA + pemetrexed regimen increased the risk of CINV. Therefore, we recommend additional supportive antiemetics treatment for these patients.

Association between sex and outcomes in patients with non-small-cell lung cancer receiving combination chemoimmunotherapy as a first-line therapy: a systematic review and meta-analysis of randomized clinical trials.

INTRODUCTION: Recently, several meta-analyses have investigated the association between sex and the efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC). However, this issue remains controversial, because the results have been inconsistent. Moreover, the effect of sex on outcomes in patients with NSCLC receiving combination chemoimmunotherapy as a first-line therapy is poorly understood. The aim of this study was to examine the association between sex and outcomes in patients with NSCLC receiving combination chemoimmunotherapy as a first-line therapy. METHODS: We searched PubMed and Scopus from database inception to Feb 18, 2022 and performed a systematic review and meta-analysis of randomized and controlled clinical trials investigating ICI+non-ICI vs non-ICI as a first-line therapy in NSCLC. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) in male and female patients were calculated using common and random-effects models. RESULTS: We analyzed 5,830 patients, comprising 4,137 (71.0%) males and 1,693 (29.0%) females, from nine randomized clinical trials. The pooled HR (95%CI) for OS comparing ICI+non-ICI vs non-ICI was 0.80 (0.72-0.87) for males and 0.69 (0.54-0.89) for females. The pooled HR (95%CI) for PFS comparing ICI+non-ICI vs non-ICI was 0.60 (0.55-0.66) for males and 0.56 (0.44-0.70) for females. CONCLUSIONS: In patients with NSCLC receiving combination chemoimmunotherapy as a first-line therapy, a greater improvement in OS and PFS was observed in female patients than in male patients.

Antibiotic-dependent effect of probiotics in patients with non-small cell lung cancer treated with PD-1 checkpoint blockade.

BACKGROUND: We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. MATERIALS AND METHODS: We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. RESULTS: Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53-0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52-0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54-0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54-0.69). CONCLUSIONS: Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

Relationship between consolidation tumor ratio and tumor-infiltrating lymphocytes in small-sized lung adenocarcinoma.

BACKGROUND: Consolidation tumor ratio (CTR) is associated with cancer progression and histological invasiveness in lung adenocarcinoma (LAD). However, little is known about the association between CTR and immune-related factors, including tumor-infiltrating lymphocytes (TILs) density or tumor expression of programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) in small-sized LAD. METHODS: This study included 258 patients with LAD (<3 cm) who underwent surgery. Patients were assigned to four groups: CTR = 0; 0 < CTR <0.5; 0.5 ≤ CTR <1 (ground-glass opacity [GGO] group); and CTR = 1 (pure-solid group). CD4+ , CD8+ , and FoxP3+ TIL density and PD-L1 and IDO1 tumor expression were assessed by immunohistochemistry. RESULTS: Among the GGO group, CD8+ and FoxP3+ TIL density increased significantly with increasing CTR (p < 0.001 and p < 0.001, respectively). Moreover, PD-L1 and IDO1 expression was significantly higher in the pure-solid group than in the GGO group (p < 0.001 and p < 0.001, respectively). CONCLUSIONS: CTR was correlated with the abundance of CD8+ and FoxP3+ TILs in the GGO group. PD-L1 and IDO1 positivity rates were significantly higher in the pure-solid group than in the GGO group. Increased CTR may be correlated with immunosuppressive condition.

A propensity score-matched analysis of the impact of statin therapy on the outcomes of patients with non-small-cell lung cancer receiving anti-PD-1 monotherapy: a multicenter retrospective study.

BACKGROUND: Many studies have recently reported the association of concomitant medications with the response and survival in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy. However, the clinical impact of statin therapy on the outcome of cancer immunotherapy in patients with NSCLC is poorly understood. METHODS: In our database, we retrospectively identified and enrolled 390 patients with advanced or recurrent NSCLC who were treated with anti-programmed cell death-1 (PD-1) monotherapy in clinical practice between January 2016 and December 2019 at 3 medical centers in Japan to examine the clinical impact of statin therapy on the survival of patients with NSCLC receiving anti-PD-1 monotherapy. A propensity score-matched analysis was conducted to minimize the bias arising from the patients' backgrounds. RESULTS: The Kaplan-Meier curves of the propensity score-matched cohort showed that the overall survival (OS), but not the progression-free survival (PFS), was significantly longer in patients receiving statin therapy. However, a Cox regression analysis in the propensity score-matched cohort revealed that statin therapy was not an independent favorable prognostic factor, although it tended to be correlated with a favorable outcome. CONCLUSIONS: Statin therapy may be a combination tool for cancer immunotherapy in patients with NSCLC. These findings should be validated in further prospective studies with larger sample sizes.

The clinical impact of concomitant medication use on the outcome of postoperative recurrent non-small-cell lung cancer in patients receiving immune checkpoint inhibitors.

A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan-Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study.

A case of successful conversion surgery for locally advanced pancreatic cancer with synchronous triple cancer of the lung and esophagus: a case report.

BACKGROUND: The number of reports of multiple primary cancer (MPC) is increasing because of the advancement in diagnostic imaging technology. However, the treatment strategy for MPCs involving pancreatic cancer is controversial because of the extremely poor prognosis. We herein report a patient with synchronous triple cancer involving the pancreas, esophagus, and lung who underwent conversion surgery after intensive chemotherapy for unresectable locally advanced pancreatic cancer. CASE PRESENTATION: A 59-year-old man was admitted to our hospital with epigastric pain, anorexia, and weight loss. Computed tomography and upper gastrointestinal endoscopy revealed that the patient had synchronous triple cancer of the pancreas, esophagus, and lung. While the esophageal and lung cancer were relatively non-progressive, the pancreatic tail cancer had invaded the aorta, celiac axis, and left kidney, and the patient was diagnosed with unresectable locally advanced disease. Because the described lesion could have been the prognostic determinant for this patient, we initiated intensive chemotherapy (gemcitabine plus nab-paclitaxel) for pancreatic cancer. After six courses of chemotherapy, the tumor size shrank remarkably and no invasion to the aorta or celiac axis was observed. No significant changes were observed in the esophageal and lung cancers; endoscopic submucosal dissection could be still a curative treatment for the esophageal cancer. Therefore, we performed curative resection for pancreatic cancer (distal pancreatomy, splenectomy, and left nephrectomy; ypT3N0cM0, ypStage IIA, UICC 8th). Pathologically, complete resection was achieved. The patient then underwent endoscopic submucosal dissection for early esophageal cancer (pT1a[M]-LPM) and video-assisted thoracoscopic right upper lobectomy in combination with right lower partial resection for early lung cancer (pT2aN0M0, pStage IB, UICC 8th). Eight months after pancreatic cancer surgery, the patient is alive and has no sign of recurrence; as a result of the successful treatment, the patient has a good quality of life. CONCLUSIONS: Treatment of MPC is challenging, especially for cases with unresectable tumors. Although synchronous triple cancer can involve unresectable pancreatic cancer, radical resection may be possible after careful assessment of the appropriate treatment strategy and downstaging of unresectable tumors.