Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia.

OBJECTIVES: In this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. MATERIALS AND METHODS: The efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. RESULTS: Of the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35-3.46]; ICIs vs docetaxel, 1.49 [1.21-1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07-0.64]). CONCLUSIONS: After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

Exceptionally long-lasting response to dabrafenib plus trametinib treatment in a patient with lung adenocarcinoma harboring the BRAF V600E mutation with high expression of PD-L1: A case report.

We present a patient with lung adenocarcinoma showing high PD-L1 expression and BRAF V600E mutation, who achieved a remarkable long-term response to the combination therapy of dabrafenib and trametinib (DT treatment) after disease progression on immunotherapy. This case may provide an opportunity for clinicians to consider the order of administration of immunotherapy and molecular targeted therapy for BRAF V600E-positive lung cancer.

Prognostic impact of clinical and radiological factors on leptomeningeal metastasis from solid cancers.

PURPOSE: The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types. METHODS: We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021. RESULTS: The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results. CONCLUSIONS: This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.

Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG-E8.

The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG-E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor-derived and systemically existing MFG-E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL-dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG-E8, and that such responses were enhanced further with the administration of anti-PD-1 antibody. In mice with decreased levels of systemic MFG-E8, the dominance of regulatory T cells in tumor-infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG-E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG-E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG-E8, but not MFG-E8 expression in tumor cells, before the treatment was associated with objective responses to anti-PD-1 therapy in patients with non-small cell lung cancer. These results suggest that systemic MFG-E8 plays a critical role during the immunological initiation process of antigen-presenting cells to increase tumor-specific CTLs. Regulation of the systemic level of MFG-E8 might induce efficient antitumor immune responses and enhance the potency of anti-PD-1 therapy.

Clinical application of the Lung Cancer Compact PanelTM using various types of cytological specimens in patients with lung cancer.

BACKGROUND: The Lung Cancer Compact PanelTM (compact panel) is a gene panel that can detect driver alterations with high sensitivity in liquid samples, including tumor cells. This study examined the ability of a compact panel to detect genetic mutations in liquid specimens used in clinical practice. METHODS: Three cohorts, bronchoscopic biopsy forceps washing (washing cohort), pleural effusion (pleural cohort), and spinal fluid (spinal cohort), were analyzed using the compact panel. Liquid samples were added into the GM (Genemetrics) tubes and analyzed. The washing cohort assessed the concordance rate of gene panel analysis outcomes in tissue specimens derived from the primary tumor. Meanwhile, the pleural cohort investigated the impact of storing specimens for 8 weeks and more on nucleic acid and mutation detection rates. RESULTS: In the washing cohort (n = 79), the concordance rate with mutations detected in tissues was 75/79 (94.9 %). This rate reached 100 % when focusing solely on driver alterations for treatment. The pleural cohort (n = 8) showed no deterioration in nucleic acid quality or quantity after 8 weeks of storage in GM tubes. Similarly, in the spinal cohort (n = 9), spinal fluid with malignant cells exhibited driver alterations similar to those in the primary tumor. These findings underscore the efficacy of the compact panel in accurately identifying genetic mutations in different liquid specimens. CONCLUSIONS: The compact panel is a reliable tool for detecting driver alterations in various cytological specimens. Its consistent performance across diverse sample types emphasizes its potential for guiding targeted therapies for patients with lung cancer and enhancing precision medicine approaches.

The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions.

Neuregulin 1 (NRG1) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block®' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

NRG1 gene fusions are rare mutations that cause cancer cells to grow. These fusions are found in many different types of cancer. Tumors with NRG1 gene fusions do not respond well to standard treatment options. Zenocutuzumab, or Zeno, is a treatment that is being tested to see if it can stop cancer that is growing because of NRG1 gene fusions. Here, we describe the reasoning for and design of an ongoing clinical trial (eNRGy) designed to study the efficacy (how well it works) and safety of Zeno in patients with cancer that has NRG1 gene fusions. The eNRGy trial is recruiting patients with cancer that has NRG1 gene fusions, including non-small-cell lung cancer, pancreatic cancer and others. Patients who join this trial will receive Zeno once every 2 weeks until their cancer grows. The main goal (primary end point) of this trial is to determine the percentage of patients whose tumors decrease in size by 30% or more. The eNRGy trial is currently enrolling patients. For more information, refer to ClinicalTrials.gov (Identifier: NCT02912949), visit https://nrg1.com/, or call 1-833-NRG-1234.

RELAY, Erlotinib Plus Ramucirumab in Untreated, EGFR-Mutated, Metastatic NSCLC: Outcomes by EGFR Exon 19 Deletion Variants.

Introduction: EGFR gene mutations are drivers of NSCLC. The RELAY double-blind, placebo (PBO)-controlled phase 3 study revealed superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus PBO (PBO + ERL) in patients with untreated advanced NSCLC and an EGFR-activating mutation. This exploratory analysis evaluated potential associations between EGFR exon 19 deletion (ex19del) variants and clinical outcomes. Methods: Patients (N = 449) were randomized (1:1) to RAM plus ERL or PBO plus ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations were investigated by Guardant360 next-generation sequencing. Patients with a valid baseline plasma sample and ex19del were included (RAM + ERL, n = 62; PBO + ERL, n = 72). Results: The most common ex19del variant was E746_A750del (67.2%); EGFR E746 deletions (E746del) occurred more frequently than L747 deletions (74.6% versus 25.4%, respectively). TP53 mutations were the most frequently co-occurring baseline gene alterations. With treatment arms combined, median PFS was 18.0 months versus 12.5 months for patients with uncommon (non-E746_A750del, n = 44) versus common (E746_A750del, n = 90) ex19del variants (hazard ratio [HR] = 1.657 [95% confidence interval or CI:1.044-2.630]). Median PFS was longer with RAM plus ERL versus PBO plus ERL for patients with the common (15.2 versus 9.9 mo; HR = 0.564 [95% CI: 0.344-0.926]) and E746del (15.4 versus 9.9 mo; HR = 0.587 [95% CI: 0.363-0.951]) variants. Treatment-emergent post-progression EGFR T790M rates were higher in the common versus uncommon and E746del versus L747 deletion subgroups. Conclusions: RAM plus ERL provides benefit and improves treatment outcomes for patients with metastatic NSCLC with EGFR ex19del variants.

Real-world outcomes of nivolumab plus ipilimumab and pembrolizumab with platinum-based chemotherapy in advanced non-small cell lung cancer: a multicenter retrospective comparative study.

INTRODUCTION: Nivolumab plus ipilimumab with chemotherapy (NICT) and pembrolizumab with chemotherapy (PCT) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). Compared with immune checkpoint inhibitor (ICI) monotherapy, ICI combination therapy can increase immune-related toxicity instead of prolonging survival. This study aimed to compare the efficacy and safety of NICT and PCT to decide on the favorable treatment. METHODS: We conducted a multi-center retrospective cohort study on patients who underwent NICT or PCT between December 2018 and May 2022. Propensity score matching (PSM) was performed with the variables age, sex, smoking status, performance status, stage, histology, and programmed cell death ligand-1 (PD-L1). The Kaplan-Meier method was used to compare survival for the matched patients. RESULTS: Six hundred consecutive patients were included. After PSM, 81 and 162 patients were enrolled in the NICT and PCT groups, respectively. The baseline characteristics were well-balanced. The median progression-free survival was equivalent (11.6 vs. 7.4 months; P = 0.582); however, the median overall survival (OS) was significantly longer in the NICT group than in the PCT group (26.0 vs. 16.8 months; P = 0.005). Furthermore, OS was better in PD-L1-negative patients who underwent NICT than in those who underwent PCT (26.0 vs. 16.8 months; P = 0.045). Safety profiles did not differ significantly in terms of severe adverse event and treatment-related death rates (P = 0.560, and 0.722, respectively). CONCLUSIONS: Real-world data suggests that NICT could be a favorable treatment option compared with PCT for patients with advanced NSCLC. Further follow-up is needed to determine the long-term prognostic benefit.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

Utility of needle biopsy in centrally located lung cancer for genome analysis: a retrospective cohort study.

BACKGROUND: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. METHODS: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. RESULTS: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. CONCLUSIONS: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

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.

A highly specific antibody against the core fucose of the N-glycan in IgG identifies the pulmonary diseases and its regulation by CCL2.

Glycan structure is often modulated in disease or predisease states, suggesting that such changes might serve as biomarkers. Here, we generated a monoclonal antibody (mAb) against the core fucose of the N-glycan in human IgG. Notably, this mAb can be used in Western blotting and ELISA. ELISA using this mAb revealed a low level of the core fucose of the N-glycan in IgG, suggesting that the level of acore fucosylated (noncore fucosylated) IgG was increased in the sera of the patients with lung cancer, chronic obstructive pulmonary disease, and interstitial pneumonia compared to healthy subjects. In a coculture analysis using human lung adenocarcinoma A549 cells and antibody-secreting B cells, the downregulation of the FUT8 (α1,6 fucosyltransferase) gene and a low level of core fucose of the N-glycan in IgG in antibody-secreting B cells were observed after coculture. A dramatic alteration in gene expression profiles for cytokines, chemokines, and their receptors were also observed after coculturing, and we found that the identified C-C motif chemokine 2 was partially involved in the downregulation of the FUT8 gene and the low level of core fucose of the N-glycan in IgG in antibody-secreting B cells. We also developed a latex turbidimetric immunoassay using this mAb. These results suggest that communication with C-C motif chemokine 2 between lung cells and antibody-secreting B cells downregulate the level of core fucose of the N-glycan in IgG, i.e., the increased level of acore fucosylated (noncore fucosylated) IgG, which would be a novel biomarker for the diagnosis of patients with pulmonary diseases.

Genetic dissection of intratumor heterogeneity of PD-L1 expression in EGFR-mutated lung adenocarcinoma.

In this study, we investigated the association between PD-L1 expression in tumor cells and underlying genetic mutations, which was analyzed in detail using laser microdissection and next-generation sequencing analysis. To investigate whether driver mutations are involved in the background of PD-L1 expression, the EGFR major activating mutation was selected as the most frequent driver mutation. Surgical resection specimens were used to extract sufficient amounts of nucleic acids for analysis, and the high tumor proportion score (TPS:100%) and low (TPS: 0%) PD-L1-expressing parts of the tumor were each laser microdissected to examine the association between PD-L1 expression heterogeneity and genetic mutations within the same tumor. The association between PD-L1 heterogeneity and gene mutations within the same tumor was investigated. Analysis showed no association between PD-L1 expression heterogeneity and genetic variants, which were found to be almost identical. However, PD-L1 expression was found to be associated with the number of tumor infiltrating lymphocytes (TILs) present in the tumor, which may be related to whether or not lymphocytes can infiltrate into the tumor depending on the tumor histological type (solid pattern, lepidic pattern, etc.) and other factors.

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.

Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312).

BACKGROUND: Zoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. METHODS: We conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. RESULTS: Between November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. CONCLUSIONS: An eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Effectiveness and Safety of Atezolizumab Monotherapy in Previously Treated Japanese Patients With Unresectable Advanced or Recurrent NSCLC: A Multicenter, Prospective, Observational Study (J-TAIL).

Introduction: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial. Methods: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated. Results: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively. Conclusions: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.

Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial.

Background: Approximately 3-4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC. Methods: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591). Findings: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7-17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54-76) overall (n = 79), 71% (95% CI 55-83) in treatment-naïve patients (n = 44), and 60% (95% CI 42-76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients. Interpretation: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later. Funding: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for "Clinical Research of Gumarontinib, a highly selective MET inhibitor" (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).

Clinical application of the AMOY 9-in-1 panel to lung cancer patients.

INTRODUCTION: To investigate the clinical performance of the AMOY 9-in-1 kit (AMOY) in comparison with a next-generation sequencing (NGS) panel in lung cancer patients. METHODS: Lung cancer patients enrolled in the LC-SCRUM-Asia program at a single institution were analyzed for the success rate of AMOY analysis, the detection rate of targetable driver mutations, the turn around time (TAT) from specimen submission to the result reporting, and the concordance rate of results with the NGS panel. RESULTS: Of the 406 patients included in the analysis, 81.3% had lung adenocarcinoma. The success rates of AMOY and NGS were 98.5% and 87.8%, respectively. With AMOY, genetic alterations were detected in 54.9% of cases. Of the 42 cases in which NGS analysis failed, targetable driver mutations were detected by AMOY in ten cases through analysis of the same sample. Of the 347 patients for whom the AMOY and NGS panels were successful, 22 showed inconsistent results. In four of the 22 cases, the mutation was detected only in the NGS panel because AMOY did not cover the EGFR mutant variant. Mutations were detected only by AMOY in five of the six discordant pleural fluid samples, with AMOY having a higher detection rate than NGS. The TAT was significantly shorter five days after AMOY. CONCLUSION: AMOY had a higher success rate, shorter turnaround time, and higher detection rate than NGS panels. Only a limited number of mutant variants were included; thus be careful not to miss promising targetable driver mutations.

Bevacizumab Plus Carboplatin Plus Nab-paclitaxel for Non-squamous Non-small Cell Lung Cancer in a Real-world Setting.

BACKGROUND/AIM: Regimens with bevacizumab (Bev) have high response rates. We previously showed the efficacy of Bev plus carboplatin (CBDCA)/nab-paclitaxel (nab-PTX) in the treatment of non-squamous (non-SQ) non-small lung cell cancer (NSCLC) with malignant pleural effusion in a phase II trial. However, few studies have reported the efficacy and safety of this regimen. Therefore, we conducted a retrospective analysis of the efficacy and safety of Bev plus CBDCA/nab-PTX for patients with NSCLC. PATIENTS AND METHODS: We included patients with non-SQ NSCLC that underwent any number of treatment lines. Patients received a maximum of six cycles of Bev plus CBDCA/nab-PTX every three to four weeks followed by Bev plus nab-PTX every three to four weeks without disease progression or severe toxicities. The administration dose was left to the discretion of the attending physician. RESULTS: We enrolled 48 patients treated with Bev plus CBDCA/nab-PTX between June 2015 and August 2021. The best response rate was 56.3% and the disease control rate was 79.2%. Twenty-three patients received maintenance therapy. Median progression-free and overall survival times were 6.8 and 10.4 months, respectively. Common adverse events included hematological toxicities, including ≥grade 3 neutropenia and neurosensory toxicity. One patient experienced severe bleeding events (grade 3 gastrointestinal bleeding) and another experienced grade 5 toxicity (infection). CONCLUSION: The combination of Bev plus CBDCA/nab-PTX showed good efficacy with acceptable toxicities in non-SQ NSCLC patients, despite the inclusion of patients with late treatment lines and poor performance status.