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Introduction Small cell bladder cancer is a relatively rare tumor, representing

Abstract Background Amrubicin (AMR) regimens have shown efficacy as second‐line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P‐PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P‐PEG as second‐line chemotherapy for SCLC. Methods We retrospectively reviewed patients with SCLC who received AMR as second‐line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P‐PEG in their regimen, patients (n = 60) were divided into P‐PEG (n = 21) and non‐P‐PEG groups, and their clinical outcomes were evaluated. Results Median of AMR treatment cycles was five (range: 1–39 cycles) in P‐PEG group and four (range: 1–15 cycles) in non‐P‐PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P‐PEG group than in the non‐P‐PEG group. The objective response rates were 52.4% and 30.8%, and median progression‐free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P‐PEG and non‐P‐PEG groups, respectively. Conclusions AMR with P‐PEG as second‐line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P‐PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Background: Amrubicin (AMR) regimens have shown efficacy as second‐line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P‐PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P‐PEG as second‐line chemotherapy for SCLC. Methods: We retrospectively reviewed patients with SCLC who received AMR as second‐line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P‐PEG in their regimen, patients (n = 60) were divided into P‐PEG (n = 21) and non‐P‐PEG groups, and their clinical outcomes were evaluated. Results: Median of AMR treatment cycles was five (range: 1–39 cycles) in P‐PEG group and four (range: 1–15 cycles) in non‐P‐PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P‐PEG group than in the non‐P‐PEG group. The objective response rates were 52.4% and 30.8%, and median progression‐free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P‐PEG and non‐P‐PEG groups, respectively. Conclusions: AMR with P‐PEG as second‐line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P‐PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC. [ABSTRACT FROM AUTHOR]

Abstract Background Amrubicin (AMR) has become the standard of care for post‐relapse small cell lung cancer (SCLC). It has also been reported to achieve long‐term disease control in patients with good treatment response. However, the optimal patient population for whom AMR is effective and the factors associated with long‐term disease control are yet to be identified. The aim of the study was to identify the clinical characteristics and factors associated with long‐term disease control in patients with recurrent SCLC who would benefit from AMR therapy. Methods The clinical records of 33 patients diagnosed with recurrent SCLC and treated with AMR were retrospectively reviewed. Clinical information was compared between patients who achieved disease control (effective group) and who developed disease progression (noneffective group) on the first efficacy assessment after AMR and between patients who continued AMR for more than seven cycles (maintenance group) and those who terminated treatment after 1–6 cycles (discontinuation group). Results The noneffective group included significantly more patients with AMR dose reductions after the second cycle (p = 0.006). AMR dose reduction was an independent risk factor for disease progression. The maintenance group had significantly lower pretreatment lactate dehydrogenase (LDH) levels than the discontinuation group (p = 0.046). A high LDH level was an independent risk factor for short AMR discontinuation. Overall survival was significantly longer in the effective group than in the noneffective group (p

Background: Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose (40 mg/m2) is problematic; the optimal dose remains undetermined. Patients and methods: To evaluate the optimal dose of AMR in terms of efficacy and safety, we reviewed consecutive data on patients with relapsed SCLC who received AMR at doses of 40, 35, and 30 mg/m2 (on days 1–3) at Nippon Medical School Hospital between October 2010 and November 2021. Results: We reviewed the data of 86 patients (20, 45, 27 who received AMR doses of 40, 35, 30 mg/m2, respectively) according to our study criteria. For patients ≥ 75 years, the proportion who received second-line treatment tended to be higher in the 30–35 mg/m2 group. Objective response rates were 37/46/35%, median progression-free survival (PFS) were 3.0/4.7/3.2 months, and median overall survival (OS) were 7.8/16.3/8.0 months, respectively. Grade 4 neutropenia occurred in 58/39/31% of patients, which was higher for the 40 mg/m2 group. The incidence of febrile neutropenia did not differ between groups. Multivariate analysis identified the AMR dose was not associated with longer PFS and OS. Conclusion: Treatment with AMR between 30 and 35 mg/m2 showed relatively mild hematologic toxicity compared with AMR at 40 mg/m2, without any significant difference in efficacy. Lower dose of AMR for relapsed SCLC could be a promising treatment option. [ABSTRACT FROM AUTHOR]

Abstract Background The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non–small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second‐line amrubicin (AMR) following first‐line platinum‐based chemotherapy and ICI combination therapy (chemo‐ICI) in SCLC. Patients and Methods We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second‐line following chemo‐ICI as first‐line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy‐enhancing variables of AMR. Results Overall, 89 patients treated with AMR after first‐line chemo‐ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1–39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27–3.65). Patients who relapsed more than 90 days after receiving first‐line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in

Background: Amrubicin (AMR) has become the standard of care for post‐relapse small cell lung cancer (SCLC). It has also been reported to achieve long‐term disease control in patients with good treatment response. However, the optimal patient population for whom AMR is effective and the factors associated with long‐term disease control are yet to be identified. The aim of the study was to identify the clinical characteristics and factors associated with long‐term disease control in patients with recurrent SCLC who would benefit from AMR therapy. Methods: The clinical records of 33 patients diagnosed with recurrent SCLC and treated with AMR were retrospectively reviewed. Clinical information was compared between patients who achieved disease control (effective group) and who developed disease progression (noneffective group) on the first efficacy assessment after AMR and between patients who continued AMR for more than seven cycles (maintenance group) and those who terminated treatment after 1–6 cycles (discontinuation group). Results: The noneffective group included significantly more patients with AMR dose reductions after the second cycle (p = 0.006). AMR dose reduction was an independent risk factor for disease progression. The maintenance group had significantly lower pretreatment lactate dehydrogenase (LDH) levels than the discontinuation group (p = 0.046). A high LDH level was an independent risk factor for short AMR discontinuation. Overall survival was significantly longer in the effective group than in the noneffective group (p < 0.001). Conclusions: In AMR therapy for patients with relapsed SCLC, continuation of AMR without dose reduction after the second cycle may contribute to disease control and prolonged survival. [ABSTRACT FROM AUTHOR]

Abstract Background Etoposide plus cisplatin (EP) combined with concurrent accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard treatment strategy for unresectable limited‐disease (LD) small cell lung cancer (SCLC), which has remained unchanged for over two decades. Based on a previous study that confirmed the non‐inferiority of amrubicin (AMR) plus cisplatin (AP) when compared with EP for extensive‐disease (ED) SCLC, we have previously conducted a phase I study assessing AP with concurrent TRT (2 Gy/time, once daily, 50 Gy in total) for LD‐SCLC therapy. Our findings revealed that AP with concurrent TRT could prolong overall survival to 39.5 months with manageable toxicities. Therefore, we plan to conduct a phase I study to investigate and determine the effect of AP combined with AHTRT, recommended dose (RD), maximum tolerated dose (MTD), and dose‐limiting toxicity (DLT) of AP in patients with LD‐SCLC. Methods Treatment‐naive patients with LD‐SCLC, age between 20 and 75 years, who had a performance status of 0 or 1 and adequate organ functions will be enrolled. For chemotherapy, cisplatin 60 mg/m2/day (day 1) and AMR (day 1 to 3) will be administered with AHTRT (1.5 Gy/time, twice daily, 45 Gy in total). The initial AMR dose is set to 25 mg/m2/day. RD and MTD will be determined by evaluating toxicities. Discussion Based on our previous study, the initial dose of AMR 25 mg/m2 is expected to be tolerated and acceptable. Here, we aim to determine whether treatment with AP and concurrent AHTRT would be an optimal choice with manageable toxicities for LD‐SCLC.

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

This study examined the activity and safety of amrubicin monotherapy among relapsed small-cell lung cancer (SCLC) patients who had previously been treated with atezolizumab plus carboplatin and etoposide (AteCE). This retrospective study evaluated patients with relapsed SCLC who were treated with previously AteCE combination therapy followed by amrubicin monotherapy between August 2019 and May 2021. Clinical efficacy and toxicity were analyzed. Overall, 40 patients were included: 12 and 28 patients had sensitive and refractory relapse, respectively. The response rate was 32.5% (25.0% in the sensitive group and 35.7% in the refractory group). The median progression-free survival (PFS) and overall survival (OS) from the first amrubicin treatment was 3.4 months (95% CI: 1.9–4.9 months) and 9.9 months (95% CI: 4.5–11.5 months), respectively. There was no significant between-group difference in median PFS (3.6 months vs. 3.2 months, p = 0.42) or median OS (11.2 months vs. 7.3 months, p = 0.78). Grade ≥ 3 hematological adverse events occurred as follows: decreased white blood cells in 52.5% of patients; decreased neutrophil count in 57.5%; and febrile neutropenia in 10.0%. Grade 3 pneumonitis was observed in one patient. There were no treatment-related deaths. Amrubicin is feasible and effective for relapsed SCLC patients previously treated with AteCE therapy. Although immune checkpoint inhibitor treatment (ICI) does not improve the effect of amrubicin, the toxicity is not increased, suggesting that amrubicin remains effective even after ICI administration. Thus, amrubicin after AteCE could be the preferred standard chemotherapeutic choice in patients with relapsed SCLC. [ABSTRACT FROM AUTHOR]

Background: We conducted a randomize phase II study to evaluate the efficacy and safety of topoisomerase II inhibitor amrubicin plus topoisomerase I inhibitor irinotecan (AI) compared with cisplatin plus irinotecan (PI) as first-line therapy in patients with extensive-disease (ED) small-cell lung cancer (SCLC)., Patients and Methods: Chemo-naïve patients with pathologically proven ED-SCLC (including limited disease (LD) SCLC with malignant effusion) were enrolled. Patients were randomized 1:1 to receive either AI (amrubicin 90mg/m 2 on day 1 and irinotecan 50mg/m 2 on days 1 and 8 of a 21-day cycle) or PI (cisplatin 60mg/m 2 on day 1 and irinotecan 60mg/m 2 on days 1, 8 and 15 of a 28-day cycle). The primary endpoint was overall survival proportion at 1 year., Results: A total of 100 patients were randomly assigned to AI (n = 50) or to PI (n = 50). The 1-year overall survival proportions were 68.0% (95% confidence interval (CI): 56.2-82.2%) for AI and 59.2% (46.9-74.7%) for PI (1-sided P = .18). Median survival time was 14.8 months for AI and 13.5 months for PI with a hazard ratio (HR) of 0.618 (0.398-0.961, stratified log-rank test P = .031). Median progression-free survival time was 4.8 months for AI and 5.4 months for PI (stratified log-rank test, P = .54). Objective response rate was 70.0% (55.4-82.1%) for AI and 55.1% (40.2-69.3%) for PI (Fisher exact test, P = .15). There was no significant difference in hematological toxicity, whereas rates of vomiting, loss of appetite, diarrhea, and elevated serum creatinine are more frequent in PI. Interstitial lung disease (Grade 2 or 3) developed in 5 patients in AI and in 1 patient in PI. There was no treatment-related death., Conclusion: Although the study did not meet its primary endpoint, AI showed promising efficacy and good tolerability in chemo-naïve patients with ED-SCLC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Simple Summary: Therapeutic efficacy of chemotherapy combined with immune checkpoint inhibitors as first-line therapy has been previously demonstrated in extensive-stage small cell lung cancer. However, there are no reports of any cytotoxic drug that is effective as second-line therapy in extensive-stage small cell lung cancer patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. In the present study, we retrospectively evaluated patients with extensive-stage small cell lung cancer to clarify whether the previous treatment with chemotherapy and immune checkpoint inhibitors impacts the efficacy and safety of amrubicin as a second-line treatment. This study shows that the efficacy and safety of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with chemotherapy and immune checkpoint inhibitors. Adding an immune checkpoint inhibitor to chemotherapy to treat extensive-stage small cell lung cancer is effective. However, there are no reports of an effective second-line treatment in patients previously treated with chemotherapy and immune checkpoint inhibitors as a first-line treatment. Here, we assessed the efficacy and safety of amrubicin as a second-line treatment for extensive-stage small cell lung cancer after chemotherapy and immune checkpoint inhibitor combination therapy. The study enrolled 150 patients with extensive-stage small cell lung cancer. The efficacy and the incidence of adverse events were compared between patients previously treated with immune checkpoint inhibitors and patients without previous immune checkpoint inhibitor treatment. One hundred and twenty-three patients were eligible. There was no difference in objective response rate, time-to-treatment failure, progression-free survival, and overall survival between both groups. The incidence of adverse events was similar in both treatment groups. Pretreatment with immune checkpoint inhibitors was not associated with an increase in amrubicin-related adverse events. This study shows that the efficacy of amrubicin in extensive-stage small cell lung cancer remains unchanged irrespective of previous treatment with immune checkpoint inhibitors. Amrubicin-related adverse events did not increase in patients previously treated with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Etoposide plus cisplatin (EP) combined with concurrent accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard treatment strategy for unresectable limited‐disease (LD) small cell lung cancer (SCLC), which has remained unchanged for over two decades. Based on a previous study that confirmed the non‐inferiority of amrubicin (AMR) plus cisplatin (AP) when compared with EP for extensive‐disease (ED) SCLC, we have previously conducted a phase I study assessing AP with concurrent TRT (2 Gy/time, once daily, 50 Gy in total) for LD‐SCLC therapy. Our findings revealed that AP with concurrent TRT could prolong overall survival to 39.5 months with manageable toxicities. Therefore, we plan to conduct a phase I study to investigate and determine the effect of AP combined with AHTRT, recommended dose (RD), maximum tolerated dose (MTD), and dose‐limiting toxicity (DLT) of AP in patients with LD‐SCLC. Methods: Treatment‐naive patients with LD‐SCLC, age between 20 and 75 years, who had a performance status of 0 or 1 and adequate organ functions will be enrolled. For chemotherapy, cisplatin 60 mg/m2/day (day 1) and AMR (day 1 to 3) will be administered with AHTRT (1.5 Gy/time, twice daily, 45 Gy in total). The initial AMR dose is set to 25 mg/m2/day. RD and MTD will be determined by evaluating toxicities. Discussion: Based on our previous study, the initial dose of AMR 25 mg/m2 is expected to be tolerated and acceptable. Here, we aim to determine whether treatment with AP and concurrent AHTRT would be an optimal choice with manageable toxicities for LD‐SCLC. [ABSTRACT FROM AUTHOR]

Abstract Background A cisplatin plus irinotecan (CPT‐11) regimen is used for patients with extensive disease small cell lung cancer (ED‐SCLC). Amrubicin (AMR) is primarily used for relapsed SCLC. The HOT1401/NJLCG1401 trial, an open‐label randomized phase II trial, was designed to assess the benefit of maintenance therapy in patients with ED‐SCLC who responded to induction therapy. Methods Patients with histologically‐ or cytologically‐confirmed ED‐SCLC were included and were treated with an induction therapy of four cycles of cisplatin (60 mg/m2 on day 1) plus CPT‐11 (60 mg/m2 on days 1, 8, and 15) every four weeks. After induction therapy, patients who had nonprogressive disease were randomized to receive either maintenance CPT‐11 (60 mg/m2 on days 1 and 8) every three weeks, or AMR (35 mg/m2 on days 1–3) every three weeks. Results A total of 34 patients were enrolled; 20 patients had progressive disease or received incomplete induction chemotherapy. Finally, 14 patients were randomly assigned to receive CPT‐11 (n = 7) or AMR (n = 7). This study was terminated prematurely because of low patient accrual. The overall objective response rate was 73%, the median PFS was 5.7 months (95% confidence interval [CI]: 3.6–11.8), and the median overall survival was 20.1 months (95% CI: 13.7–not reached). No statistically significant difference in progression‐free survival (PFS) were noted between patients treated with CPT‐11 and those treated with AMR. There were no treatment‐related deaths in this study. Conclusions Maintenance therapy with CPT‐11 or AMR after induction therapy might be effective in some patients.

Abstract Background Treatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe cardiac toxicities. Amrubicin (AMR) is a next‐generation anthracycline that is commonly used to treat lung cancer. Here, we conducted a phase II trial of this drug in patients with previously treated MPM. Methods Eligible patients with MPM having adequate organ function and a performance status of 0–2 were enrolled after disease progression following pemetrexed/platinum therapy. Patients received 35 mg/m2 AMR on days 1–3 every three weeks until tumor progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. Median progression‐free survival (PFS), overall survival (OS), number of treatment cycles, and adverse events were evaluated as secondary endpoints. Results This trial was discontinued because of low accrual. From September 2013 to July 2018, five patients with MPM were enrolled. Stable disease (SD) was observed in three patients (60%), and progressive disease was noted in two patients (40%). The median PFS was 2.4 (range, 1.2–11.2) months, and the median OS was 9.1 (range, 6.2–22.0) months. The median number of treatment cycles was three (range, 2–11). Grade 1/2 toxicities were observed in all patients. Grade 3/4 neutropenia was observed in four patients (80%), but there were no cases of febrile neutropenia. Conclusions Despite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM.

Background The aim of this study was to assess the efficacy and safety of amrubicin for previously treated malignant pleural mesothelioma. Methods The eligibility criteria were: previously treated unresectable malignant pleural mesothelioma; performance status 0–1; age ≤ 75; adequate hematological, hepatic, and renal function. The patients were injected with 35 mg/m2 amrubicin on days one, two, and three every 3–4 weeks. The planned number of patients was 32. Results The study was terminated due to delay in enrollment and 10 patients were subsequently enrolled (nine males and one female; median age 67 [range 49–73]), of which four had epithelioid tumors, three had sarcomatoid tumors and three had biphasic tumors, respectively. According to the International Mesothelioma Interest Group (IMIG), one, four, and four patients had stage II, III, and IV, respectively, and one had postoperative recurrence. There was one (10%) partial response, four (40%) had stable disease, and five (50%) patients exhibited disease progression. The overall response and disease control rates were 10% (95% CI: 0.3–44.5%) and 60% (95% CI: 26.2–87.8%), respectively. The median progression‐free survival time was 1.6 months. The median overall survival time was 6.6 months, and the one‐, two‐, and three‐year survival rates were 23%, 23%, and 0%, respectively. The observed grade 3 or 4 toxicities included neutropenia in six (60%) patients; leukopenia in five (50%) patients; and febrile neutropenia, thrombocytopenia, anemia, and pneumonia in one (10%) patient each. Conclusions There was not enough data to evaluate the efficacy because the study was terminated early. However, amrubicin showed limited activity and acceptable toxicities when used in previously treated malignant pleural mesothelioma patients.

Satoshi Igawa,1 Taihei Ono,1 Masashi Kasajima,1 Hideaki Manabe,1 Tomoya Fukui,1 Hisashi Mitsufuji,2 Masanori Yokoba,3 Masaru Kubota,3 Masato Katagiri,3 Jiichiro Sasaki,4 Katsuhiko Naoki1 1Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara-City, Kanagawa 252-0374, Japan; 2Kitasato University School of Nursing, Sagamihara-City, Kanagawa 252-0329, Japan; 3School of Allied Health Sciences, Kitasato University, Sagamihara-City, Kanagawa 252-0373, Japan; 4Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara-City, Kanagawa 252-0374, JapanCorrespondence: Satoshi IgawaDepartment of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-Ku, Sagamihara-City, Kanagawa 252-0374, JapanTel +81 42 778 8506Fax +81 42 778 6412Email igawa@kitasato-u.ac.jpPurpose: Amrubicin (AMR) is an anticancer drug for patients with relapsed small-cell lung cancer (SCLC). However, the efficacy of AMR in elderly patients with relapsed SCLC after chemotherapy by carboplatin plus etoposide (CE) has not been sufficiently evaluated.Patients and Methods: The medical records of patients with relapsed SCLC who received AMR as second-line chemotherapy were retrospectively reviewed, and their treatment outcomes were evaluated.Results: Forty-one patients with a median age of 76 years were analyzed. The overall response rate was 26.8%. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 8.1 months, respectively. While the median PFS of 4.7 and 2.8 months in the sensitive relapse and the refractory relapse group differed significantly (P=0.043), respectively, the median OS of 10.7 and 6.8 months in the respective relapse groups did not indicate a statistically significant difference (P=0.24). The median PFS in a group with a modified Glasgow prognostic score (mGPS) of 0 and a group with a mGPS 1 or 2 were 4.5 and 1.6 months (P=0.052), respectively, and the median OS in the respective mGPS groups were 10.7 and 4.4 months (P=0.034). Multivariate analysis identified good performance status, limited disease, and mGPS 0 as favorable independent predictors of PFS and OS of AMR monotherapy. Grade 3 or higher neutropenia was observed in 23 patients (56%), and febrile neutropenia was observed in nine patients (22%). Non-hematological toxic effects were relatively mild, and pneumonitis and treatment-related deaths were not observed.Conclusion: AMR is an effective and feasible regimen for elderly patients with relapsed SCLC after CE therapy.Keywords: small-cell lung cancer, amrubicin, elderly, second-line chemotherapy, modified Glasgow prognostic score

Abstract Background Amrubicin chemotherapy is a treatment option for patients with non‐small cell lung cancer (NSCLC) after third‐line treatment in Japan. Although topoisomerase‐II (Topo‐II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown. Methods Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo‐II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection. Results The majority of enrolled patients were men (68%) with a median age of 67 (range, 43–78) years. The most common histological type was adenocarcinoma (70%). High Topo‐II expression was observed in 13 (30%) of the 44 patients. The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression. Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. Conclusion Low expression of Topo‐II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo‐II inhibitor. Key points Significant findings of the study The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression. Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. What this study adds This study is the first to assess the effects of topoisomerase‐II (Topo‐II), a target of amrubicin, as a prognostic or predictive marker for chemosensitivity and clinical outcomes in the Japanese population.

Introduction: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.

Background: Treatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe cardiac toxicities. Amrubicin (AMR) is a next‐generation anthracycline that is commonly used to treat lung cancer. Here, we conducted a phase II trial of this drug in patients with previously treated MPM. Methods: Eligible patients with MPM having adequate organ function and a performance status of 0–2 were enrolled after disease progression following pemetrexed/platinum therapy. Patients received 35 mg/m2 AMR on days 1–3 every three weeks until tumor progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. Median progression‐free survival (PFS), overall survival (OS), number of treatment cycles, and adverse events were evaluated as secondary endpoints. Results: This trial was discontinued because of low accrual. From September 2013 to July 2018, five patients with MPM were enrolled. Stable disease (SD) was observed in three patients (60%), and progressive disease was noted in two patients (40%). The median PFS was 2.4 (range, 1.2–11.2) months, and the median OS was 9.1 (range, 6.2–22.0) months. The median number of treatment cycles was three (range, 2–11). Grade 1/2 toxicities were observed in all patients. Grade 3/4 neutropenia was observed in four patients (80%), but there were no cases of febrile neutropenia. Conclusions: Despite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM. [ABSTRACT FROM AUTHOR]

Background The efficacy of amrubicin for relapsed small‐cell lung cancer (SCLC) has been reported in previous studies. Few reports, however, describe the efficacy and survival benefit of third‐line amrubicin chemotherapy in patients with extensive disease (ED)‐SCLC. Methods We retrospectively analyzed the clinical records of ED‐SCLC patients treated with amrubicin salvage chemotherapy as a third‐line chemotherapy between January 2005 and July 2016 (salvage amrubicin group). The efficacy and toxicities of amrubicin were evaluated. Overall survival (OS) in the amrubicin salvage group was compared with OS among ED‐SCLC patients treated with at least second‐line chemotherapy between May 2000 and July 2016 and without subsequent amrubicin salvage chemotherapy. Results A total of 18 patients with a median age of 70 years were analyzed in the amrubicin salvage group. The median number of treatment cycles of amrubicin was four. The response rate was 27.8% (95% confidence interval (CI), 7.1%–48.5%), and the disease control rate (DCR) was 66.7% (95% CI, 44.9%–88.4%). Median progression‐free survival was 2.9 months (95% CI, 1.0–4.9 months), and median OS after an initial chemotherapy was 18.1 months (95% CI, 10.2–26.0 months). OS in the amrubicin salvage group was significantly longer than in the no‐amrubicin group (n = 19; 12.6 months, 95% CI, 11.5–13.8 months, P = 0.005). The frequency of neutropenia greater than grade 3 was 72.2%, with febrile neutropenia developing in 38.9% of patients in the amrubicin salvage group. Conclusions Despite a high frequency of febrile neutropenia, amrubicin salvage chemotherapy may improve OS in patients with relapsed ED‐SCLC.

Background The first‐line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination of nedaplatin and amrubicin would be a promising treatment approach for patients with SCC. Therefore, a phase II study of this chemotherapeutic combination was designed to evaluate its efficacy and safety for treatment‐naïve patients with advanced SCC. Methods A total of 21 treatment‐naïve patients with stage IIIB/IV or postoperative recurrent SCC were enrolled from six institutions. Nedaplatin (100 mg/m2) on day 1 and amrubicin (25 mg/m2) on days 1–3 were administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR), while the secondary endpoints included overall survival (OS), progression‐free survival (PFS), and drug toxicities. Results Partial response was observed in seven of 21 cases (ORR, 33.3%; 95% confidence interval [CI], 14.5–52.2). Disease control rate, which includes stable disease, was 71.4%. Median OS and PFS was 14.6 and 4.1 months, respectively. This regimen did not cause any treatment‐related deaths. Grade 3/4 neutropenia developed in 8 of 21 cases (38.1%); however, febrile neutropenia developed in only 9.5% of the cases. Grade 3/4 gastrointestinal or neuromuscular toxicities were not observed. Conclusion The efficacy of the combination of nedaplatin and amrubicin was comparable to that of other conventional chemotherapeutic regimens for treatment‐naïve patients with advanced SCC, and no severe gastrointestinal or neuromuscular toxicities were observed. This combination therapy may be an alternative treatment approach, particularly in patients who cannot tolerate gastrointestinal or neuromuscular toxicities.

Summary: Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0–1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (Ctrough) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1–5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the Ctrough of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582. [ABSTRACT FROM AUTHOR]

Background: The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and postprogression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy.Materials and Methods: We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman's rank correlation and linear regression analyses.Results: The correlation between PPS and OS was strong (r = 0.88, P < 0.05, R2 = 0.87), while that between PFS and OS was weak (r = 0.60, P < 0.05, R2 = 0.15). The number of regimens administered after disease progression postsecond-line chemotherapy was significantly associated with PPS (P = 0.003).Conclusions: OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess the efficacy and safety of amrubicin for previously treated malignant pleural mesothelioma. Methods: The eligibility criteria were: previously treated unresectable malignant pleural mesothelioma; performance status 0–1; age ≤ 75; adequate hematological, hepatic, and renal function. The patients were injected with 35 mg/m2 amrubicin on days one, two, and three every 3–4 weeks. The planned number of patients was 32. Results: The study was terminated due to delay in enrollment and 10 patients were subsequently enrolled (nine males and one female; median age 67 [range 49–73]), of which four had epithelioid tumors, three had sarcomatoid tumors and three had biphasic tumors, respectively. According to the International Mesothelioma Interest Group (IMIG), one, four, and four patients had stage II, III, and IV, respectively, and one had postoperative recurrence. There was one (10%) partial response, four (40%) had stable disease, and five (50%) patients exhibited disease progression. The overall response and disease control rates were 10% (95% CI: 0.3–44.5%) and 60% (95% CI: 26.2–87.8%), respectively. The median progression‐free survival time was 1.6 months. The median overall survival time was 6.6 months, and the one‐, two‐, and three‐year survival rates were 23%, 23%, and 0%, respectively. The observed grade 3 or 4 toxicities included neutropenia in six (60%) patients; leukopenia in five (50%) patients; and febrile neutropenia, thrombocytopenia, anemia, and pneumonia in one (10%) patient each. Conclusions: There was not enough data to evaluate the efficacy because the study was terminated early. However, amrubicin showed limited activity and acceptable toxicities when used in previously treated malignant pleural mesothelioma patients. [ABSTRACT FROM AUTHOR]

Background: Concurrent chemoradiotherapy (CCRT) is the gold standard for limited-stage small-cell lung cancer (LS-SCLC); however, most patients inevitably experience relapse. We hypothesized consolidation amrubicin following CCRT to be a potential treatment for LS-SCLC. Patients and Methods: All enrolled patients were treated using induction CCRT consisting of four cycles of etoposide and cisplatin plus concurrent thoracic radiotherapy. Eligible patients then received three cycles of amrubicin as consolidation therapy (consolidation population). The primary endpoint was the 2-year progression-free survival rate in the consolidation population. Results: Of the 36 intention-to-treat patients, 28 (78%) received amrubicin and 24 (67%) completed all planned treatments. The 2-year progression-free survival rate and overall response rate were 35.7% and 86%, respectively. The median progression-free and overall survival were 14.3 and 60.9 months, respectively. There were no treatment-related deaths in the intention-to-treat population. Conclusion: This study was terminated due to slow patient accrual; however, this treatment strategy was feasible and demonstrated promising efficacy. [ABSTRACT FROM AUTHOR]

Background: Amrubicin chemotherapy is a treatment option for patients with non‐small cell lung cancer (NSCLC) after third‐line treatment in Japan. Although topoisomerase‐II (Topo‐II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown. Methods: Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo‐II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection. Results: The majority of enrolled patients were men (68%) with a median age of 67 (range, 43–78) years. The most common histological type was adenocarcinoma (70%). High Topo‐II expression was observed in 13 (30%) of the 44 patients. The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression. Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. Conclusion: Low expression of Topo‐II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo‐II inhibitor. Key points: Significant findings of the study: The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively.While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression.Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. What this study adds: This study is the first to assess the effects of topoisomerase‐II (Topo‐II), a target of amrubicin, as a prognostic or predictive marker for chemosensitivity and clinical outcomes in the Japanese population. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) remains a challenging malignancy due to its aggressive nature and the lack of efficacious therapeutic interventions. Nanotechnology-based approaches exhibit promise in GBM treatment; however, the successful translation of these strategies from preclinical models to clinical settings is hindered by inefficient nanoparticle clearance from vital organs. Addressing this concern, we investigated the therapeutic potential of amrubicin (AMR) encapsulated within poly (lactic-co-glycolic acid) nanoparticles (AMR-PLGA-NPs) in combating temozolomide (TMZ) resistant GBM. The study demonstrated that AMR-PLGA-NPs exerted a pronounced inhibitory effect on the cellular viability and migratory capacity of TMZ-resistant GBM cells. Furthermore, these nanoparticles exhibited considerable efficacy in downregulating the PI3K/AKT signaling pathway, thereby inducing apoptosis specifically in TMZ-resistant glioma cells and glioma stem-like cells through the activation of PTEN. Notably, in vivo experimentation revealed the ability of AMR-PLGA-NPs to traverse biological barriers within murine models. Collectively, these findings underscore the potential therapeutic utility of AMR-PLGA-NPs as a versatile nanoplatform for addressing the formidable challenges posed by GBM, particularly in mitigating drug resistance mechanisms. The study substantiates the stability and safety profile of AMR-PLGA-NPs, positioning them as a promising avenue for combating drug resistance in GBM therapeutics., (Creative Commons Attribution license.)

• Amrubicin was active in a cohort of pretreated patients with thymic tumors. • Amrubicin was well-tolerated with the exception of febrile neutropenia. • Amrubicin availability is limited but this data may encourage more investigation. There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor. This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1–3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients. A total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%–32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient. Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted. [ABSTRACT FROM AUTHOR]