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Expert Opinion on Investigational Drugs Jan 2019Soft-tissue sarcomas (STS) are a heterogeneous group of diseases that are characterized by a historic lack of active treatment options. However, several new drugs and... (Review)
Review
INTRODUCTION
Soft-tissue sarcomas (STS) are a heterogeneous group of diseases that are characterized by a historic lack of active treatment options. However, several new drugs and indications have become available in recent years.
AREAS COVERED
This article reviews the most relevant phase II studies that utilize chemotherapy agents (aldoxorubicin, amrubicin, trabectedin alone or in combination with doxorubicin, and gemcitabine plus docetaxel), targeted therapies (Imatinib, dasatinib, regorafenib, tivozanib, palbociclib and selinexor), a combination of chemotherapy plus targeted therapies (fucusing on doxorubicin plus olaratumab) and immunotherapies (pembrolizumab, combination of nivolumab plus ipilimumab and adaptive cell therapy) in STS (other than gastrointestinal stromal tumors) (GIST) published from 2015. Some of these strategies are under further clinical development or will likely be assessed in future phase III studies.
EXPERT OPINION
A series of novel treatments have shown encouraging results in STS in recent years. The most important is the combination of the standard cytotoxic agent doxorubicin plus the platelet-derived growth factor receptor (PDGFR) inhibitor olaratumab, although definitive results from a phase III trial are expected. Immunotherapy has not been as successful in STS so far. However, further investigations are ongoing.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Drug Design; Drugs, Investigational; Humans; Immunotherapy; Molecular Targeted Therapy; Sarcoma
PubMed: 30513001
DOI: 10.1080/13543784.2019.1555236 -
Cancer Science Nov 2019This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic...
This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.
Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Area Under Curve; Asian People; Body Surface Area; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Humans; Japan; Lung Neoplasms; Male; Membrane Transport Proteins; Middle Aged; Neutropenia; Polymorphism, Single Nucleotide; Prospective Studies; Severity of Illness Index
PubMed: 31505087
DOI: 10.1111/cas.14194 -
Thoracic Cancer Sep 2019The first-line treatment for squamous cell lung cancer (SCC) has not necessarily been established; however, our previous exploratory study suggested that the combination...
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/m ) on day 1 and amrubicin (25 mg/m ) 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.
Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prognosis; Survival Rate
PubMed: 31309738
DOI: 10.1111/1759-7714.13134 -
Thoracic Cancer Jan 2023The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however,...
Clinical efficacy of amrubicin in patients with small cell lung cancer relapse after first-line treatment including immune checkpoint inhibitors: A retrospective multicenter study (TOPGAN 2021-01).
BACKGROUND
The therapeutic efficacy of cytotoxic anticancer drugs has been reported to be enhanced after immune checkpoint inhibitors (ICI) in non-small cell lung cancer; however, it is unclear whether the same is applicable for small cell lung cancer (SCLC). We evaluated the efficacy of second-line amrubicin (AMR) following first-line platinum-based chemotherapy and ICI combination therapy (chemo-ICI) in SCLC.
PATIENTS AND METHODS
We retrospectively enrolled consecutive patients with SCLC treated with AMR as a second-line following chemo-ICI as first-line between July 2019 and April 2021 from 16 institutions throughout Japan. We investigated the therapeutic effectiveness, safety, and efficacy-enhancing variables of AMR.
RESULTS
Overall, 89 patients treated with AMR after first-line chemo-ICI were analyzed. The overall response rate (ORR) was 29.2% (95% confidence intervals [CI], 20.1-39.8) and median PFS (m PFS) was 2.99 months (95% CI, 2.27-3.65). Patients who relapsed more than 90 days after receiving first-line platinum combination therapy (sensitive relapse) exhibited greater ORR (58.3% vs. 24.7%, p = 0.035) and m PFS (5.03 vs. 2.56 months, p = 0.019) than patients who relapsed in <90 days (refractory relapse). Grade 3 or higher adverse events were mainly hematological toxicity.
CONCLUSIONS
Our study suggested that the therapeutic effect of AMR was not enhanced after ICI on SCLC. However, AMR may be effective in cases of sensitive relapse after chemo-ICI. There was no increase in severe toxicity associated with AMR after ICI.
Topics: Humans; Lung Neoplasms; Immune Checkpoint Inhibitors; Retrospective Studies; Carcinoma, Non-Small-Cell Lung; Neoplasm Recurrence, Local; Small Cell Lung Carcinoma; Antineoplastic Agents; Treatment Outcome; Recurrence
PubMed: 36408699
DOI: 10.1111/1759-7714.14729 -
Clinical Lung Cancer Mar 2017Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and... (Comparative Study)
Comparative Study
BACKGROUND
Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients.
PATIENTS AND METHODS
Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients' characteristics and treatments to explore factors associated with the survival outcomes were reviewed.
RESULTS
A total of 580 patients diagnosed as having SCLC received first-line chemotherapy/chemoradiotherapy, of which 343 (59%) received second-line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second-line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression-free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P = .007) and AMR as second-line treatment (vs. PEI) (P = .005) as independent favorable prognostic factors for survival.
CONCLUSION
AMR showed a favorable trend compared with PEI in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted.
Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Etoposide; Female; Follow-Up Studies; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Retrospective Studies; Small Cell Lung Carcinoma; Survival Rate; Young Adult
PubMed: 27867001
DOI: 10.1016/j.cllc.2016.09.005 -
JTO Clinical and Research Reports Jul 2021In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor....
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/m 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.
PubMed: 34590034
DOI: 10.1016/j.jtocrr.2021.100184 -
Anticancer Research Mar 2020The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated.
BACKGROUND/AIM
The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated.
PATIENTS AND METHODS
Amrubicin was administered for 3 days to patients with previously treated advanced NSCLC, whereas bevacizumab was administered on day 1 of each cycle; this regimen was repeated every 3 weeks.
RESULTS
Among the 16 patients, an overall response rate of 12.5% (for two patients) was achieved, and the overall disease control rate was 93.7%. Progression free survival and overall survival were 8.5 and 16.6 months, respectively. Grade 3 or 4 haematological toxicities were leukopenia, neutropenia, and febrile neutropenia. Grade 3 proteinuria and infection were the non haematological adverse events.
CONCLUSION
The combination of amrubicin and bevacizumab is a promising regimen in the second or third-line treatment for advanced non-squamous NSCLC; however, physicians must recognise the risk of proteinuria related with this regimen.
Topics: Aged; Anthracyclines; Antineoplastic Agents; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Feasibility Studies; Female; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies
PubMed: 32132059
DOI: 10.21873/anticanres.14104 -
Cancer Chemotherapy and Pharmacology Nov 2019Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy...
BACKGROUND
Amrubicin and cisplatin is one of the active regimens used to treat patients with extensive-disease (ED)-small cell lung cancer (SCLC), whereas combined therapy involving chemotherapy and concurrent thoracic radiotherapy is the standard treatment for limited-disease (LD)-SCLC.
PURPOSE
This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of amrubicin and cisplatin with concurrent thoracic radiotherapy (TRT) for LD-SCLC.
PATIENTS AND METHODS
Patients that fulfilled the following eligibility criteria were enrolled: being aged ≤ 75 years and chemotherapy-naïve and having a performance status (PS) of 0-1, LD-SCLC, and adequate organ function. The patients received escalating doses of amrubicin on days 1, 2, and 3, and a fixed 60-mg/m dose of cisplatin on day 1. Four cycles of chemotherapy were administered, with each cycle lasting 4 weeks. TRT involving 2 Gy/day, once daily, commenced on day 2 of the first cycle of chemotherapy. The initial dose of amrubicin was 20 mg/m (level 1), and the dose was escalated to 25 mg/m (level 2) and then 30 mg/m (level 3).
RESULTS
Eight patients from three institutions were enrolled at three dose levels. The patients' characteristics were as follows: male/female: 3/5; median age (range): 68.5 (60-73); PS 0/1: 4/4; stage IIIA/IIIB disease: 3/5. Both level 3 patients experienced DLT (grade 4 neutropenia and/or leukopenia lasting > 4 days). Level 3 was defined as the MTD, and level 2 was recommended as the dose for this regimen. Seven patients exhibited partial responses, and 1 displayed progressive disease (response rate: 88%). The median progression-free survival and overall survival periods were 11.1 and 39.5 months, respectively. No treatment-related deaths occurred.
CONCLUSIONS
When this regimen was combined with TRT for LD-SCLC, the MTD was 30 mg/m for amrubicin and 60 mg/m for cisplatin. In addition, neutropenia and leukopenia were DLT, and doses of 25 mg/m for amrubicin and 60 mg/m for cisplatin are recommended for this regimen.
Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Progression-Free Survival; Small Cell Lung Carcinoma; Survival Rate
PubMed: 31486872
DOI: 10.1007/s00280-019-03940-0 -
Asia-Pacific Journal of Clinical... Apr 2018Currently, amrubicin is used as first-line in the treatment of patients with small-cell lung cancer (SCLC). However, the effect of amrubicin-based treatment in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Currently, amrubicin is used as first-line in the treatment of patients with small-cell lung cancer (SCLC). However, the effect of amrubicin-based treatment in extensive-disease (ED) SCLC remains controversial. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of amrubicin-based regimen in the treatment of patients with ED-SCLC.
METHODS
RCTs published in PubMed, Web of Science, Embase, and ClinicalTrials.gov were systematically reviewed. Eligible studies were these that evaluated the efficacy and safety profiles of amrubicin-based regimen in ED-SCLC. Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and adverse events. Results were expressed with hazard ratio (HR) with 95% confidence intervals (CIs), and risk ratio (RR) with 95% CIs.
RESULTS
Four RCTs involving a total of 740 patients met the inclusion criteria and were included in this meta-analysis. Amrubicin-based regimen was not associated with significantly prolonged PFS (HR = 1.07, 95% CI: 0.90-1.30; P = 0.463) and OS (HR = 1.07, 95% CI: 0.89-1.29; P = 0.443) in patients with ED-SCLC. However, it significantly improved ORR (RR = 1.14, 95% CI: 1.04-1.25; P = 0.008). Subgroup analysis demonstrated that neither amrubicin alone nor in combination with cisplatin prolonged the PFS and OS, and only the combination therapy significantly increased ORR. The incidence of grade ≥3 adverse events was comparable between amrubicin-containing and other treatment groups (RR = 1.42, 95% CI: 0.78-2.58; P = 0.248). However, amrubicin-based treatment induced a significantly higher incidence of febrile neutropenia (RR = 3.32, 95% CI: 2.04-5.41; P < 0.001), anemia (RR = 1.44, 95% CI: 1.06-1.97; P = 0.022), leukopenia (RR = 2.17, 95% CI: 1.41-3.33; P < 0.001), neutropenia (RR = 1.33, 95% CI: 1.04-1.70; P = 0.021), and interstitial lung disease (RR = 1.58, 95% CI: 1.21-1.98; P < 0.001).
CONCLUSION
Amrubicin-based regimen used as first-line had no survival benefits in patients with ED-SCLC. But it significantly improved ORR. Further well-conducted, large-scale trials are needed to validate these findings.
Topics: Anthracyclines; Antineoplastic Agents; Disease-Free Survival; Humans; Lung Neoplasms; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Small Cell Lung Carcinoma
PubMed: 29071806
DOI: 10.1111/ajco.12778 -
Japanese Journal of Clinical Oncology Sep 2018The treatment efficacy of second-line chemotherapy in poor-risk patients with refractory-relapsed small-cell lung cancer is unclear.
BACKGROUND
The treatment efficacy of second-line chemotherapy in poor-risk patients with refractory-relapsed small-cell lung cancer is unclear.
METHODS
We defined refractory relapse as treatment-free interval <90 days and poor-risk as Eastern Cooperative Oncology Group Performance Status ≥2. We retrospectively examined the medical record data of patients who were treated at our hospital between September 2002 and December 2014.
RESULTS
Twenty-three poor-risk patients with refractory-relapsed small-cell lung cancer were treated in our hospital. The characteristics of patients at the time of first-line treatment were as follows: median age (range) 71 (57-83) years; male 74%; extensive disease 96%; proportion of patients with PS 0 or 1 and those with 2-4 was 43 and 57%, respectively; median treatment-free interval 26 days. Amrubicin was the most commonly used drug and was administered in 15 patients (65%). The overall response rate of all patients was 22%. Median progression-free survival and overall survival was 2.2 and 3.7 months, respectively. Among patients treated with amrubicin, overall response rate was 13%, median progression-free survival was 2.2 months, and median overall survival was 3.9 months. The most common grade 3 or worse adverse events were hematologic toxicities, including leukopenia (66%), neutropenia (69%), thrombocytopenia (9%) and anemia (22%). Febrile neutropenia was observed in two patients (9%).
CONCLUSIONS
Second-line chemotherapy might have poor efficacy to poor-risk patients with refractory-relapsed small-cell lung cancer.
Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Risk Factors; Small Cell Lung Carcinoma; Treatment Outcome
PubMed: 30113639
DOI: 10.1093/jjco/hyy107