Significant Improvement In Overall Response Rate Research Articles

Indirect Treatment Comparison of Lurbinectedin vs. Other Second-Line Treatments for Small-Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Lurbinectedin received accelerated approval from the US Food and Drug Administration in 2020 for patients with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy based on the results of a single-arm phase 2 basket trial . In this trial, lurbinectedin demonstrated an overall response rate (ORR) of 35.2% and a median overall survival (OS) of 9.3 months. Here, we performed an indirect treatment comparison of lurbinectedin vs relevant second-line treatments for SCLC by means of a network meta-analysis (NMA). <h3>Materials/Methods</h3> A systematic literature review (1990–Jan 2021) identified 3 randomized controlled trials (RCTs) of second-line SCLC therapies recommended by NCCN guidelines that met the criteria for the NMA. Unanchored matching-adjusted indirect comparison (MAIC) connected Study B-005 to the network of RCTs. The RCT with the most overlap with Study B-005 was used as the target population in the base case, and a MAIC was performed to estimate the relative treatment effect of lurbinectedin vs oral topotecan (central node of the network). Relative treatment effects from the MAIC were used as direct evidence in the NMA. Analyses were conducted in a Bayesian framework for OS and ORR using a fixed-effect NMA, and relative effectiveness was assessed with hazard ratios (HR) and odds ratio. <h3>Results</h3> The 3 RCTs included in the NMA were Baize 2020 (carboplatin/etoposide vs oral topotecan), and Eckardt 2007 and von Pawel 2001 (oral topotecan vs IV topotecan). In the base case, Baize 2020 was the target population, which consisted only of patients with platinum-sensitive disease (chemotherapy-free interval ≥90 day); therefore, the platinum-sensitive subgroup of Study B-005 was connected to the network. In the base case analysis, the HR for OS significantly favored lurbinectedin vs oral topotecan, IV topotecan, and carboplatin/etoposide (Table). There was a significant improvement in ORR for lurbinectedin vs oral topotecan; the ORR was similar for lurbinectedin vs carboplatin/etoposide (Table). Two sensitivity analyses were also conducted. <h3>Conclusion</h3> In the absence of head-to-head RCTs, indirect treatment comparisons provide a means of estimating the relative efficacy of lurbinectedin vs relevant comparators for the second-line treatment of SCLC. In this NMA, lurbinectedin showed a robust survival benefit for the second-line treatment of platinum-sensitive patients with SCLC compared with platinum rechallenge and vs oral and IV topotecan. Study B-005; NCT02454972

Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC Study

Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC Study

Use of taxane-containing induction chemotherapy in combination with concurrent chemoradiotherapy in Chinese patients with locally advanced nasopharyngeal carcinoma: a meta-analysis.

PurposeTaxane-containing induction chemotherapy (IC) regimens in combination with concurrent chemoradiotherapy (CCRT) have been compared with non-taxane-containing IC combined with CCRT in randomized controlled trials (RCTs) in Chinese patients with advanced nasopharyngeal carcinoma (NPC). This meta-analysis aimed to systematically evaluate their clinical efficacy and safety profiling in this ethnic population.MethodsThe electronic databases, PubMed, Embase, MEDLINE, and Chinese Biomedical Database, were searched for eligible studies. The outcomes included overall response rate (ORR), 1-year survival rate, and different types of adverse events. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations.ResultsA total of 12 RCTs (representing 835 patients) were identified. The pooled analysis showed that taxane-containing regimens had a significant improvement in ORR for nasopharyngeal lesion (OR =4.57, 95% CI =1.14–18.30, P=0.032, z=2.15) but not in cervical lymph nodes (OR =1.23, 95% CI =0.65–2.36, P=0.532, z=0.64) and in 1-year survival rates (OR =1.19, 95% CI =0.10–14.82, P=0.893, z=0.13) compared with non-taxane-containing regimens. Regarding the adverse events and toxicities, grade 3–4 leukopenia and neutropenia were significantly different between the two groups (P<0.001) in favor of the non-taxane-containing regimens, but grade 3–4 vomiting was significantly different between the two groups (P<0.005) in favor of the taxane-containing regimens.ConclusionWhen combined with CCRT, taxane-containing IC regimens may be more efficient for short-term local control in Chinese patients with locally advanced NPC than the non-taxane-containing IC regimens. Moreover, the major toxic effects, which were bone marrow suppression, could be tolerated by majority of patients. More long-term follow-up and high-quality trials of NPC are needed to validate our findings.

Effectiveness and safety of chemotherapy combined with dendritic cells co-cultured with cytokine-induced killer cells in the treatment of advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BackgroundLung cancer, particularly non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality. Chemotherapy combined dendritic cells co-cultured with cytokine-induced killer cells (DC-CIK) immunotherapy has been applied in advanced NSCLC patients' treatment, but couldn't provide consistent beneficial results. Therefore, it is necessary to evaluate the efficiency and safety of combination therapy to promote the application.MethodsA literature search for randomized controlled trials of NSCLC was conducted in PubMed database. Before meta-analysis was performed, studies were evaluated heterogeneity. Pooled risk ratios (RRs) were estimated and 95% confidence intervals (CIs) were calculated using a fixed-effect model. Sensitivity analysis was also performed.ResultsSix eligible trials were enrolled. Efficiency and safety of chemotherapy followed by DC-CIK immunotherapy (experimental group) and chemotherapy alone (control group) were compared. 1-year overall survival (OS) (P = 0.02) and progression free survival (PFS) (P = 0.005) in the experimental group were significantly increased compared with the control. Disease control rate (DCR) (P = 0.006) rose significantly in experimental group. However, no significant differences between the two groups were observed in 2-year OS (P = 0.21), 2-year PFS (P = 0.10), overall response rate (ORR) (P = 0.76) and partial response (PR) (P = 0.22). Temporary fever, anemia, leukopenia and nausea were the four major adverse events (AEs) treated by chemotherapy. The incidence of anemia, leukopenia and nausea in the experimental group was obviously lower than the control group. Temporary fever rate was higher in experimental group than that in the control, but could be alleviated by taking sufficient rest.ConclusionsChemotherapy combined with DC-CIK immunotherapy showed superiority in DCR, 1-year OS and PFS, and no more AEs appeared, however, there was no significant improvement in ORR, PR, 2-year OS and PFS. As a whole, the combination therapy is safer but modest in efficacy for advanced NSCLC patients.

Multitargeted antiangiogenic tyrosine kinase inhibitors combined to chemotherapy in metastatic breast cancer: a systematic review and meta-analysis

We undertook a meta-analysis of randomized trials to evaluate the efficacy of multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) in addition to chemotherapy in metastatic breast cancer. PubMed, Web of Knowledge databases and the ASCO meeting abstracts were searched for eligible literature published up to August 30, 2013. The endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and toxicities. Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data with 95 % confidence intervals (CIs) were derived. Eight studies including 2,077 participants were analyzed. Compared to chemotherapy alone, adding MATKIs to chemotherapy resulted in a 14 % risk reduction of PFS events. However, the benefit did not reach statistical significance (HR 0.86; 95 % CI 0.70-1.04, P=0.126). Also, no OS benefit was observed (HR 1.03; 95 % CI 0.89-1.18, P=0.724). The addition of MATKIs significantly increased the ORR (OR 1.57; 95 % CI 1.30-1.91, P=0.000). Subgroup analysis revealed that sorafinib showed a significantly greater effect on PFS in patients with HER2 negative metastatic breast cancer (HR 0.67; 95 % CI 0.55-0.82, P=0.000) in comparison to chemotherapy alone. Additionally, sunitinib seemed to have no substantial efficacy for metastatic breast cancer. Toxicities were more frequent in patients receiving MATKIs. Overall, regimens consisting of MATKIs seemed not to be superior to chemotherapy alone in terms of PFS and OS, although significant improvement in ORR was observed. However, the addition of sorafenib significantly improved PFS. Further studies are needed to corroborate this finding.

Efficacy and safety of first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a meta-analysis

Background What benefits and toxicities patients acquire from the use of bevacizumab combined with first-line chemotherapy remains controversial. This study was performed to evaluate the efficacy and safety of first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer (mCRC). Methods Several databases, including PubMed, Embase, and Cochrane Library, were searched up to April 30, 2013. Eligible studies were only randomized, controlled trials (RCTs) with a direct comparison between mCRC patients treated with and without bevacizumab. Overall risk ratio (RR), hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CI) were calculated employing fixed or random-effects models depending on the heterogeneity of the included trials. Results Six RCTs, including 1582 patients in chemotherapy plus bevacizumab group and 1484 patients in chemotherapy-alone group, were included. Overall, the addition of bevacizumab to first-line chemotherapy increased overall response rate (ORR) by 4.5%, prolonged both progression-free survival (PFS) and overall survival (OS), and increased the rate of total Grades 3 or 4 adverse events (G3/4AEs) by 6.9%. Significant differences were found in ORR (RR=1.22 (95% CI 1.01-1.46), P=0.03), PFS (HR=0.60 (95% CI 0.47-0.77), P&lt;0.0001), OS (HR=0.83 (95% CI 0.70-0.97), P=0.02), and any G3/4AEs (OR=1.56 (95% CI 1.29-1.89), P&lt;0.00001). Conclusion Bevacizumab is a valuable addition to the current first-line chemotherapy regimens used in patients with mCRC, because of conferring a significant improvement in ORR, PFS, and OS, even though it increased adverse events.

The role of vascular epithelial growth factor receptor–tyrosine kinase inhibitors in the treatment of advanced breast cancer: a meta-analysis of 12 randomized controlled trials

Aim:To perform a systematic review and meta-analysis of randomized controlled trials to determine the efficacy and toxicity of approved vascular epithelial growth factor receptor–tyrosine kinase inhibitors (VEGFR-TKIs) in advanced breast cancer.Methods:A comprehensive literature search for studies published up to August 2013 was performed. The endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.Results:Twelve randomized controlled trials involved 3256 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that VEGFR-TKI therapy significantly improved ORR (RR 1.14, 95% CI: 1.03–1.28, p = 0.016), but it did not translate into benefits in PFS (HR 0.99, 95% CI: 0.81–1.22, p = 0.93) and OS (HR 1.11, 95% CI 0.99–1.24, p = 0.084) when compared to non-VEGFR-TKI therapy. Additionally, a higher incidence of grade 3 or 4 anemia, neutropenia, thrombocytopenia, diarrhea, hand-foot syndrome and fatigue was observed in VEGFR-TKI-based therapy.Conclusions:The VEGFR-TKI-based therapy offered a significant improvement in ORR in patients with advanced breast cancer but did not benefit PFS and OS. With present available data from randomized clinical trials, we were still unable to clearly set the role of VEGFR-TKIs in the treatment of metastatic breast cancer (MBC).

A Randomized Phase II Study of Paclitaxel and Bevacizumab With and Without Gemcitabine as First-Line Treatment for Metastatic Breast Cancer

Background The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB). Patients and Methods In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m 2 (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m 2 (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life. Results Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia ( P = .001) and dyspnea ( P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) ( P = .021), FACT-B Social/Family Well-being ( P = .041), and Breast Cancer-Additional Concerns ( P = .008) scores than patients treated with PB+G. Conclusion The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.

Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status.

3506 Background: The CRYSTAL and OPUS studies showed that adding cetuximab to CT in the first-line treatment of mCRC significantly improved treatment outcome compared with CT alone, in patients (pts) with KRAS wild-type (wt) tumors. This pooled analysis of the CRYSTAL and OPUS pt populations evaluated overall survival (OS), progression-free survival (PFS), and best overall response (OR) using updated data. Methods: The analysis was performed on individual pt data from both studies for all efficacy endpoints according to KRAS/BRAF mutation status. KRAS and BRAF mutation status was determined by quantitative PCR. Treatment arms were compared according to mutation status using log rank and Cochran-Mantel-Haenszel tests. Results: The data with respect to KRAS wt and BRAF tumor mutation status are presented in the Table. Conclusions: This analysis confirms that the addition of cetuximab to CT first line in pts with KRAS wt tumors achieves a statistically significant improvement in OR rate, PFS, and OS compared...

Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non–Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099

PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio [HR] = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.

A phase III multi-institutional randomized study of immunization with the gp100: 209–217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma

CRA9011 Background: In a phase II study, 13 (42%) of 31 patients with metastatic melanoma receiving high-dose (HD) IL-2 plus gp100:209–217(210M) peptide experienced objective responses (S.A. Rosenberg, et al, Nature Medicine 4: 321–327, 1998). Other studies showed a lower response rate (RR) but no randomized studies have been done. Methods: A prospective randomized phase III trial was conducted at 21 centers with 185 patients. Eligibility: stage IV or locally advanced stage III cutaneous melanoma, HLA A0201, no brain metastases, eligible for HD IL-2, and no previous HD IL-2 or gp100:209–217(210M). Arm 1 received HD IL-2 alone (720,000 IU/kg/dose) and Arm 2 gp100:209–217(210M) peptide + Montanide ISA followed by HD IL-2. The primary objective was clinical response. Secondary objectives were toxicity, disease free/progression free survival, immunologic response and quality of life. Central HLA typing, pathology review, and blinded response assessment were done at the NIH. Central data monitoring was done by The EMMES Corp. and a Data Safety Monitoring Board. Results: Numbers of patients enrolled, treated, and evaluable for response in Arm 1 were 94, 93, and 93 respectively; in Arm 2 91, 86, and 86. Toxicities were consistent with HD IL-2 ± vaccine. Investigator assessed RR showed significant improvement in overall RR for Arm 2=22.1% vs 9.7% (P=0.0223, Chi-Square) and progression free survival (PFS) in favor of Arm 2=2.9 months (1.7–4.5) vs 1.6 (1.5–1.8) (P=0.0101). Median overall survival favors Arm 2=17.6 months (11.8–26.6) vs 12.8 (8.7–16.3) (P=0.0964). Blinded response review is ongoing. Conclusions: RR and PFS were superior with peptide vaccine and HD IL-2 compared to HD IL-2 alone. This represents the first evidence of clinical benefit of vaccination in patients with melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis NIH, Novartis

A phase III multi-institutional randomized study of immunization with the gp100: 209–217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma

CRA9011 Background: In a phase II study, 13 (42%) of 31 patients with metastatic melanoma receiving high-dose (HD) IL-2 plus gp100:209–217(210M) peptide experienced objective responses (S.A. Rosenberg, et al, Nature Medicine 4: 321–327, 1998). Other studies showed a lower response rate (RR) but no randomized studies have been done. Methods: A prospective randomized phase III trial was conducted at 21 centers with 185 patients. Eligibility: stage IV or locally advanced stage III cutaneous melanoma, HLA A0201, no brain metastases, eligible for HD IL-2, and no previous HD IL-2 or gp100:209–217(210M). Arm 1 received HD IL-2 alone (720,000 IU/kg/dose) and Arm 2 gp100:209–217(210M) peptide + Montanide ISA followed by HD IL-2. The primary objective was clinical response. Secondary objectives were toxicity, disease free/progression free survival, immunologic response and quality of life. Central HLA typing, pathology review, and blinded response assessment were done at the NIH. Central data monitoring was done by The EMMES Corp. and a Data Safety Monitoring Board. Results: Numbers of patients enrolled, treated, and evaluable for response in Arm 1 were 94, 93, and 93 respectively; in Arm 2 91, 86, and 86. Toxicities were consistent with HD IL-2 ± vaccine. Investigator assessed RR showed significant improvement in overall RR for Arm 2=22.1% vs 9.7% (P=0.0223, Chi-Square) and progression free survival (PFS) in favor of Arm 2=2.9 months (1.7–4.5) vs 1.6 (1.5–1.8) (P=0.0101). Median overall survival favors Arm 2=17.6 months (11.8–26.6) vs 12.8 (8.7–16.3) (P=0.0964). Blinded response review is ongoing. Conclusions: RR and PFS were superior with peptide vaccine and HD IL-2 compared to HD IL-2 alone. This represents the first evidence of clinical benefit of vaccination in patients with melanoma. [Table: see text]

A Systematic Review and Meta-Analysis of Thalidomide in Patients with Previously Untreated Multiple Myeloma.

Background: Multiple myeloma disproportionately affects the elderly and is currently an incurable malignancy. New therapies for myeloma, particularly oral therapies, are urgently needed.Objectives:To determine if thalidomide with or without other agents, improves response rate (≥ 50% reduction in monoclonal protein), survival, and/or progression in patients with previously untreated myeloma.To determine the frequency and significance of major adverse events associated with thalidomide in this setting.Methods: A literature search of Medline (1966–June 2006), Embase (1980–June 2006), the Cochrane Library, abstracts from the annual meetings of the American Society of Hematology (1999–2005) and the American Society of Oncology (1999–2006) was completed with a pre-specified search strategy. No language restrictions were applied. Randomized controlled trials of induction thalidomide (any dose, any duration) for adults with previously untreated multiple myeloma were included. Trials of exclusively maintenance therapy were excluded. Two reviewers independently extracted data. The methodological quality of selected trials was assessed and summarized. Weighted data was expressed as relative risk, risk difference, number needed to treat (NNT), and number needed to harm (NNH). A random-effects model was used.Results: Six eligible studies involving almost two thousand patients (N=1875) were identified and meta-analyzed. Two studies were published and four were reported in abstract form only. Five studies reported overall response rate (ORR); the four largest trials reported statistically significant improvements in ORR with the addition of thalidomide to standard therapy. The weighted relative risk of responding to a thalidomide-containing regimen versus control was 1.50 (95% CI 1.21 to 1.86). The NNT to achieve one additional response with thalidomide was 4 (95% CI 2.9 to 8.3). Two trials reported improvements in EFS/PFS. One trial reported an improvement in OS. The risk of VTE, peripheral neuropathy, and constipation was consistently elevated with thalidomide such that for every 50 patients treated with a thalidomide-containing-regimen, one could expect 12 to 13 additional patients to respond, 4 additional patients to develop VTE (NNH 12.5; 95% CI 8.3 to 20), 2 additional patients to develop peripheral neuropathy (NNH 25; 95% CI 16.7 to 50), and 4 additional patients to develop constipation (NNH14; 95% CI 10 to 25). In our analyses, prophylactic anticoagulation appeared to decrease, but not abolish, the risk of VTE with thalidomide.Conclusions: Thalidomide improves response rate and possibly progression free and overall survival in patients with previously untreated myeloma. It also increases the incidence of VTE, neuropathy, constipation and other adverse events. Further studies are required to confirm the survival advantage seen in one study, and to determine the optimum strategy for VTE prophylaxis.