Classification and regression tree for estimating predictive markers to detect T790M mutations after acquired resistance to first line EGFR-TKI: HOPE-002.

BACKGROUND AND OBJECTIVE: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations. METHODS: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment. RESULTS: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P < 0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P = 0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P = 0.004) and OS (1053 vs. 956 days; HR: 0.68; P = 0.051) than first-generation EGFR-TKIs. CONCLUSION: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

Durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis following concurrent chemoradiotherapy: a multicenter prospective cohort study.

Introduction/Background Durvalumab demonstrated a good efficacy and safety in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in the PACIFIC trial. Although a history of radiation pneumonitis (RP) has been reported to increase the risk of pneumonitis associated with programmed death-1 inhibitors, the safety and efficacy of durvalumab in patients with baseline Grade 1 RP have not been assessed. Therefore, we carried out a multicenter prospective cohort study to evaluate the efficacy and safety of durvalumab in these patients. Patients and Methods This was a multicenter prospective cohort study of 35 patients with Grade 1 RP after CCRT and before durvalumab initiation. This study was a first prespecified analysis for the first 20 patients with the primary objective of assessing the short-term safety; it was assessed 3 months after durvalumab initiation. Results Twenty patients were enrolled in this study between March 1, 2019, and September 3, 2019. Three patients (15%) experienced drug-related Grade ≥3 adverse events, while three patients (15%) had Grade ≥2 pneumonitis/RP within 3 months after durvalumab initiation. Three months after durvalumab initiation, all the patients were alive and four patients (20%) experienced disease progression. Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.).

Clinical factors associated with shorter durable response, and patterns of acquired resistance to first-line pembrolizumab monotherapy in PD-L1-positive non-small-cell lung cancer patients: a retrospective multicenter study.

BACKGROUND: Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. METHODS: We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. RESULTS: Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. CONCLUSIONS: Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non-small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Prediction of patients with a tumor proportion score > 50% who do not respond to first-line monotherapy with pembrolizumab.

BACKGROUND: Pembrolizumab is effective as first-line therapy against advanced non-small cell lung cancer (NSCLC) in patients with programmed death ligand-1 (PD-L1) expression levels ≥50% [1]. However, it is not effective in all patients, and the factors predicting responses among this population remain unknown. METHODS: We retrospectively analyzed patients with NSCLC and a PD-L1 tumor proportion score (TPS) > 50%, who received first-line monotherapy with pembrolizumab from February 1, 2017 to April 30, 2018. The study included 11 hospitals, which participated in the Hanshin Oncology clinical Problem Evaluation group (HOPE). We analyzed the differences between responders and non-responders in terms of age, sex, performance status score, degree of progression, histological type, smoking history, expression of PD-L1, use of steroids prior to treatment, metastasis site, and laboratory data. RESULTS: A total of 205 patients were included in this study. Of those, 108 patients exhibiting complete or partial response were defined as responders. Those exhibiting progressive disease (N = 52) were defined as non-responders. In the univariate analysis, Eastern Cooperative Oncology Group performance status score ≥ 2 (p = 0.0832), stage IV disease or recurrence (p = 0.0487), PD-L1 TPS 50-89% (p = 0.0657), use of steroids prior to the administration of pembrolizumab (p = 0.0243), malignant pleural effusion (p = 0.0032), and baseline C-reactive protein (CRP) levels > 1.0 mg/dL (p = 0.0390) were significantly associated with non-response to treatment. In the multivariate analysis, use of steroids prior to the administration of pembrolizumab (odds ratio [OR]: 5.86; 95% confidence interval [CI]: 1.32-31.8; p = 0.0200), malignant pleural effusion (OR: 2.68; 95% CI: 1.15-6.35; p = 0.0228), and baseline CRP > 1.0 mg/dL (OR: 2.17; 95% CI: 1.03-4.68; p = 0.0402) were significantly associated with non-response to treatment. CONCLUSION: In real-world patients with NSCLC and a PD-L1 TPS ≥50%, use of steroids prior to treatment, malignant pleural effusion, and baseline CRP levels > 1.0 mg/dL reduced the response of first-line monotherapy with pembrolizumab.

Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39-91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0-1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50-74%, 75-89%, and 90-100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0-1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05-2.72; p = 0.03138), CRP/Alb (<0.3 vs. ≥0.3: HR: 1.92, 95.0% CI: 1.28-2.87; p = 0.00153), steroid usage (not usage vs. usage: HR: 2.94, 95.0% CI: 1.45-5.95; p = 0.00267), and PD-L1 TPS (50-89% vs. 90-100%: HR: 0.65, 95.0% CI: 0.43-1.00; p = 0.04984) were significantly and independently correlated with PFS of pembrolizumab. Conclusion The results confirm the efficacy and safety of pembrolizumab in real-world patients. Poor PS and steroid usage at the time of commencing pembrolizumab treatment indicate poor outcomes. First-line pembrolizumab particularly benefits patients with PD-L1 TPS ≥90% or low inflammatory states (CRP/ALB<0.3).

Differential efficacy of cisplatin plus pemetrexed between L858R and Del-19 in advanced EGFR-mutant non-squamous non-small cell lung cancer.

BACKGROUND: LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R. METHODS: This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis. RESULTS: Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0-12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6-8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62-0.98) (p = 0.033). CONCLUSION: Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.

Impact of Lymphopenia Recovery After Chemoradiotherapy on Durvalumab Consolidation Therapy in Stage III NSCLC.

Introduction: Durvalumab maintenance therapy after definitive concurrent chemoradiotherapy (CRT) is the standard treatment modality for stage III NSCLC. Although severe treatment-related lymphopenia (TRL) during CRT may impair the efficacy of subsequent durvalumab therapy, data on the effect of TRL recovery on consolidation durvalumab therapy are lacking. Methods: This retrospective study evaluated patients with unresectable stage III NSCLC treated with durvalumab after concurrent CRT. The patients were enrolled across nine institutes throughout Japan between August 2018 and March 2020. The effect of TRL recovery on survival was evaluated. The patients were divided into two groups on the basis of their lymphocyte recovery status: the recovery group involved patients who did not experience severe TRL or experienced TRL but exhibited lymphocyte count recovery at durvalumab initiation, and the nonrecovery group involved patients who experienced severe TRL and did not exhibit lymphocyte count recovery on durvalumab initiation. Results: Among the 151 patients evaluated, 41 (27%) and 110 (73%) patients were classified into the recovery and the nonrecovery groups, respectively. The nonrecovery group had significantly worse progression-free survival than the recovery group (21.9 mo versus not reached, p = 0.018). Recovery from TRL (p = 0.027) and high pre-CRT lymphocyte count (p = 0.028) independently influenced progression-free survival. Conclusions: Baseline lymphocyte count and recovery from TRL at the start of durvalumab therapy were predictive factors for survival outcomes in patients with NSCLC treated with durvalumab consolidation after concurrent CRT.

Clinical benefit of platinum doublet combination therapy in older adults with advanced non-small cell lung cancer: A prospective multicenter study by the National Hospital Organization in Japan.

BACKGROUND: Previous trials suggest that older adults with non-small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first-line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC. METHODS: Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre-first-line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117-5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070-2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013-13.39, p = 0.0478), and high C-reactive protein (HR 2.038, 95% CI: 1.141-3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470-0.995, p = 0.0453). DISCUSSION: Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy.

Pneumonitis During Durvalumab Consolidation Therapy Affects Survival in Stage III NSCLC.

Introduction: Durvalumab consolidation therapy is the standard of care after concurrent chemoradiotherapy (CRT) for stage III NSCLC. Immune-related pneumonitis during durvalumab treatment is potentially fatal; however, information is lacking regarding the impact of pneumonitis on patient survival. This study investigates the effect of pulmonary and nonpulmonary immune-related adverse events (irAEs) on the efficacy of durvalumab treatment in patients with stage III NSCLC. Methods: We retrospectively assessed 158 patients who received durvalumab after CRT at nine Japanese institutions between July 2018 and March 2020. Survival outcomes were compared between patients who developed pneumonitis with those who developed irAEs other than pneumonitis. Patients who survived for less than 3 months were excluded to reduce immortal time bias. Results: Among 158 evaluated patients, 76 (48%) experienced grade less than or equal to one irAEs, whereas 82 (52%) experienced grade greater than or equal to two irAEs. Among the patients with grade greater than or equal to two irAEs, those with grade greater than or equal to two pneumonitis (n = 55) were compared with those with grade greater than or equal to two irAEs other than pneumonitis (n = 27). Patients with grade greater than or equal to two pneumonitis exhibited a significantly worse overall survival than those with grade greater than or equal to two irAEs that excluded pneumonitis. Multivariate analysis revealed that grade greater than or equal to two pneumonitis (hazard ratio = 3.71; 95% confidence interval, 1.85-7.45; p < 0.001) and squamous histology (hazard ratio = 2.64; 95% confidence interval, 1.29-5.42; p = 0.008) were independently associated with worse overall survival. Conclusions: After minimizing immortal time bias, pneumonitis grade two or greater and squamous histology were poor prognostic factors in patients who received consolidation durvalumab after CRT.

Safety and efficacy of osimertinib rechallenge or continuation after pneumonitis: A multicentre retrospective cohort study.

INTRODUCTION: Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis. METHODS: We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge. RESULTS: In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1-21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months - not reached). CONCLUSION: Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis.

Outcomes of Chemoimmunotherapy Among Patients With Extensive-Stage Small Cell Lung Cancer According to Potential Clinical Trial Eligibility.

Importance: Chemoimmunotherapy is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). However, whether findings from pivotal trials can be extrapolated to the clinical practice setting remains unclear. Objective: To compare treatment outcome gaps following first-line chemoimmunotherapy for patients with ES-SCLC between those who met and did not meet the eligibility criteria used in previous clinical trials. Design, Setting, and Participants: A prospective cohort study was conducted from September 1, 2019, to September 30, 2020, at 32 hospitals in Japan, with at least 12 months of follow-up. Participants included consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as first-line therapy. Exposures: Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered trial-eligible. Main Outcomes and Measures: The primary outcome was 6-month progression-free survival. The secondary outcomes were differences in progression-free survival, overall survival, and safety according to whether key clinical trial eligibility criteria were met. Results: A total of 207 patients were analyzed (median age, 72 years; range, 46-87 years; 170 [82%] were male). Sixty-four patients (31%) were older adults (age ≥75 years), and most (184 [89%]) had an Eastern Cooperative Oncology Group performance status of 0 or 1. There were 132 (64%) trial-eligible patients. The 6-month progression-free survival rate for all patients was 38.8% (95% CI, 32.4%-45.7%). The median progression-free survival was 5.1 months in trial-eligible patients and 4.7 months in trial-ineligible patients (hazard ratio, 0.72; 95% CI, 0.53-0.97; P = .03). The proportion of patients who achieved disease control was 93% (118 of 127) in trial-eligible patients and 77% (55 of 71) in trial-ineligible patients (P = .002). The median overall survival was 15.8 months in trial-eligible patients and 13.1 months in trial-ineligible patients (hazard ratio, 0.73; 95% CI, 0.51-1.07; P = .10). The rate of severe adverse events was numerically higher among trial-ineligible patients than among trial-eligible patients (39% vs 27%; P = .07). Conclusions and Relevance: In this cohort study, the overall treatment outcome was comparable to that reported in pivotal clinical trials. However, treatment outcomes after chemoimmunotherapy might differ between trial-eligible and trial-ineligible patients. These findings suggest that trial-eligibility criteria may be useful in clinical practice, and further studies using data from clinical practice settings are required to inform regulatory approval and clinical decision-making.

Clinical efficacy of amrubicin in patients with small cell lung cancer relapse after first-line treatment including immune checkpoint inhibitors: A retrospective multicenter study (TOPGAN 2021-01).

BACKGROUND: The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC. PATIENTS AND METHODS: We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR. RESULTS: Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity. CONCLUSIONS: Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.

Non-small cell lung cancer with tumor proportion score > 90% could increase the risk of severe immune-related adverse events in first-line treatments with immune checkpoint inhibitors: A retrospective single-center study.

BACKGROUND: Since 2015, immune checkpoint inhibitors have been a clinical treatment strategy for patients with advanced or recurrent non-small cell lung cancer (NSCLC). However, the relationship between immune-related adverse event (irAE) risk factors and patient clinical characteristics is unclear. This study aimed to evaluate the relationship between irAE risk and the clinical characteristics of patients with NSCLC. METHODS: We included patients with advanced or recurrent NSCLC with known programmed death-ligand 1 expression levels treated with immune checkpoint inhibitors. We retrospectively examined the medical records of 260 patients with NSCLC (March 2016-November 2020) and analyzed the relationship between the patient clinical characteristics and irAEs. RESULTS: Our retrospective analysis revealed that tumor proportion score (TPS) ≥ 90% and adenocarcinoma histology were independent risk factors for irAEs (odds ratio: 3.750 95% confidence interval [CI]: 1.58-8.89 and 0.424 95% CI: 0.19-0.97, respectively) in first-line treatment. However, in patients receiving second- or later-line treatments, no clinical characteristics were identified as risk factors for irAEs. Furthermore, no difference was observed in the response rates to first-line treatments between the TPS ≥ 90% and TPS < 90% groups (74% vs. 71%, p = 0.83). In later-line treatments, the TPS ≥ 90% group had a better response rate than the TPS < 90% group (55% vs. 17%, p < 0.05). However, no significant differences in overall survival were observed in either of the groups. CONCLUSIONS: TPS ≥ 90% and adenocarcinoma histology were independent risk factors for irAEs in previously untreated patients with advanced or recurrent NSCLC. Therefore, patients at high risk of irAEs require additional monitoring.

Prospective multicenter cohort study of durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis.

OBJECTIVE: Durvalumab was safe and effective in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in a phase 3 trial (PACIFIC trial). Although a history of radiation pneumonitis (RP) has been reported to increase the risk of exacerbation of pneumonitis associated with programmed death-1 axis inhibitors, the detailed clinical results of durvalumab treatment in patients with baseline grade 1 RP were not reported in the PACIFIC trial. Therefore, we aimed to evaluate the safety and effectiveness of durvalumab therapy in these patients. MATERIALS AND METHODS: This was a multicenter prospective cohort study involving 35 patients. Patients were eligible if they met the following criteria: inoperable stage III NSCLC, administration of durvalumab within 42 days after CCRT using platinum-based chemotherapy, no disease progression after CCRT, Eastern Cooperative Oncology Group performance status of 0-1, and presence of grade 1 RP at baseline. We assessed the effectiveness and safety of durvalumab with a minimum 1-year follow-up period for all patients. RESULTS: Thirty-five patients were enrolled in our study from February 2019 to December 2019. The median progression-free survival was 11.4 months (95 % confidence interval, 7.1 months-not reached), and the median overall survival was not reached. Eleven (31 %) patients had grade ≥2 pneumonitis/RP, 10 (28 %) developed grade 2 pneumonitis/RP, and 1 (3 %) developed grade 5 pneumonitis/RP. Five (14 %) patients experienced treatment-related grade ≥3 adverse events. CONCLUSION: Durvalumab might be safe and effective in patients with stage III NSCLC with baseline grade 1 RP following chemoradiotherapy.

Predicting systemic therapy toxicity in older adult patients with advanced non-small cell lung cancer: A prospective multicenter study of National Hospital Organization in Japan.

INTRODUCTION: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients. MATERIALS AND METHODS: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%). DISCUSSION: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients.

Efficacy of Immune Checkpoint Inhibitor With or Without Chemotherapy for Nonsquamous NSCLC With Malignant Pleural Effusion: A Retrospective Multicenter Cohort Study.

Introduction: Malignant pleural effusion (MPE) is associated with poor treatment outcome in patients with NSCLC receiving immune checkpoint inhibitors (ICIs). ICIs and chemotherapy (ICI/Chemo) combination therapy is currently the standard therapy for NSCLC, and some ICI/Chemo regimens for nonsquamous (non-Sq) NSCLC contain bevacizumab (BEV), which is effective for controlling MPE and may enhance immune response. This study aimed to determine the optimal first-line treatment for this clinical population. Methods: We retrospectively enrolled consecutive patients with non-Sq NSCLC with MPE who received ICI/Chemo or pembrolizumab monotherapy. Treatment outcomes were analyzed in patients with programmed death-ligand 1 (PD-L1) tumor proportion score more than or equal to 50% who were administered ICI/Chemo or pembrolizumab monotherapy (PD-L1 high cohort) and in patients with any PD-L1 status, treated with ICI/Chemo with or without BEV (ICI/Chemo cohort). We used propensity score matching (PSM) to reduce bias. Results: PD-L1 high and ICI/Chemo cohorts included 143 and 139 patients, respectively. In PD-L1 high cohort, 37 patients received ICI/Chemo. With PSM, the median progression-free survival was significantly longer in the ICI/Chemo group than in the pembrolizumab group (11.1 versus 3.9 mo, respectively, p = 0.0409). In the ICI/Chemo cohort, 23 patients received BEV. With PSM, no significant difference occurred in median progression-free survival between BEV and non-BEV groups (6.1 versus 7.4 mo, p = 0.9610). Conclusion: ICI/Chemo seemed more effective than pembrolizumab monotherapy for patients with non-Sq NSCLC with MPE. Nevertheless, the synergistic effect of BEV with ICI/Chemo may be limited. Further studies are needed to clarify the key factor in the tumor-induced immunosuppression environment in these patients.

Histologic transformation of epidermal growth factor receptor-mutated lung cancer.

PURPOSE: This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). PATIENTS AND METHODS: We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. RESULTS: In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. CONCLUSION: HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

Bronchial ethanol injection therapy for airway obstruction in lung cancer patients.

Obstructive endobronchial tumours often cause decreased quality of life. Bronchial ethanol injection (BEI) therapy is considered an effective modality for airway dilatation or haemoptysis without specialist equipment. Here, we report experiences of two cases in which BEI therapy was effective for obstructive endobronchial tumours. In Case 1 with adenoid cystic carcinoma of the lung, BEI therapy and balloon dilatation were performed as treatment for the left main bronchus restenosis after metallic stent insertion. In Case 2 with squamous cell carcinoma of the lung, BEI therapy was performed after radiation therapy to the lesion that recurred in the entrance of the superior segment of the right lower lobe. Tumour progression was controlled with multiple BEI therapy. We consider BEI therapy useful because this procedure is easy to conduct, has low cost and can be done under particular conditions including post-tracheobronchial stent placement and post-radiation.