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Simple Summary: Data on the efficacy and safety of pharmacotherapy for advanced non-small cell lung cancer (NSCLC) with poor performance status (PS) 2 are insufficient. Cytotoxic chemotherapy for patients with PS 2 is insufficiently effective, and there are concerns about toxicity. Immune checkpoint inhibitors are a promising treatment with the potential for less severe toxicity, but data are more limited than with cytotoxic chemotherapy. In this review article, we summarize the current evidence on pharmacotherapy for NSCLC patients with PS 2 and without druggable genetic alterations, and we discuss future perspectives and challenges. Most pivotal clinical trials in advanced non-small cell lung cancer (NSCLC) have excluded patients with poor performance status (PS), and data on the efficacy and safety of pharmacotherapy have not been fully accumulated. For NSCLC patients with PS 2 and without druggable genetic alterations, monotherapy with cytotoxic agents or carboplatin-based combination therapy is usually administered based on the results of several randomized trials. However, the evidence of cytotoxic chemotherapy for patients with PS 2 is insufficient, with limited efficacy and toxicity concerns. Immune checkpoint inhibitors (ICIs) are a promising treatment for patients with PS 2 because of lower incidence of severe toxicity compared to cytotoxic chemotherapy. Meanwhile, several reports suggest that anti-PD-1 antibodies monotherapy is less effective for patients with PS 2, especially for those with PS 2 caused by disease burden. Although the combination therapy of nivolumab and ipilimumab is a promising treatment option, there is a divergence in efficacy data between clinical trials. The standard of care for advanced NSCLC with PS 2 has not been established, and future therapeutic strategies should take into account the heterogeneity of the PS 2 population. [ABSTRACT FROM AUTHOR]

Aim: Flexible bronchoscopy (FB) is a common modality for the diagnosis of lung cancer. Recently, the number of older patients with lung cancer is increasing, and FB is being utilized more for these patients. Methods: FB carried out in patients aged ≥85 years at St. Marianna University Hospital, Kawasaki, Japan, were reviewed. The indication of FB was decided on a case‐by‐case basis, taking into consideration the condition of the patient, which included mental status and accessibility of the lesion. Outcomes included complications, diagnostic yields, treatment options and survival after FB evaluation. Results: From April 2015 to March 2019, 1604 diagnostic FBs were carried out. A total of 28 were carried out for the diagnosis of lung cancer (19 transbronchial lung biopsy, 9 transbronchial needle aspiration) in patients aged ≥85 years. Although there were three complications reported (pneumonia, fever, asthma exacerbation), they were successfully treated. A total of 19 cases were diagnosed with malignancy; five were treated with stereotactic body radiation therapy, five were prescribed targeted therapy, two underwent surgery and one was treated by cytotoxic monotherapy. Six patients were not included for active treatment. A total of 12 patients who received active treatment for lung cancer reported a 2‐year survival rate of >60%. Conclusions: FB for lung cancer diagnosis in patients aged ≥85 years were carried out with acceptable safety and diagnostic yield. Considering the development of less invasive therapeutic measures for lung cancer, FB is safe and valuable in individuals aged ≥85 years suspected of lung cancer with therapeutic indications. Geriatr Gerontol Int 2022; 22: 32–35. [ABSTRACT FROM AUTHOR]

Background: In this study we aimed to clarify the PD‐L1 positive expression in lung adenocarcinoma, including various adenocarcinoma subtypes paying particular attention to its component. Methods: A total of 307 lung adenocarcinoma patients who underwent lobectomy or segmentectomy, as well as systematic lymph node dissection (ND2a), from February 2008 to March 2020 at our hospital, were enrolled into the study. A final diagnosis of adenocarcinoma was obtained from the resected lung specimens of all 307 patients to determine the histological type, adenocarcinoma subtype, and component of adenocarcinoma by ethics of 5%. PD‐L1 was immunohistochemically stained using the murine monoclonal antibody clone 22C3. Results: When PD‐L1 expression‐positive was defined by tumor proportion score (TPS) ≥1%, the positive cases were 6/33 in adenocarcinoma (Ad) in situ (AIS), 2/26 in minimally invasive Ad (MIA), 12/60 in lepidic predominant Ad (LPA), 44/91 in papillary predominant Ad (PPA), 24/49 in acinar predominant Ad (APA), 23/28 in solid predominant Ad (SPA), 4/7 in micropapillary predominant Ad (MPA), and 0/13 in invasive mucinous Ad (IMA). In the high proportion group (APA, PPA, SPA, and MPA) of PD‐L1 expression, SPA was the only subtype which was statistically significant when both PD‐L1 expression‐positive was defined by TPS ≥ 1% (p < 0.0001) and TPS ≧ 50% (p < 0.0001). We then considered the solid component. We investigated 279 cases of the other subtype group excluding SPA. The group containing a solid component (≥5%) tended to be PD‐L1 expression‐positive both when defined by TPS ≥1% (p < 0.0001) and TPS ≧50% (p = 0.0049). Conclusions: The PD‐L1 expression tended to be positive when a solid component was confirmed (≥5%) in specimens of lung adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Background: Consolidation therapy with durvalumab after concurrent chemoradiotherapy has been reported to significantly prolong progression‐free survival and overall survival in patients with stage III unresectable non‐small cell lung cancer (NSCLC). However, which chemotherapy regimen should be selected for consolidation therapy with durvalumab is currently unknown. Methods: We retrospectively reviewed consecutive patients with unresectable stage III NSCLC who received concurrent definitive chemoradiotherapy with platinum‐based chemotherapy. We reviewed the timing and severity of radiation pneumonitis by assessing chemotherapy regimens and histology. Results: A total of 103 patients were identified. Fourteen patients (13.6%) developed grade 2 or greater radiation pneumonitis within 42 days after chemoradiotherapy. No adenocarcinoma patients treated with a regimen of cisplatin plus pemetrexed developed grade 2 or greater radiation pneumonitis within 42 days; however, 20% of patients who were treated with carboplatin plus paclitaxel developed grade 2 or greater radiation pneumonitis. Furthermore, the objective response rates and disease control rates of cisplatin plus pemetrexed were equal to or greater than those of carboplatin plus paclitaxel in adenocarcinoma patients. Conclusion: Cisplatin plus pemetrexed regimen may be a preferable option to consider for subsequent consolidation therapy with durvalumab in patients with unresectable stage III adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Atezolizumab is a programmed death‐ligand 1 (PD‐L1) targeted monoclonal antibody that inhibits PD‐L1 interacting with its receptors PD‐1 and B7‐1, thereby enhancing anticancer immunity. Some real‐world efficacy and safety studies of anti‐PD‐1 antibody have been previously reported. However, there have been no reports investigating the efficacy of atezolizumab monotherapy in clinical practice which have focused on performance status and previous anti‐PD‐1 antibody treatment. Methods: We retrospectively reviewed consecutive advanced NSCLC patients who received atezolizumab monotherapy between April 2018 and February 2019 at eight institutions. A total of 152 patients with NSCLC were enrolled in this study. Results: A total of 38 patients (25%) had already been treated with anti‐PD‐1 treatment (nivolumab or pembrolizumab) before atezolizumab. The median OS and TTF was 384 days (12.8 months) (95% confidence interval [CI]: 206–424), and 42 days (1.4 months) (95% CI: 27–56) in all patients, respectively. ECOG PS 0 had significantly longer OS (median OS; not reached, p < 0.0001) and TTF (median TTF; 63 days, p = 0.012) compared with PS 1 or 2–3. Most retreated patients were unable to continue atezolizumab for a longer period, but seven patients (18.4%) were able to continue atezolizumab over four months as an ICI retreatment. Conclusions: In previously treated advanced NSCLC patients, atezolizumab monotherapy demonstrated good efficacy and safety regardless of heavily treated patients in real‐world clinical practice, and ECOG PS 0 was a favorable predictive factor. The efficacy of retreatment with atezolizumab was limited but was well tolerated in patients treated with prior anti‐PD‐1 antibody. [ABSTRACT FROM AUTHOR]

Next‐generation sequencing (NGS) enables the diagnosis of large numbers of gene aberrations during one examination, and precision medicine has been developed for patients with advanced non–small cell lung cancer (NSCLC). However, peripheral lung lesions account for the majority of advanced lung cancers, especially lung adenocarcinoma. In these cases, it is difficult to obtain tissue samples which contain sufficient tumor cells by transbronchial biopsy (TBB) with forceps. Even when the target lesions are quite small, bronchial brushing can obtain enough tumor cells by endobronchial ultrasonography using guide sheath (EBUS‐GS). In this study, we investigate the suitability of bronchial brushing cytology specimens obtained by EBUS‐GS‐TBB to evaluate the correlation between the success rate of NGS and extracted DNA/RNA yields according to biopsy method. We prospectively collected 222 tumor samples obtained from patients with advanced lung cancer. All patients were enrolled in a prospective nationwide genomic screening project for lung cancer (LC‐SCRUM‐Japan/Asia). Genomic data were obtained from the clinico‐genomic database of LC‐SCRUM‐Japan/Asia. The extraction yields of DNA/RNA from samples obtained by EBUS‐GS‐TBB were relatively low compared with tissue samples. The success rate of DNA sequencing for EBUS‐GS‐TBB was 97.9%, with no significant differences between biopsy methods. The success rate of RNA sequencing for EBUS‐GS‐TBB was 80.4%, which was relatively low compared with surgical biopsy samples (P = 0.069). However, some rare oncogenic driver aberrations were detected from these specimens. This study demonstrated that cytology samples obtained by transbronchial brushing with EBUS‐GS‐TBB were suitable for NGS analysis. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are the key drugs used in patients with non‐small cell lung cancer (NSCLC). However, anti‐PD‐1 therapy might worsen chronic infection by reactivating the immune response to infectious diseases. Here, we describe a case of successful treatment with nivolumab in a patient with NSCLC complicated by pulmonary aspergilloma, which was safely treated by surgical resection before administration of nivolumab. In conclusion, to safely treat patients with locally limited chronic pulmonary aspergillosis (CPA), surgical resection should be considered before ICI therapy. [ABSTRACT FROM AUTHOR]

Objectives: Currently, combination therapy of ramucirumab (RAM) + docetaxel (DOC) must play a more important role as a second-line treatment. Epithelial growth factor receptor (EGFR) mutation accounts for around 50% of oncogenic driver mutations in patients with advanced non-small cell lung cancer (NSCLC) in Asian subsets. The number of brain metastases (BM) is relatively higher in EGFR mutation-positive patients compared to EGFR wild-type patients. The objective of this study is to evaluate the efficacy of RAM + DOC focusing on EGFR mutation and BM. Methods: We retrospectively reviewed consecutive advanced NSCLC patients who received combination therapy of RAM + DOC at three institutions. A total of 112 patients with NSCLC were enrolled for efficacy analyses. We evaluated the efficacy of RAM + DOC for EGFR-mutated NSCLC with endpoints including progression-free survival (PFS), time to treatment failure (TTF) and overall survival. Results: Median PFS was 5.7 months for the EGFR mutant group compared with 3.6 months for the EGFR wild-type group (HR 0.53, 95% CI 0.32–0.87; p = 0.01). Median TTF was 5.1 months for the EGFR mutant group compared with 2.8 months for the EGFR wild-type group (HR 0.53, 95% CI 0.33–0.85; p = 0.007). Median PFS and TTF of the EGFR mutant group was significantly longer than median PFS and TTF of the EGFR wild-type group. The multivariate analysis identified EGFR mutation status as an independent favorable factor of PFS. In subset analyses of BM, median PFS of the EGFR mutant group (2.8 months) was significantly shorter than that of the EGFR wild-type group (5.1 months) (HR 7.27, 95% CI 1.78–29.68; p = 0.002). Conclusion: This study revealed that EGFR mutation status and BM might be predictive or prognostic factors for PFS. [ABSTRACT FROM AUTHOR]

It is unclear how epidermal growth factor receptor EGFR major driver mutations (L858R or Ex19del) affect downstream molecular networks and pathways. This study aimed to provide information on the influences of these mutations. The study assessed 36 protein expression profiles of lung adenocarcinoma (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Weighted gene co-expression network analysis together with analysis of variance-based screening identified 13 co-expressed modules and their eigen proteins. Pathway enrichment analysis for the Ex19del mutation demonstrated involvement of SUMOylation, epithelial and mesenchymal transition, ERK/mitogen-activated protein kinase signalling via phosphorylation and Hippo signalling. Additionally, analysis for the L858R mutation identified various pathways related to cancer cell survival and death. With regard to the Ex19del mutation, ROCK, RPS6KA1, ARF1, IL2RA and several ErbB pathways were upregulated, whereas AURK and GSKIP were downregulated. With regard to the L858R mutation, RB1, TSC22D3 and DOCK1 were downregulated, whereas various networks, including VEGFA, were moderately upregulated. In all mutation types, CD80/CD86 (B7), MHC, CIITA and IFGN were activated, whereas CD37 and SAFB were inhibited. Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Ramucirumab plus docetaxel (RAM+DOC) is expected to prolong survival in patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy and safety for older patients remains unknown. The objective of this study was to evaluate the efficacy and safety of RAM+DOC in patients 75 years and older. Methods: We retrospectively reviewed consecutive patients with advanced NSCLC who had received RAM+DOC treatment at three institutions. We compared the efficacy and safety in patients 75 years and older to those under 75 years of age. Results: A total of 114 patients were identified. The median progression‐free survival, time to treatment failure and overall survival was 3.6 (95% CI: 0.4–6.7), 3.1 (95% CI: 2.4–3.9) and 11.2 months (95% CI: 5.6–16.8) in the older group (N = 23), and 4.2 (95% CI: 3.3–5.0), 3.4 (95% CI: 3.3–5.0) and 12.2 months (95% CI: 9.1–15.4) in the younger group (N = 91), respectively. Survival curves were similar for each group, while the objective response rate was 30.4% (95% CI: 13.2–52.9%) in older patients and 35.2% (95% CI, 25.4–45.9%) for the younger group. A total of 22 older patients (95.7%) and 73 (80.2%) younger patients received primary prophylactic pegylated‐granulocyte‐colony stimulating factor (PEG‐G‐CSF). Four older patients (17.3%) and 14 younger patients (15.3%) discontinued RAM+DOC due to adverse events. Conclusions: RAM+DOC is expected to be efficacious and tolerable in older patients when supported with prophylactic PEG‐G‐CSF therapy. Key points: Significant findings of the study ・PFS, OS, and ORR in older patients were similar to those under 75 years of age. ・Safety of RAM+DOC was well tolerated in older patients with prophylactic PEG‐G‐CSF. ・Prophylactic PEG‐G‐CSF with RAM+DOC may contribute to better efficacy. What this study adds ・This study suggests that RAM+DOC with prophylactic PEG‐G‐CSF is expected to be a useful option in older patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Treatment options for patients with epidermal growth factor receptor (EGFR) -mutated non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (TKI) treatment failure are limited. An exploratory analysis of 26 patients in the IMpower150 study indicated that treatment with atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) was effective in patients with EGFR -mutated NSCLC. This phase II study was conducted to assess the efficacy of ABCP in EGFR -mutated NSCLC patients after TKI treatment. Patients with non-squamous NSCLC harboring sensitizing EGFR mutations were enrolled. ABCP therapy was administered every 3 weeks for four cycles, followed by maintenance therapy with atezolizumab and bevacizumab. The primary endpoint was progression-free survival (PFS) according to extramural review (ER). Key secondary endpoints and preplanned analysis included overall survival (OS), overall response rate (ORR), and differences in the efficacy of ABCP according to prior EGFR-TKI administration, liver metastases, and brain metastases. Sixty patients from 26 centers were enrolled. Median PFS was 7.4 months (95% confidence interval [CI]: 5.7–8.2). The median OS was 23.1 months (95% CI: 13.1-not reached), and the ORR was 55.9%. PFS was significantly shorter in patients who had received osimertinib as a first-line treatment (7.2 months vs. 7.4 months, hazard ratio [HR] 1.932, p = 0.023), those with brain metastases (5.7 months vs. 8 months, HR 1.86, p = 0.032), or those with liver metastases (5.4 months vs. 7.9 months, HR 2.779, p = 0.003). Although this study did not meet the primary endpoint, ABCP showed clinically meaningful efficacy in EGFR -mutated NSCLC patients. • EGFR -mutated NSCLC respond poorly to monotherapy of PD-1 and PD-L1 inhibitors. • This study showed clinically meaningful efficacy of ABCP in EGFR -mutated NSCLC. • This is the first study to evaluate ABCP in EGFR -mutated NSCLC after TKI failure. • This study suggests that ABCP is a treatment option for EGFR -mutated NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: Lung cancer is the leading cause of cancer death worldwide. Proteogenomics, a way to integrate genomics, transcriptomics, and proteomics, have emerged as a way to understand molecular causes in cancer tumorigenesis. This understanding will help identify therapeutic targets that are urgently needed to improve individual patient outcomes. Areas covered: To explore underlying molecular mechanisms of lung cancer subtypes, several efforts have used proteogenomic approaches that integrate next generation sequencing (NGS) and mass spectrometry (MS)-based technologies. Expert opinion: A large-scale, MS-based, proteomic analysis, together with both NGS-based genomic data and clinicopathological information, will facilitate establishing extensive databases for lung cancer subtypes that can be used for further proteogenomic analyzes. Proteogenomic strategies will further be understanding of how major driver mutations affect downstream molecular networks, resulting in lung cancer progression and malignancy, and how therapy-resistant cancers resistant are molecularly structured. These strategies require advanced bioinformatics based on a dynamic theory of network systems, rather than statistics, to accurately identify mutant proteins and their affected key networks. [ABSTRACT FROM AUTHOR]

Background Recent studies have revealed a reduction in the skeletal muscle area in patients with advanced non-small cell lung cancer ( NSCLC) after chemotherapy. EGFR and ALK tyrosine kinase inhibitor ( TKI)-based therapies are less cytotoxic than chemotherapy, but differences in skeletal muscle mass between patients receiving EGFR and ALK TKI therapies and patients receiving cytotoxic chemotherapy have not yet been reported. Methods Data of pathologically proven NSCLC patients were reviewed, and chest computed tomography and/or positron emission tomography-computed tomography images obtained from January 2012 to December 2014 were selected. Patients were divided into two groups: cytotoxic chemotherapy ( CG) and molecular targeted ( MG). Muscle mass was measured with a single cross-sectional area of the muscle at the third lumber vertebra ( L3 MA). To estimate skeletal muscle changes during chemotherapy, we defined the following L3 skeletal muscle index ( L3 SMI) ratio: post L3 SMI/pre L3 SMI. Differences in the SMI ratio between the groups were evaluated using the Wilcoxon signed-rank test. Results Sixty-five patients were included in this study: 44 patients received cytotoxic chemotherapy and 21 received molecular targeted therapy ( EGFR and ALK TKI). The loss of L3 MA in the CG was higher than in the MG ( P = 0.03). In the CG, the L3 SMI ratio defined to evaluate skeletal muscle mass changes was significantly lower than in the MG ( P = 0.0188). Conclusion Our results suggest that skeletal muscle loss during first-line therapy was significantly different between patients receiving cytotoxic chemotherapy and those receiving TKIs. Specifically, skeletal muscle loss was lower in patients receiving TKIs than in patients receiving cytotoxic chemotherapy. [ABSTRACT FROM AUTHOR]

This phase I/II study assessed the efficacy and safety of combination therapy with carboplatin (CBDCA) and nab-paclitaxel (nab-PTX) in advanced elderly patients (aged ≥75 years) with advanced squamous cell lung cancer (SqCLC). In this phase I study, the doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL/min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m2) on days 1, 8, and 15 every 4 weeks for up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6 m PFS) rate. A total of 46 patients were enrolled in this study. Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia; at dose level 2, 1/3 patient exhibited grade 3 anorexia as a DLT. The recommended dose was determined to be level 2. Efficacy was then evaluated in 39 patients enrolled in a phase II study. The median number of cycles was 4 (range, 1–6), and the median follow-up time was 17.5 months (range, 5.6–28.9 months). The 6 m PFS rate was 59.4% (90% confidence interval [CI], 44.8%–71.4%), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6–35.4), and the median PFS was 6.8 months (95% CI, 5.4–9.1). The response rate was 54%, and the disease control rate was 92%. Sixteen patients (41%) received immune checkpoint inhibitors post-study. Common grade 3 or 4 toxicities were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%). Combination chemotherapy consisting of CBDCA with weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly patients (aged ≥75 years) with advanced SqCLC. [ABSTRACT FROM AUTHOR]