Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

A phase II study of ME2136 (Asenapine Maleate) plus standard antiemetic therapy for patients, including diabetic patients, receiving cisplatin-based chemotherapy.

Olanzapine combined with the neurokinin-1 receptor antagonist, palonosetron and dexamethasone is the standard treatment for chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). However, the use of olanzapine poses challenges in patients with diabetes mellitus (DM) due to the potential risk of hyperglycemia. ME2136, antipsychotic similar to olanzapine, is associated with a lower risk of hyperglycemia. This study investigated the antiemetic efficacy and safety of ME2136 for HEC. This single-arm phase 2 study examined the safety and efficacy of ME2136 5 mg for 4 days in combination with triplet-combination antiemetic therapy. Two cohorts were established for the safety assessment: DM and non-DM. Eligible patients had malignant tumors and were receiving cisplatin-based chemotherapy for the first time. The primary endpoint was the complete response (CR) rate, defined as the percentage of patients without vomiting and not requiring rescue medications in the delayed phase (24-120 h). Between December 2020 and January 2022, 40 patients were enrolled, with 20 in each cohort. All patients were included in the safety analysis and 35 in the efficacy analysis. The CR rate in the delayed phase was 71.4% [60% CI 63.1-78.6%] for all patients, 66.7% in the DM cohort, and 76.5% in the non-DM cohort. No treatment-related adverse events ≥ grade 3, including hyperglycemia, were reported. ME2136, when combined with standard triplet-combination antiemetic therapy, is expected to exert similar antiemetic effects to the standard treatment for CINV due to HEC. Currently, ME2136-02 trial is underway to examine the safety and efficacy of triplet-combination antiemetic therapy and a 5-day treatment with ME2136. This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020. Clinical trial registration: This study was registered with the Japan Registry of Clinical Trials (jRCT2041200071) on 10 December 2020.

High-cost treatments for advanced lung cancer in Japan (Lung Cancer Study Group of the Japan Clinical Oncology Group).

BACKGROUND: The treatment of lung cancer has made dramatic progress in the past decade, but due to the high cost of drugs, the total pharmaceutical cost has been rising explosively. There are currently no data available in Japan on which regimens are used, to what extent they are used, and what their total cost is. METHODS: Sixty Japanese centers belonging to the Lung Cancer Study Group of the Japan Clinical Oncology Group were surveyed for information about the first-line treatment for advanced lung cancer in practice from July 2021 to June 2022. Three types of cancer were included: driver gene mutation-negative NSCLC, EGFR mutation-positive NSCLC, and extensive-stage small cell lung cancer (ES-SCLC). RESULTS: Recent treatment costs for ICIs or ICI plus chemotherapy were about 20-55 times higher than those for conventional chemotherapy. Of the 3738 patients with driver gene aberration-negative NSCLC, 2573 (68.8%) received treatments with monthly cost of 500 000 Japanese yen (JPY) or more; 2555 (68.4%) received ICI therapy. Of the 1486 patients with EGFR mutation-positive NSCLC, 1290 (86.8%) received treatments with a monthly cost of 500 000 JPY or more; 1207 (81.2%) received osimertinib. ICI treatments with a monthly cost of 500 000 JPY or more were administered to 607 (56.3%) of 1079 patients with ES-SCLC. Elderly NSCLC patients received slightly more high-cost treatment than younger patients. CONCLUSION: Recent treatments cost many times more than conventional chemotherapy. This study revealed that high-cost treatments were widely used in advanced lung cancer and some of high-cost treatments were used despite the lack of clear evidence. Physicians should pay attention to the cost of treatments they use.

Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study.

BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.

Concordance of ALK fusion gene-rearrangement between immunohistochemistry and next-generation sequencing.

BACKGROUND: Although various companion diagnostic tests of ALK fusion gene-rearrangement are approved, few reports have assessed the concordance of ALK fusion gene-rearrangement in two companion diagnostic tests: next-generation sequencing (NGS) testing and immunohistochemistry (IHC). METHODS: The samples evaluated for gene alterations using NGS testing between May 2019 and November 2021 were included in this study. The inclusion criteria were as follows: samples were diagnosed with non-small cell lung cancer; the results of the NGS analysis were informative; and samples had residual specimens for IHC. We performed IHC on the residual specimens and retrospectively collected sample characteristics from medical records. RESULTS: A total of 185 samples were analyzed using NGS. Twenty-six samples were excluded because of failure to analyze gene alterations using NGS, no residual samples, and inadequate IHC. We analyzed 159 samples. The major histological type was adenocarcinoma (115 samples). The number of surgical and transbronchial lung biopsy specimens was 59 and 56, respectively. ALK fusion gene-rearrangement was detected in four samples using NGS, and five were detected using IHC. The sensitivity and specificity of IHC referred to by NGS were 75.0% and 98.7%, respectively. The concordance rate between IHC and NGS was 98.1%. ALK rearrangement was detected in two patients using IHC but not using NGS. In addition, ALK rearrangement was detected in one patient using NGS but not using IHC. CONCLUSION: Our results suggest that IHC and NGS might be complementary tests. In patients suspected of harboring ALK fusion gene-rearrangement, it should be analyzed using another diagnostic method.

The efficacy and safety of anamorelin among patients with diabetes.

BACKGROUND: Anamorelin is a selective ghrelin receptor agonist approved for cancer cachexia in Japan. Little is known about predictors of anamorelin efficacy. This study aimed to assess the effect of diabetes on the efficacy and safety of anamorelin in patients with cancer cachexia. METHODS: Medical records of patients with advanced non-small-cell lung, gastric, pancreatic, or colorectal cancer who received anamorelin between January 2021 and March 2023 were retrospectively reviewed. The diabetic (DM) group included patients with a confirmed diagnosis of type 2 diabetes mellitus, random plasma glucose of ≥ 200 mg/dL, or hemoglobin A1c of ≥ 6.5%. The maximum body weight gain and adverse events during anamorelin administration were compared between the DM and non-DM groups. Patients with a maximum body weight gain ≥ 0 kg were classified as the responders. RESULTS: Of 103 eligible patients, 31 (30.1%) were assigned to the DM group. The DM group gained less weight (median of -0.53% vs. + 3.00%, p < 0.01) and had fewer responders (45.2% vs. 81.9%, p < 0.01) than the non-DM group. The odds ratio for non-response in the DM group was 6.55 (95% confidential interval 2.37-18.06, p < 0.01), adjusted by age and performance status. The DM group had a higher cumulative incidence of hyperglycaemic adverse events (72.2% vs. 6.3%, p < 0.01) and more discontinuations due to hyperglycaemic adverse events (25.8% vs. 4.2%, p < 0.01) than the non-DM group. CONCLUSIONS: Patients with diabetes and cancer cachexia are less likely to gain weight with anamorelin despite a high risk of hyperglycaemic adverse events.

Immunohistochemical analysis of B7-H3 expression in patients with lung cancer following various anti-cancer treatments.

B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0-3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3.

Validation of the initial brain metastasis velocity in non-small cell lung cancer at a single cancer center.

PURPOSE: The initial brain metastasis velocity (iBMV) was recently reported as a survival predictor after brain metastases (BM) in patients treated by stereotactic radiosurgery. In this study, we validated whether iBMV is a prognostic tool, regardless of treatment modality, in patients with non-small cell lung cancer (NSCLC) with metachronous BM. METHODS: We retrospectively reviewed consecutive 3,792 new lung cancer cases in which no BM was found on magnetic resonance (MR) screening between February 2014 and December 2019, and enrolled 176 NSCLC patients with subsequent BM. Overall survival (OS) was calculated from the date of MR to identify the time from BM to death. RESULTS: The median iBMV score was 1.9. We used an iBMV score of 2.0 as the cutoff level, as previously reported. An iBMV score ≥ 2.0 was significantly associated with older age, high neutrophil-to-lymphocyte ratio, and Stage IV (P = 0.04, 0.02, and 0.02, respectively). The median OS was 0.92 years. The median OS for patients with iBMV score ≥ 2.0 and < 2.0 were 0.59 years and 1.33 years, respectively (P < 0.001). Multivariate analysis showed that an iBMV score ≥ 2.0, ECOG performance status score of 1-3, Stage IV, and non-adenocarcinoma histology were independent poor prognostic factors (hazard ratio (HR), 1.94; P = 0.0001; HR, 1.53; P = 0.04; HR, 1.45; P = 0.04; and HR, 1.14; P = 0.03, respectively). Patients with iBMV scores of < 2.0 were more likely to undergo craniotomy or stereotactic irradiation. CONCLUSIONS: An iBMV score ≥ 2.0 is an independent predictor of survival in NSCLC patients with metachronous BM, regardless of the treatment modality.

Prognostic impact of pneumonitis after durvalumab therapy in patients with locally advanced non-small cell lung cancer.

BACKGROUND: Prognostic data on Japanese patients receiving durvalumab after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC) are insufficient. Whether pneumonitis has prognostic implications in patients with LA-NSCLC who have received durvalumab also remains unclear. METHODS: We retrospectively assessed the data of 82 consecutive patients who had received durvalumab after CRT at our institution between May 2018 and August 2020. A multi-state model was used to establish the associations between co-variables and progression-free survival (PFS). RESULTS: The median observation period for all the censored cases was 14.5 months (5.7-28.9 months), the median PFS was 22.7 months, and the 12-month PFS rate was 62.3% (95% CI: 50.2%-72.3%). The median percentage of the lung volume receiving a radiation dose in excess of 20 Gray (V20) was 22% (4%-35%). Thirteen patients (16%) had Grade 1 pneumonitis before receiving durvalumab, and 62 patients developed pneumonitis after durvalumab (Grades 1, 2, and 3 in 25 [30%], 32 [39%], and 4 [5%], respectively). Twenty-four patients (29%) completed the 1-year durvalumab treatment period, 16 patients (20%) were continuing to receive treatment, and 42 (51%) had discontinued treatment. In a multi-state analysis, patients with pneumonitis before durvalumab therapy had a poorer PFS than those without pneumonitis (HR: 4.29, p = 0.002). The development of Grade 2 or higher pneumonitis after durvalumab was not a significant prognostic factor for PFS (HR: 0.71, p = 0.852). CONCLUSION: Grade 2 or higher pneumonitis after durvalumab was not a prognostic factor of PFS in LA-NSCLC patients received durvalumab.

Long-term survival data of patients with limited disease small cell lung cancer: a retrospective analysis.

INTRODUCTION: In patients with limited disease small cell lung cancer (LD-SCLC) treated with concurrent chemoradiotherapy (CCRT), long-term survival data have not been fully evaluated. Moreover, the association between long-term prognosis and prognostic factors has not been sufficiently investigated. METHODS: In this retrospective study, we evaluated the efficacy of CCRT in 120 patients with LD-SCLC with a plan for curative CRT using concurrent accelerated hyperfractionated radiotherapy. RESULTS: The patients had a median age of 65.5 years, predominantly male (73%), and had clinical stage III disease (80%). The median follow-up time for overall survival (OS) was 72.2 months, median OS was 42.5 months, and the 3-year and 5-year survival rates were 52.4% and 41.8%, respectively. The median progression-free survival (PFS) was 12.5 months, and the 3-year and 5-year PFS rates were 37.6% and 33.6%, respectively. The 5-year OS rates of patients who achieved PFS at each time point were 70.9%, 83.6%, and 91.9% at 12, 24, and 36 months, respectively. The gradual increase in the 5-year OS rate following PFS extension and initial depression of the Kaplan-Meier curve showed disease progression frequently occurred in the first 2 years after initiation of CCRT. The Cox proportional hazards model showed no significant factors correlated with long-term survival through univariate and multivariate analyses. Although the prognostic factors associated with long-term prognosis in LD-SCLC were not identified, the 5-year survival rate was 41.8%, and among patients without disease progression at 2 years, the 5-year survival rate was 83.6%. CONCLUSION: These data suggested that the prognosis of patients with LD-SCLC was improving.

The real-world safety of atezolizumab as second-line or later treatment in Japanese patients with non-small-cell lung cancer: a post-marketing surveillance study.

BACKGROUND: We conducted a post-marketing surveillance study to evaluate the clinical tolerability and safety of atezolizumab in Japanese patients with non-small-cell lung cancer (NSCLC). METHODS: This prospective, observational post-marketing cohort study was conducted in NSCLC patients who received atezolizumab 1200 mg every 3 weeks at 770 facilities in Japan between April 18, 2018, and March 31, 2020 (study number UMIN000031978). Case report forms were completed, recording patient characteristics, treatment details, adverse events, adverse drug reactions (ADRs), their severity, onset and outcomes. Follow-up was for 12 months or until atezolizumab discontinuation. RESULTS: Overall, 2570 patients were included, median age was 69.0 years, and 69.9% were males. ADRs were reported in 29.1% of patients, most commonly pyrexia (4.2%). Grade ≥ 3 ADRs occurred in 9.7% of patients aged <75 and 9.7% of those aged ≥75 years. The incidence of Grade ≥ 3 ADRs was not affected by the number of lines of previous treatment or the presence or history of an autoimmune disorder. Immune-related ADRs of interest that occurred in >1% of patients were interstitial lung disease (ILD; 4.4%), endocrine disorder (4.3%), and hepatic dysfunction (2.8%). ILD was significantly more common in patients with a history of, or concurrent, ILD versus those without (P ≤ 0.001). Risk factors of Grade ≥ 3 ADRs were a history of, or concurrent, ILD. Grade 5 ADRs occurred in 35 patients, 11 of whom had concurrent ILD. CONCLUSIONS: This large cohort study confirmed the clinical tolerability of atezolizumab in a real-world group of Japanese patients with NSCLC.

Impact of weight loss on treatment with PD-1/PD-L1 inhibitors plus chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy have become the standard first line of treatment in patients with advanced non-small-cell lung cancer (NSCLC). However, few studies have explicitly focused on the impact of weight loss on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy. Thus, we evaluated the clinical implications of weight loss on the survival outcomes in patients who received this treatment. METHODS: We conducted a retrospective review of medical records of patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors plus chemotherapy from December 2018 to December 2020. Significant weight loss was defined as an unintentional weight loss of 5% or more over 6 months. We evaluated the progression-free survival (PFS) and overall survival (OS) of patients with or without weight loss. RESULTS: Among the 80 included patients, 37 (46%) had weight loss, and were associated with a lower objective response rate (30 vs 51%, P < 0.05), poorer PFS (2.3 vs 12.0 months, P < 0.05), and poorer OS (10.8 vs 23.9 months, P < 0.05) than those without weight loss. The Cox proportional-hazard ratios (95% confidence interval) of weight loss were 1.77 (1.01-3.10) for PFS and 2.90 (1.40-6.00) for OS, with adjustments for Eastern Cooperative Oncology Group performance status, PD-L1 tumour proportion score, histology, and central nervous system metastases. CONCLUSION: Pre-treatment weight loss may reduce treatment efficacy and shorten survival time in patients receiving PD-1/PD-L1 inhibitors plus chemotherapy. Early evaluation and intervention for weight loss might improve oncological outcomes in patients with advanced NSCLC.

Multi-institutional feasibility study of intensity-modulated radiotherapy with chemotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: This multi-institutional clinical trial evaluated the feasibility of intensity-modulated radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: The major inclusion criteria were clinical stage III NSCLC, age 20-74 years, and Eastern Cooperative Oncology Group performance status 0-1. Patients were treated with either cisplatin + S-1 (CS; four cycles every 4 weeks) or carboplatin + paclitaxel (CP; administered weekly with thoracic radiotherapy [RT], plus two consolidation cycles) concurrently with IMRT (60 Gy in 30 fractions). The primary endpoint was a treatment completion rate, defined as at least two cycles of CS or five cycles of CP during IMRT and completing 60 Gy IMRT within 56 days after the start of treatment, assumed its 90% confidence interval exceeds 60%. RT quality assurance was mandatory for all the patients. RESULTS: Twenty-two patients were registered. One patient withdrew due to pulmonary infection before starting treatment. RT plans were reviewed and none was judged as a protocol violation. Grade 2 and 3 pneumonitis occurred in four (19%) and one (5%) patients, respectively. Seventeen patients met the primary endpoint, with a treatment completion rate of 77.3% (90% confidence interval [CI] 58.0%-90.6%). Four patients failed to complete chemotherapy due to chemotherapy-related adverse events, but 20 patients completed IMRT. There were no treatment-related deaths. The 2-year progression-free and overall survival rates were 31.8% (95% CI 17.3%-58.7%) and 77.3% (95% CI 61.6%-96.9%), respectively. CONCLUSION: The treatment completion rate did not meet the primary endpoint, but 20 of 22 patients completed IMRT.

Osteosclerotic change as a therapeutic response to gefitinib in symptomatic non-small cell lung cancer bone metastasis.

BACKGROUND: Despite improvement in the overall survival of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, the effects of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment on bone metastasis remain unclear. This study investigated radiological responses to gefitinib regarding bone metastasis in patients. METHODS: We treated 260 patients with NSCLC and symptomatic bone metastasis. Thirty-seven patients harboring EGFR mutation were treated with gefitinib for more than 30 days and followed up for more than 3 months (GEF group). We performed a retrospective observational study by selecting 36 cases without EGFR-TKI treatment, at least 3 months of follow-up, and at least two radiological evaluations as the control group. We assessed the best overall radiological response, interval from treatment initiation to appearance of a radiological response, and the local response maintenance rate. RESULTS: The best effect in the GEF group was 98% partial response or better, which was significantly higher than the 57% observed in the control group (p < 0.001). The GEF and control groups maintained 83% and 42% local response maintenance rates at one year, respectively (p < 0.001). In the GEF with radiotherapy group, the local response maintenance rate was maintained at 92% at 1 year, while in the GEF without RT group, there was a decrease in the local response maintenance rate from 270 days. CONCLUSION: Gefitinib treatment for bone metastases in patients harboring EGFR mutation resulted in a beneficial osteosclerotic change in most patients. Combined gefitinib and radiotherapy provide long-lasting local control of bone metastases.

Proposing synchronous oligometastatic non-small-cell lung cancer based on progression after first-line systemic therapy.

Despite the importance of accurate disease definitions for effective management and treatment decisions, there is currently no consensus on what constitutes oligometastatic non-small-cell lung cancer (NSCLC). Predominant patterns of initial progressive disease (PD) after first-line systemic therapy have been shown to be a substantial basis for local ablative therapy (LAT) for all disease sites in patients with oligometastatic NSCLC, suggesting that these patterns could be helpful in defining synchronous oligometastatic NSCLC. Therefore, this retrospective study aimed to propose a threshold number of metastases for synchronous oligometastatic NSCLC, based on the pattern of initial PD after first-line systemic therapy. The cut-off threshold number of metastases compatible with synchronous oligometastatic NSCLC was determined using receiver operating characteristic (ROC) curve analyses of PD at the initially involved sites alone. ROC analysis of 175 patients revealed that the presence of 1-3 metastases before first-line treatment (sensitivity, 85.9%; specificity, 97.3%; area under the curve, 0.91) was compatible with oligometastatic NSCLC, therefore we divided patients into oligometastatic NSCLC and non-oligometastatic NSCLC groups. Multivariate logistic regression analyses revealed oligometastatic NSCLC to be the only independent predictor of PD at initially involved sites alone (odds ratio 165.7; P < .001). The median survival times in patients with oligometastatic or non-oligometastatic NSCLC were 23.0 and 10.9 mo (hazard ratio, 0.51; P = .002), respectively. Based on these findings, we propose synchronous oligometastatic NSCLC as 1-3 metastases in accordance with patterns of initial progression. The result of our study might be contributory to provide a common definition of synchronous oligometastatic NSCLC.

Comparison of clinical features between immune-related sclerosing cholangitis and hepatitis.

Background Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis. Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness. Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P < 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively. Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020).

Retrospective analysis of osimertinib re-challenge after osimertinib-induced interstitial lung disease in patients with EGFR-mutant non-small cell lung carcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0-80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.

Rechallenge with previously administered epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer with leptomeningeal metastasis.

Objectives In EGFR-mutated non-small cell lung cancer (NSCLC) patients, approximately 80-90% of leptomeningeal metastasis (LM) develops after failed initial treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI). However, the efficacy of rechallenging with previously administered EGFR-TKIs in patients with EGFR-mutated NSCLC and the LM that develops following EGFR-TKI treatment failure remains unknown. Materials and methods We retrospectively reviewed medical records of patients with EGFR-mutated NSCLC and LM, from November 2011 to August 2019. The patients were classified according to the LM treatment type: switched to previously unadministered EGFR-TKIs (Switch-TKI) or rechallenge with previously administered EGFR-TKIs (Rechallenge-TKI). Results In total, 50 patients treated with EGFR-TKI after LM diagnosis were included; 35 were treated with Switch-TKI and 15 with Rechallenge-TKI. The median overall survival (OS) from the time of LM diagnosis was 6.2 months in all study patients. According to the treatment type, the median OS from the time of LM diagnosis was 6.9 months in Switch-TKI patients and 4.9 months in Rechallenge-TKI patients. There was no significant difference in the OS between the Switch-TKI and Rechallenge-TKI groups (P = 0.864). Thirty-five patients were treated with erlotinib and 15 with osimertinib; Regardless of the type for EGFR-TKI, there was no significant difference in OS between patients treated with Switch-TKI and those treated with Rechallenge-TKI. Conclusion Rechallenge of previously administered EGFR-TKIs may be a therapeutic option for LM development after EGFR-TKI treatment failure in patients with EGFR-mutated NSCLC, not only switching to previously unadministered EGFR-TKIs.

Association between oligo-residual disease and patterns of failure during EGFR-TKI treatment in EGFR-mutated non-small cell lung cancer: a retrospective study.

BACKGROUND: Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI. METHODS: Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 - 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated. RESULTS: A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P < 0.001), the lack of residual central nervous system metastases (P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites. CONCLUSIONS: This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment.

Long-term outcomes in extensive disease small cell lung cancer patients treated without immune checkpoint inhibitors.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have been approved as first-line treatment for patients with untreated extensive disease-small cell lung cancer (ED-SCLC). However, there are few reports about the long-term outcomes in patients with ED-SCLC treated without ICIs. Thus, we analyzed the long-term outcomes in patients with ED-SCLC. METHODS: We retrospectively examined the medical records of patients with SCLC who were treated at our hospital between September 2002 and September 2019. The main inclusion criteria were as follows: (i) histological or cytological confirmation of SCLC, (ii) diagnosed with ED-SCLC and (iii) received chemotherapy, not including ICIs, as the first-line treatment. To assess the trends of treatment outcomes, we compared the survival outcomes between 2002-2010 (early) and 2011-2019 (late) groups. RESULTS: A total of 314 patients were included in this study. Patient characteristics at the time of first-line treatment were as follows: median age was 69 years; 82% of the patients were male and 70% had a performance status of 0 or 1. The median follow-up time of overall survival (OS) was 7.4 years, and 89% of the patients died. The median progression-free survival and survival time were 4.9 and 12.1 months, respectively. Five-year survival rate was 2%. There was no significant difference in survival between the early and late groups. CONCLUSIONS: We found that the long-term outcomes in ED-SCLC patients treated without ICIs were poor. Prior to the approval of ICI treatment for ED-SCLC, there was no improvement in the OS for ~20 years.