The Tumor Immune Microenvironment Is Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

Multicenter, Retrospective Study to Evaluate Necitumumab Plus Cisplatin and Gemcitabine After Immune Checkpoint Inhibitors in Advanced Squamous Cell Lung Cancer in Japan: The NINJA Study.

Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Importance: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. Objective: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. Design, Setting, and Participants: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. Main Outcomes and Measures: The primary end point was the biomarker testing status. Treatment-related factors were examined. Results: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. Conclusions and Relevance: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Long-term outcome of patients with peripheral ground-glass opacity-dominant lung cancer after sublobar resections.

OBJECTIVE: This study aimed to evaluate the long-term prognosis of patients with peripheral small ground-glass opacity-dominant lung cancer after sublobar resection. We have already reported the 5-year safety and efficacy of sublobar resection and report the long-term outcomes after a 10-year follow-up period. METHODS: Between May 2009 and April 2011, 333 patients with radiologically noninvasive peripheral lung cancer were enrolled from 51 institutions (median age, 62 years at registration) and followed up until May 6, 2021. Of these patients, sublobar resections with wedge resection as the first choice were performed in 314 patients (258 wedge resections and 56 segmentectomies), conversion lobectomies were performed in 11 patients, and 8 patients were ineligible. RESULTS: The 10-year relapse-free survival and overall survival for the 314 patients with sublobar resections were 98.6% (95% confidence interval, 96.2-99.5) and 98.5% (95% confidence interval, 96.1-99.4), respectively. There was 1 local recurrence at the resection margin. Among the patients, second cancers were observed in 43 patients (13.4%; 95% confidence interval, 9.8-17.6), of which 18 were second lung cancers (5.8%; 95% confidence interval, 3.5-8.9). CONCLUSIONS: Peripheral ground-glass opacity-dominant lung cancer is cured by sublobar resection, with wedge resection as the first choice, and the indications for other treatment options should be further investigated. The incidence of second cancer is similar to that in the general Japanese population.

Prognostic Impact of Central Nervous System Recurrence After Surgery in Patients With Epidermal Growth Factor Receptor Mutation-positive Non-small-cell Lung Cancer.

BACKGROUND/AIM: Adjuvant therapy using third-generation tyrosine kinase inhibitors (TKI) demonstrated improved central nervous system (CNS) disease-free survival after surgery in patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, the prognostic impact of CNS recurrence in surgical patients remains unknown. We evaluated the effect of CNS recurrence on post-recurrence survival (PRS) in patients with postoperatively recurrent NSCLC. PATIENTS AND METHODS: We assessed the prognostic impact of CNS recurrence using a cohort from a prospective observational study (Kyushu University Lung Surgery Group Study 2: KLSS-2). Based on data from 340 patients in whom EGFR mutations were assessed among 498 total patients in the KLSS-2 cohort, factors related to CNS recurrence and prognosis after postoperative recurrence were analyzed. RESULTS: We noted no marked differences in the presence of EGFR mutations (p=0.14) between patients with CNS recurrence and those without CNS recurrence. Among the patients tested for EGFR mutations with stage IV recurrences (n=219), survival analysis of patients with EGFR mutations showed that the CNS group had a significantly poorer PRS than the no-CNS group (MST: 36.8 vs. 43.9 months, p=0.035). In multivariate survival analysis of stage IV EGFR mutation-positive cases, recurrence in multiple organs and recurrence of brain metastases were independent poor prognostic factors (hazard ratio=2.2, p=0.029; hazard ratio=3.2, p=0.0006, respectively). CONCLUSION: Postoperative CNS recurrence was associated with a poor prognosis among patients with EGFR mutation-positive lung cancer in the period when third-generation EGFR-TKIs were not available. In EGFR mutation-positive lung cancer, prevention of CNS recurrence after surgery may improve post-recurrence prognosis.

Is radical local therapy effective in postoperative recurrent EGFR-mutated non-small cell lung cancer?

BACKGROUND: Long-term survival can be achieved with radical local therapy in some cases of postoperative recurrence of non-small cell lung cancer (NSCLC). Here, we evaluated post-recurrence survival (PRS) after treatment of postoperative recurrent epidermal growth factor receptor (EGFR) mutated NSCLC and examined the effectiveness of radical local therapy. METHODS: This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor-related variables, primary surgery, and treatment for recurrence was collected. After registration, follow-up data (e.g., treatment and survival outcomes) were obtained and analyzed. RESULTS: From 2010 to 2015, 505 patients with recurrent NSCLC were enrolled into the study, and 154 EGFR mutation-positive cases were included. As the initial treatment for recurrence, 111 patients (72%) received chemotherapy, 14 (9%) received chemoradiotherapy, 14 (9%) received definitive radiotherapy, and seven (5%) received surgical resection. The remaining eight patients (5%) received supportive care. The median PRS and 5-year survival rates for all cases were 64 months and 53.2%, respectively. The 5-year survival rate according to the initial treatment was as follows: supportive care, 0%; chemotherapy, 53.3% and radical local therapy, 60.1%. The six patients who received radical local treatment remained recurrence-free for more than 3 years after recurrence with only initial treatment. CONCLUSIONS: Although radical local therapy may be curative in some patients, chemotherapy including EGFR-TKI treatment is expected to provide long-term survival comparable to that of radical local therapy.

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.

Prognostic impact of noninvasive areas in resected pathological stage IA lung adenocarcinoma.

MAIN PROBLEMS: In non-small-cell lung cancer, ground-glass opacity on computed tomography imaging reflects pathological noninvasiveness and is a favorable prognostic factor. However, the significance of pathological noninvasive areas (NIAs) has not been fully revealed. In this study, we aimed to elucidate the prognostic impact of NIAs on lung adenocarcinoma. METHODS: We analyzed 402 patients with pathological stage (p-Stage) IA lung adenocarcinoma who underwent surgery in 2013-2016 at two institutions and examined the association of the presence of NIAs with clinicopathological factors and prognosis. Furthermore, after using propensity-score matching to adjust for clinicopathological factors, such as age, sex, smoking history, pathological invasive area size, pathological T factor (p-T), p-Stage, and histological subtype (lepidic predominant adenocarcinoma [LPA] or non-LPA), the prognostic impact of NIAs was evaluated. RESULTS: Patients were divided into NIA-present (N = 231) and NIA-absent (N = 171) groups. Multivariable analysis showed that NIA-present was strongly associated with earlier p-T, earlier p-Stage, LPA, and epidermal growth factor receptor mutation. Kaplan-Meier survival analysis showed that the NIA-present group displayed a better prognosis than the NIA-absent group in disease-free survival (DFS) and overall survival (OS) (5-year DFS 94.6% vs. 87.2%, 5-year OS 97.2% vs. 91.1%). However, after adjusting for clinicopathological factors by propensity score matching, no significant differences in prognosis were identified between the NIA-present and NIA-absent groups (5-year DFS 92.4% vs 89.6%, 5-year OS 95.6% vs 94.3%). CONCLUSIONS: Our current study suggests that the prognostic impact of the presence of NIAs on lung adenocarcinoma is due to differences in clinicopathological factors.

The efficacy of thoracoscopic surgery for descending necrotizing mediastinitis.

OBJECTIVES: Thoracotomy is a reliable approach for descending necrotizing mediastinitis (DNM), and the use of video-assisted thoracic surgery (VATS), a minimally invasive procedure, has been increasing. However, which approach is more effective for DNM treatment is controversial. METHODS: We analysed patients who underwent mediastinal drainage via VATS or thoracotomy, using a database with DNM from 2012 to 2016 in Japan, which was constructed by the Japanese Association for Chest Surgery and the Japan Broncho-esophagological Society. The primary outcome was 90-day mortality, and the adjusted risk difference between the VATS and thoracotomy groups using a regression model, which incorporated the propensity score, was estimated. RESULTS: VATS was performed on 83 patients and thoracotomy on 58 patients. Patients with a poor performance status commonly underwent VATS. Meanwhile, patients with infection extending to both the anterior and posterior lower mediastinum frequently underwent thoracotomy. Although the postoperative 90-day mortality was different between the VATS and thoracotomy groups (4.8% vs 8.6%), the adjusted risk difference was almost the same, -0.0077 with 95% confidence interval of -0.0959 to 0.0805 (P = 0.8649). Moreover, we could not find any clinical and statistical differences between the 2 groups in terms of postoperative 30-day and 1-year mortality. Although patients who underwent VATS had higher postoperative complication (53.0% vs 24.1%) and reoperation (37.9% vs 15.5%) rates than those who underwent thoracotomy, the complications were not serious and most could be treated with reoperation and intensive care. CONCLUSIONS: The outcome of DNM treatment does not depend on thoracotomy or VATS.

Skeletal muscle area predicts the outcomes of non-small-cell lung cancer after trimodality therapy.

OBJECTIVES: Sarcopenia correlates with poor prognosis in various malignancies. However, the prognostic significance of sarcopenia remains to be determined in patients with non-small-cell lung cancer who undergo surgery after receiving neoadjuvant chemoradiotherapy (NACRT). METHODS: We retrospectively reviewed the patients with stage II/III non-small-cell lung cancer who underwent surgery following NACRT. The paravertebral skeletal muscle area (SMA) (cm2) at the 12th thoracic vertebra level was measured. We calculated the SMA index (SMAI) as SMA/squared height (cm2/m2). Patients were divided into low and high SMAI groups, and the association of SMAI with clinicopathological factors and prognosis was assessed. RESULTS: The patients' [men, 86 (81.1%)] median age was 63 (21-76) years. There were 106 patients including 2 (1.9%), 10 (9.4%), 74 (69.8%), 19 (17.9%) and 1 (0.9%) patients with stage IIA, IIB, IIIA, IIIB and IIIC, respectively. Of the patients, 39 (36.8%) and 67 (63.2%) were classified in the low and the high SMAI groups, respectively. Kaplan-Meier analysis showed that the low group had a significantly shorter overall survival and disease-free survival than the high group. Multivariable analysis identified low SMAI as an independent poor prognostic factor for overall survival. CONCLUSIONS: Pre-NACRT SMAI correlates with poor prognosis; therefore, assessing sarcopenia based on pre-NACRT SMAI may help determine optimal treatment strategies and suitable nutritional and exercise interventions.

Overall survival analysis of patients enrolled in a randomized phase III trial comparing gefitinib and erlotinib for previously treated advanced lung adenocarcinoma (WJOG5108LFS).

BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.

Necitumumab plus gemcitabine and cisplatin in previously treated lung squamous cell carcinoma.

BACKGROUND: The efficacy and safety of the anti-EGFR antibody necitumumab combined with gemcitabine and cisplatin (N + GC) in the first-line treatment of advanced lung squamous cell carcinoma (LSCC) have been proven. However, the efficacy and safety of N + GC in the second line or later treatment remain unclear. METHODS: Eleven patients who received N + GC for advanced-stage or recurrent LSCC were enrolled. We retrospectively assessed the patients' clinical characteristics and efficacy and safety of treatment. RESULTS: The median patient age was 73 years (range, 63-77 years). The cohort included nine (81.8%) men and two (18.2%) women. Two (18.2%) patients had postoperative recurrence, and one (9.1%), three (27.3%), one (9.1%), and four (36.4%) patients were diagnosed with stage IIIA, IIIB, IVA, and IVB disease, respectively. Concerning the best overall response, partial response was achieved in five (45.5%) patients, four (36.4%) patients displayed stable disease, and two (18.2%) patients were not evaluable. Median progression-free survival was 6.8 months (range, 1.4-10.3 months). The grade 3 or higher neutropenia, thrombocytopenia, and anemia occurred in six (54.5%), three (27.3%), and two (18.2%) patients, respectively. Additionally, grade 3 skin reaction, rash, lung infection, duodenal ulcer, and febrile neutropenia were observed in one (9.1%) patient each. Two (18.2%) patients required treatment interruption because of adverse events. CONCLUSION: N + GC displayed good efficacy in the second line or later treatment among patients with LSCC. This study suggested that N + GC is a useful option even after second-line treatment of advanced-stage or recurrent LSCC, although the management of adverse events is essential.

Early chest tube removal regardless of drainage volume after anatomic pulmonary resection: A multicenter, randomized, controlled trial.

OBJECTIVES: This study aimed to evaluate the safety and feasibility of early chest tube removal after anatomic pulmonary resection, regardless of the drainage volume. METHODS: We conducted a multicenter, randomized, controlled, noninferiority trial. Patients with greater than 300 mL drainage volume during postoperative day 1 were randomly assigned to group A (tube removed on postoperative day 2) and group B (tube retained until drainage volume ≤300 mL/24 hours). The primary end point was the frequency of respiratory-related adverse events (grade 2 or higher based on the Clavien-Dindo classification) within 30 days postoperatively. RESULTS: Between April 2019 and October 2021, 175 patients were assigned to group A (N = 88) or group B (N = 87). One patient in group B who experienced chylothorax was excluded from the study. Respiratory-related adverse events were observed in 10 patients (11.4%) in group A and 12 patients (14.0%) in group B (P = .008). The frequencies of thoracentesis or chest tube reinsertion were not significantly different (8.0% and 9.3% in groups A and B, respectively, P = .752). Additionally, the duration of chest tube placement was significantly shorter in group A than in group B (median, 2 vs 3 days; P < .001). No significant difference between groups A and B was found in postoperative hospital stay (median, 6 vs 7 days, P = .231). CONCLUSIONS: Early chest tube removal, regardless of drainage volume, was safe and feasible in patients who underwent anatomic pulmonary resection.

Gut microbiota diversity and specific composition during immunotherapy in responders with non-small cell lung cancer.

Cancer immunotherapy including immune checkpoint inhibitors (ICI) has revolutionized non-small cell lung cancer (NSCLC) therapy. Recently, the microbiota status "before" initiation of ICI therapy has been emphasized as a predictive biomarker in patients undergoing ICI therapy. However, the microbiota diversity and composition "during" ICI therapy is unknown. This multicenter, prospective observational study analyzed both saliva and feces from 28 patients with NSCLC. We performed 16S ribosomal RNA gene sequencing, then analyzed associations of oral and gut microbiota diversity or composition with ICI response. At the genus level, the alpha diversity of the gut microbiota was significantly greater in responders (n = 17) than in non-responders (n = 11) (Chao 1, p = 0.0174; PD whole tree, p = 0.0219; observed species, p = 0.0238; Shannon, p = 0.0362), while the beta diversity of the gut microbiota was significantly different (principal coordinates analysis, p = 0.035). Compositional differences in the gut microbiota were observed between the two groups; in particular, g_Blautia was enriched in responders, whereas o_RF32 order unclassified was enriched in non-responders. The progression-free survival (PFS) of patients enriched gut microbiota of g_Blautia was significantly longer [median survival time (MST): not reached vs. 549 days, p = 0.0480] and the PFS of patients with gut microbiota of o_RF32 unclassified was significantly shorter (MST: 49 vs. 757 days, p = 0.0205). There were no significant differences between groups in the oral microbiota. This study revealed a strong association between gut microbiota diversity and ICI response in NSCLC patients. Moreover, specific gut microbiota compositions may influence the ICI response. These findings might be useful in identifying biomarkers to predict ICI response.

Case report: Success of tepotinib therapy in overcoming resistance to osimertinib in a patient with EGFR-mutant lung adenocarcinoma with a potential acquired MET exon 14 skipping mutation.

Osimertinib is a standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor gene (EGFR) mutations, but most patients with EGFR-mutant NSCLC develop secondary resistance to osimertinib. Mesenchymal-epithelial transition gene (MET) alterations and oncogene fusions have been identified as the most common mechanisms of resistance to osimertinib. However, MET exon 14 skipping mutation (METex14del) as an acquired resistance to osimertinib has rarely been reported. A non-smoking 76-year-old woman was diagnosed with lung adenocarcinoma in the right lower lobe (cT2bN2M1c [pulmonary and bone metastases], cStage IVB). The primary tumor was submitted to cobas® EGFR Mutation Test v2 (Roche Diagnostics Ltd.), next generation sequencing (Oncomine Comprehensive Assay v3; Thermo Fisher Scientific), the AmoyDx® Essential NGS panel (Amoy Diagnostics, Xiamen, China), all of which were positive for EGFR L858R and de novo T790M. We administered daily osimertinib (80 mg/day), and achieved a partial response. However, after 14.0 months, computed tomography showed progression of the primary tumor and lung metastases. Re-biopsy of the primary tumor was conducted, and the specimen was submitted to Archer®MET companion diagnostic for detection of METex14del. Although the primary tumor was negative for METex14del, the re-biopsy specimen was positive for METex14del. We validated that the biopsy specimen of the primary tumor at diagnosis before osimertinib administration was negative for METex14del using local reverse transcription PCR. We administered daily tepotinib (500 mg/day) to the patient as a further-line treatment, and achieved a partial response (tumor shrinkage rate: 34.5%) after 2.0 months, who responded to tepotinib therapy for 8.0 months. We described a patient with lung adenocarcinoma harboring METex14del as a potential acquired resistance to osimertinib, who responded to subsequent tepotinib therapy. Re-biopsy and re-analysis of genetic profiles should be considered in NSCLC patients who develop osimertinib resistance.

Chronological analysis of the gut microbiome for efficacy of atezolizumab-based immunotherapy in non-small cell lung cancer: Protocol for a multicenter prospective observational study.

BACKGROUND: Cancer immunotherapy with immune checkpoint inhibitors (ICIs) is an innovative treatment for non-small cell lung cancer (NSCLC). Recently, the specific composition of the gut microbiome before initiation of cancer immunotherapy has been highlighted as a predictive biomarker in patients undergoing cancer immunotherapy, mainly in the US or Europe. However, the fact gut microbiome status is completely different in races or countries has been revealed. In addition, how the microbiome composition and diversity chronologically change during cancer immunotherapy is still unclear. METHODS: This multicenter, prospective observational study will analyze the association between the gut microbiome and therapeutic response in NSCLC patients who received atezolizumab-based immunotherapy. The aim of the present study is to clarify not only how the specific composition of the gut microbiome influences clinical response in NSCLC patients but the chronological changes of gut microbiota during atezolizumab-based immunotherapy. The gut microbiota will be analyzed using 16S rRNA gene sequencing. The main inclusion criteria are as follows: (1) Pathologically- or cytologically-confirmed stage IV or postoperative recurrent NSCLC. (2) Patients ≥20 years old at the time of informed consent. (3) Planned to treat with atezolizumab-based immunotherapy combined with platinum-based chemotherapy (cohort 1) and monotherapy (cohort 2) as a first immunotherapy. (4) Patients to provide fecal samples. A total of 60 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2024. DISCUSSION: This trial will provide more evidence of how gut microbiota composition and diversity chronologically change during cancer immunotherapy and contribute to the development of biomarkers to predict ICI response as well as biotic therapies which enhance the ICI response.

Survival after recurrence following surgical resected non-small cell lung cancer: A multicenter, prospective cohort study.

Objectives: The optimal treatment for recurrent non-small cell lung cancer (NSCLC) has not been standardized. In this prospective cohort study, we evaluated post-recurrence survival (PRS) after treatment of recurrent NSCLC and identified prognostic factors after recurrence. Methods: This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor-related variables, primary surgery, and treatment for recurrence was collected. After registration, follow-up data, such as treatment and survival outcomes, were obtained every 3 months. Results: From 2010 to 2015, 505 cases were enrolled, and 495 cases were analyzed. As initial treatment for recurrence, 263 patients (53%) received chemotherapy, 46 (9%) received chemoradiotherapy, 98 (20%) had definitive radiotherapy, 14 (3%) received palliative radiotherapy, and 31 (6%) underwent surgical resection. The remaining 43 patients (9%) received supportive care. The median PRS and 5-year survival rates for all cases were 30 months and 31.9%, respectively. The median PRS according to the initial treatment was as follows: supportive care, 8 months; palliative radiotherapy, 16 months; definitive radiotherapy, 30 months; chemotherapy, 31 months; chemoradiotherapy, 35 months; and surgery, not reached. A multivariate analysis showed that the age, gender, performance status, histology presence of symptoms, duration from primary surgery to recurrence, and number of recurrent foci were independent prognostic factors for PRS. Conclusions: The PRS of patients with recurrent NSCLC was different depending on the patient's background characteristics and initial treatment for recurrence.

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.

Artificial intelligence-derived gut microbiome as a predictive biomarker for therapeutic response to immunotherapy in lung cancer: protocol for a multicentre, prospective, observational study.

INTRODUCTION: Immunotherapy is the fourth leading therapy for lung cancer following surgery, chemotherapy and radiotherapy. Recently, several studies have reported about the potential association between the gut microbiome and therapeutic response to immunotherapy. Nevertheless, the specific composition of the gut microbiome or combination of gut microbes that truly predict the efficacy of immunotherapy is not definitive. METHODS AND ANALYSIS: The present multicentre, prospective, observational study aims to discover the specific composition of the gut microbiome or combination of gut microbes predicting the therapeutic response to immunotherapy in lung cancer using artificial intelligence. The main inclusion criteria are as follows: (1) pathologically or cytologically confirmed metastatic or postoperative recurrent lung cancer including non-small cell lung cancer and small cell lung cancer; (2) age≥20 years at the time of informed consent; (3) planned treatment with immunotherapy including combination therapy and monotherapy, as the first-line immunotherapy; and (4) ability to provide faecal samples. In total, 400 patients will be enrolled prospectively. Enrolment will begin in 2021, and the final analyses will be completed by 2024. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of each participating centre in 2021 (Kyushu Cancer Center, IRB approved No. 2021-13, 8 June 2021 and Kyushu Medical Center, IRB approved No. 21-076, 31 August 2021). Study results will be disseminated through peer-reviewed journals and national and international conferences. TRIAL REGISTRATION NUMBER: UMIN000046428.