Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis.

Because of lacking of head-to-head comparison among recently effective novel agents' combination regimens for newly diagnosed patients with mantle-cell lymphoma (MCL) who are ineligible for intensive therapy like autologous stem-cell transplantation, the optimal option for these patients still remains undefined. We searched relevant published reports. Three randomized controlled trials with 1459 subjects were identified. In the network meta-analysis, ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) when compared to bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP; hazard ratio [HR]: 0.55, p = .03) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; HR: 0.35, p < .001) for newly diagnosed patients with MCL ineligible for intensive therapy. Among these first-line treatment regimens (Ibru + BR, VR-CAP, R-CHOP, and BR), Ibru + BR had the highest probability of 94.9% to be the best intervention in PFS analysis. No significant difference was found in adverse events analysis. Our data indicated that Ibru + BR seemed to prolong the PFS when compared to VR-CAP and R-CHOP for newly diagnosed patients with MCL ineligible for intensive therapy. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.

Superiority of polatuzumab vedotin over other novel agents in previously untreated ABC-type diffuse large B-cell lymphoma: a network meta-analysis of 20 RCTs.

Because of lacking of head-to-head comparison among polatuzumab (Pola) vedotin and other novel agents for untreated diffuse large B-cell lymphoma (DLBCL), the optimal option remains undefined. We searched twelve relevant published reports, covering 8376 subjects. Interestingly, the PFS benefit with Pola-R-CHP over other regimens was found prominently in those B-cell-like type (ABC-type) patients. For those ABC-type patients, the PFS advantage with Pola-R-CHP was statistically significant, when compared to R-CHOP+Bort (HR: 0.52, P=0.02), R-CHOP+Ibru (HR: 0.43, P=0.001), R-CHOP+Lena (HR: 0.51, P=0.009), G-CHOP (HR: 0.46, P=0.008), and R-CHOP (HR: 0.40, P<0.001). Meanwhile, for those germinal center B-cell-like (GCB) type patients, no PFS advantage with Pola-R-CHP was found when compared to R-CHOP+Bort (HR: 1.18, P=0.46), R-CHOP+Lena (HR: 1.21, P=0.45), G-CHOP (HR: 1.39, P=0.14), R-CHOP-14 (HR: 0.94, P=0.82), and R-CHOP (HR: 1.00, P=1). The PFS advantage with Pola-R-CHP over other regimens might be confined to those patients of ABC-type DLBCL.

Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor-naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis.

Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.65, P = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free survival than brigatinib (Hazard ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.59, P = 0.03) for ALK inhibitor-naive patients. Among lorlatinib, alectinib, brigatinib, and crizotinib, lorlatinib had the highest probability to reach the best overall confirmed response rates (probability of 48%) and intracranial confirmed response rates (probability of 44%). No significant difference was found among them in overall survival and adverse events analysis. In terms of progression free survival, our results indicated that lorlatinib was the best treatment choice for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. The future head-to-head trials assessing the relative efficacy of lorlatinib, alectinib and brigatinib were warranted.

Comparison of acalabrutinib plus obinutuzumab, ibrutinib plus obinutuzumab and venetoclax plus obinutuzumab for untreated CLL: a network meta-analysis.

The optimal chemotherapy-free regimens for treatment-naive CLL still remains undefined. We searched relevant published reports. Three trials with 1017 subjects were identified. In the network meta-analysis, acalabrutinib plus obinutuzumab (Aca + Obi) improved PFS than ibrutinib plus obinutuzumab (Ibu + Obi) (HR:0.43, p = .02) and venetoclax plus obinutuzumab (Ven + Obi) (HR:0.30, p < .001) as IRC assessment. Sensitivity analysis of investigator assessment also showed improved PFS with Aca + Obi than Ibu + Obi (HR:0.46, p = .04) and Ven + Obi (HR:0.34, p = .002). Among these first-line treatments (Aca + Obi, Ibu + Obi, Ven + Obi and chlorambucil plus obinutuzumab (Chl + Obi)), Aca + Obi regimen had the highest probability of 99.1% (IRC assessment) or 98.0% (investigator assessment) to reach the longest PFS. The survival advantage with Aca + Obi was not statistically significant, compared to Ibu + Obi (HR:0.51, p = .21) and Ven + Obi (HR:0.38, p = .07). No significant difference was found in AEs analysis. Our data indicated that Aca + Obi seemed to prolong the PFS than Ibu + Obi and Ven + Obi. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.

Daratumumab added to standard of care in patients with newly diagnosed multiple myeloma: A network meta-analysis.

PURPOSE: To investigate the activity and safety of daratumumab added to standard of care and evaluate the relative efficacy of DRd vs DVMP and other regimens on survival endpoints for untreated myeloma, we undertook this meta-analysis. METHODS: We searched published reports that described the activity and safety of daratumumab added to standard of care for untreated myeloma. RESULTS: Six daratumumab trials were identified, covering 5106 subjects. Daratumumab containing combinations for untreated myeloma attained an impressive complete response or better (≥CR) rate of 24%, very good partial response or better (≥VGPR) rate of 67%, overall response rate (ORR) of 92%. Daratumumab added to standard of care significantly improved progression free survival (PFS): the HR for PFS was 0.52 [0.44, 0.61], P < .001. The HR for overall survival (OS) was 0.73 [0.52, 1.04], P = .09. In the network meta-analysis for patients ineligible for autologous stem-cell transplantation (ASCT), DRd regimen produced significant PFS advantage vs other first-line treatments (VMP HR:0.39 P < .001, Rd HR:0.55 P < .001, MPT HR:0.38 P < .001, and MP HR:0.22 P < .001); DVMP regimen also produced significant PFS advantage vs VMP (HR:0.50 P < .001), MPT (HR:0.49 P < .001), and MP (HR:0.28 P < .001). Among these first-line regimens (DRd, DVMP, VMP, Rd, MPT, and MP), DRd regimen had the highest probability to be the best intervention, with 83.4% and 91.0% probability to reach the longest PFS and OS, respectively. Toxicity consisted primarily of myelosuppression. And, the vital non-hematologic adverse events (AEs) were peripheral sensory neuropathy (41% of all grades) and upper respiratory tract infection (39% of all grades). CONCLUSIONS: Daratumumab added to standard of care could produce clinical benefits in newly diagnosed patients with multiple myeloma. DRd and DVMP could be good combination options for those patients ineligible for ASCT.

The efficacy of anti-PD-1/PD-L1 therapy and its comparison with EGFR-TKIs for advanced non-small-cell lung cancer.

PURPOSE: To better understand the efficacy and safety of anti-PD-1/PD-L1 therapy (atezolizumab, pembrolizumab, nivolumab) in patients with previously treated advanced non-small-cell lung cancer (NSCLC). METHODS: The Cochrane Controlled Trial Register, Embase, Medline, and the Science Citation Index were searched for prospective published reports of atezolizumab, pembrolizumab, nivolumab in previously treated patients with advanced NSCLC. RESULTS: Finally, we identified 14 prospective published reports including four trials of atezolizumab covering 542 subjects, three trials of pembrolizumab covering 1566 subjects, seven trials of nivolumab covering 1678 subjects. When compared to docetaxel, anti-PD-1/PD-L1 therapy could significantly improve overall survival (hazard ratio [HR] 0.67, P<0.001) and progression-free survival (HR 0.83, P=0.002) for previously treated patients with advanced NSCLC. Anti-PD-1/PD-L1 therapy produced an overall response rate of 19% in the 2374 evaluable patients. When using docetaxel as the common comparator, indirect comparison of anti-PD-1/PD-L1 therapy versus EGFR-TKIs showed progression-free survival benefit (HR 0.62, P<0.001) and overall survival benefit (HR 0.60, P<0.001) for those patients with EGFR wild-type. Meanwhile, for those EGFR mutant patients, indirect comparison indicated that anti-PD-1/PD-L1 therapy was inferior to EGFR-TKIs therapy in terms of progression-free survival (HR 3.20, P<0.001), but no survival difference (HR 1.30, P=0.18). CONCLUSION: Anti-PD-1/PD-L1 therapy could produce progression-free survival and overall survival improvement over docetaxel for patients with previously treated NSCLC. For EGFR wild-type patients, anti-PD-1/PD-L1 therapy seemed to prolong progression-free survival and overall survival when compared to EGFR-TKIs. Meanwhile, for these EGFR mutant patients, anti-PD-1/PD-L1 therapy was inferior to EGFR-TKIs therapy in terms of progression-free survival.

Association of asthma with coronary heart disease: A meta analysis of 11 trials.

PURPOSE: While the relationship of asthma and coronary heart disease (CHD) (a specific manifestation of cardiovascular disease) has not been described consistently, we tried to defined this relation and explore the influence of gender and asthma status (child- and adult-onset asthma) on this issue. METHODS: We searched published reports that described the relationship of asthma and CHD. RESULTS: Eleven trials were identified, covering 666,355 subjects. Asthma overall was significantly associated with CHD both for prospective trials (HR 1.34 [1.09,1.64], P = 0.005) and for retrospective trials(OR 1.29 [1.13,1.46], P = 0.001), when compared to individuals without asthma. Subgroup analysis split by gender indicated that females with asthma were significantly associated with CHD (HR 1.40 [1.20,1.62], P<0.001), but males with asthma were not significantly related with CHD (HR 1.19 [0.98,1.44], P = 0.07). For the four subgroups (Females with adult-onset asthma,males with adult-onset asthma,females with child-onset asthma,and males with child-onset asthma), pooled analysis of two trials indicated that only females with adult-onset asthma were significantly associated with CHD (HR 2.06 [1.32,3.19], P<0.001). CONCLUSIONS: Our data indicated that asthma was associated with CHD, and the relationship between them seemed to derived mostly from females with adult-onset asthma. Considering the limits of our study, these findings should be taken with caution.

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials.

OBJECTIVE: To investigate the activity and safety of carfilzomib-containing combinations as frontline therapy for multiple myeloma. METHODS: We searched published carfilzomib reports for newly diagnosed multiple myeloma. RESULTS: Thirteen trials were identified, covering 704 subjects. Pooled analysis showed that carfilzomib combinations as frontline therapy for multiple myeloma attained an impressive at least complete response (≥CR) rate of 21%, at least very good partial response (≥VGPR) rate of 68%, overall response rate (ORR) of 94%. The ≥CR rates of 18% pre-SCT were increased to 43% of post-ASCT, and 64% of postconsolidation (P<.001). For those patients receiving carfilzomib therapy, response quality improved further over time (≥CR rates of 10% after 2nd cycle, 20% after 4th cycle, 43% after 8th cycle; ≥VGPR of 29% after 2nd cycle, 68% after 4th cycle, 88% after 8th cycle). ≥CR rates of 49% from CFZ-LEN-DEX triplet regimen were higher than 18% from CFZ-CYC-DEX triplet regimen and 21% from CFZ-THA-DEX triplet regimen (P=.03). CONCLUSIONS: Carfilzomib combinations could produce clinical benefits in newly diagnosed patients with multiple myeloma. High-quality response rate could be further improved through ASCT, consolidation therapy, and more cycles of chemotherapy even in the era of carfilzomib. CFZ-LEN-DEX could be a good combination regimen.

The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Harboring Wild-type Epidermal Growth Factor Receptor: A Meta-analysis of 25 RCTs.

OBJECTIVE: To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) patients with wild-type (WT) EGFR tumors, we performed an indirect meta-analysis to assess the treatment effects of EGFR-TKIs in such patients. METHODS: We searched for randomized controlled trials in Medline, Embase, the Cochrane controlled trials register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. Effect measures used were hazard ratios (HR) for progression-free survival (PFS) and overall survival. RESULTS: Out of 2134 retrieved articles, 25 randomized controlled trials including more than 4467 patients were identified. This pooled analysis showed the inferior efficacy of TKI over chemotherapy among patients with WT EGFR NSCLC in terms of PFS (HR, 1.37; 95% confidence interval [CI]: 1.10, 1.72; P=0.006). When used as first-line treatment, TKIs have also fared worse than chemotherapy when compared with standard platinum doublet regimens in patients with WT EGFR in terms of PFS (HR, 2.15; 95% CI: 1.68, 2.76; P<0.001). And, the same inferior trend was found with TKIs in those trials of second-line/third-line treatment in terms of PFS (HR, 1.35; 95% CI: 1.13, 1.61; P<0.001). However, according to the pooled results, EGFR-TKIs still produced a reduction of 19% in the risk of progression over placebo in such WT EGFR patients ineligible for further chemotherapy (HR, 0.81; 95% CI: 0.68, 0.97; P=0.02). Furthermore, addition of EGFR-TKI to chemotherapy resulted in an improvement of PFS over chemotherapy alone (HR, 0.83; 95% CI: 0.71, 0.96; P=0.01). CONCLUSIONS: Among patients with advanced NSCLC harboring WT EGFR, EGFR-TKIs were inferior to standard chemotherapy both for first-line treatment and for second-line/third-line treatment, but still superior to placebo in patients unfit for further chemotherapy. And, addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such patients.

Pooled analysis of the reports of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma.

PURPOSE: The purpose of this study was to better understand the efficacy and safety of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma(R/RMM). METHODS: We retrieved and reviewed published reports including carfilzomib, panobinostat, and elotuzumab combination regimens for patients with R/RMM. RESULTS: We identified 20 prospective studies that evaluated 2220 patients. Carfilzomib combination regimens produced an overall response rate (ORR ≥ PR) of 61 % in the 1211 relapsed/refractory patients. At least very good partial response (VGPR) was 29 % in patients with carfilzomib combinations. Finally, 49 % of the 597 patients achieved ORR in patients receiving panobinostat-containing combinations. At least VGPR was 16 % in patients with panobinostat combinations. Three hundred twenty-eight of these 449 patients (73 %) receiving elotuzumab-containing combinations achieved ORR. And at least VGPR was 37 %. And, the vital nonhematologic adverse events (AEs) were cardiac events and pneumonia. CONCLUSION: Carfilzomib, panobinostat, and elotuzumab combination regimens produced clinical benefits in patients with R/RMM.

The Efficacy of Single-Agent Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Biologically Selected Patients with Non-Small-Cell Lung Cancer: A Meta-Analysis of 19 Randomized Controlled Trials.

OBJECTIVE: To determine the efficacy of first-generation single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in advanced non-small-cell lung cancer patients with known EGFR mutation status, we undertook this pooled analysis. METHOD: We searched for randomized controlled trials (RCTs) in Medline, Embase, the Cochrane Controlled Trials Register, the Science Citation Index, and the American Society of Clinical Oncology annual meetings. RESULTS: Out of 2,129 retrieved articles, 19 RCTs enrolling 2,016 patients with wild-type EGFR tumors and 1,034 patients with mutant EGFR tumors were identified. For these EGFR mutant patients, single-agent EGFR-TKI therapy improved progression-free survival (PFS) over chemotherapy: the summary hazard ratios (HRs) were 0.41 (p < 0.001) for the first-line setting and 0.46 (p = 0.02) for the second-/third-line setting. For those EGFR wild-type patients, single-agent EGFR-TKI therapy did not do as well as chemotherapy in the first-line setting (HR = 1.65, p = 0.03) and in the second-/third-line setting (HR = 1.27, p = 0.006). No statistically significant difference was observed in terms of overall survival (OS). Using platinum-based doublet chemotherapy as a common comparator, indirect comparison showed the superior efficacy of single-agent EGFR-TKI therapy over EGFR-TKIs added to chemotherapy in PFS [HR = 1.35 (1.03, 1.77), p = 0.03]. Additionally, a marginal trend towards the same direction was found in the OS analysis [HR = 1.16 (0.99, 1.35), p = 0.06]. Interestingly, for those EGFR wild-type tumors, single-agent EGFR-TKI therapy was inferior to EGFR-TKIs added to chemotherapy in PFS [HR = 0.38 (0.33, 0.44), p < 0.001] and OS [HR = 0.83 (0.71, 0.97), p = 0.02]. CONCLUSIONS: For these EGFR mutant patients, single-agent EGFR-TKI therapy prolonged PFS over chemotherapy. However, single-agent EGFR-TKI therapy was inferior to chemotherapy in PFS for those EGFR wild-type patients. Single-agent EGFR-TKI therapy could improve PFS over the combination of EGFR-TKIs and chemotherapy in these EGFR mutant patients. However, EGFR-TKIs combined with chemotherapy could provide additive PFS and OS benefit over single-agent EGFR-TKI therapy in those EGFR wild-type patients.

Pooled analysis of the reports of pomalidomide after failure of lenalidomide and (or) bortezomib for multiple myeloma.

The use of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of pomalidomide after failure of lenalidomide and (or) bortezomib. We searched published reports including pomalidomide, lenalidomide and (or) bortezomib. Seven reports were identified. Pomalidomide-based regimen was pomalidomide plus low-dose dexamethasone (POM + LoDEX). Six randomized controlled trials enrolling a total of 641 patients that evaluated the treatment effects of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma were included. Pooled results showed that the overall response rate (ORR) was 31% in the POM + LoDEX group. Analysis of heterogeneity showed very little (p = 0.997, I(2) = 0%), suggesting that response rates of POM + LoDEX therapy were consistent across those included trials. Stable disease was achieved in 40% of 603 patients (heterogeneity: p = 0.980, I(2) = 0%). In those >65 years, overall response was achieved in 32% of 71 patients (heterogeneity: p = 0.77, I(2) = 0%). POM + LoDEX showed promising activity in the 95 patients with high-risk cytogenetic abnormalities: ORR was 27% (heterogeneity: p = 0.97, I(2) = 0%). In the pooled analysis, toxicity consisted primarily of myelosuppression: Grade 3 or 4 neutropenia was seen in 53% (heterogeneity: p = 0.857, I(2) = 0%). Pomalidomide may produce clinical benefits in patients who had shown refractory on prior lenalidomide and (or) bortezomib therapy. Moreover, elder patients and high-risk cytogenetic abnormalities were not negative predictors for pomalidomide response after lenalidomide and (or) bortezomib failure. Copyright © 2015 John Wiley & Sons, Ltd.

The Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Molecularly Selected Patients with Non-Small Cell Lung Cancer: A Meta-Analysis of 30 Randomized Controlled Trials.

OBJECTIVE: To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in molecularly selected patients with advanced non-small cell lung cancer (NSCLC), we performed this pooled analysis. METHOD: Randomized trials of EGFR-TKIs as treatment for advanced NSCLC were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs in the selected patients by EGFR-mutation status were calculated. RESULTS: Out of 2134 retrieved articles, 30 randomized controlled trials (RCTs) enrolling more than 4053 patients with wild-type EGFR tumors and 1592 patients with mutant EGFR tumors were identified. For EGFR mutant patients, EGFR-TKIs treatment improved progression-free survival (PFS) compared with chemotherapy: the summary HRs were 0.41 (p < 0.00001) for the first-line setting and 0.46 (p = 0.02) for second/third-line setting, respectively. Also, the same superior trend was found with TKIs maintenance over placebo (HR = 0.14, p < 0.00001) and with TKIs combined with chemotherapy over chemotherapy (HR = 0.49, p = .002) in both the first-line and maintenance therapy settings. For EGFR wild-type patients, EGFR-TKIs have fared worse than chemotherapy in the first-line setting (HR = 1.65, p = .03) and in the second/third-line setting (HR = 1.27, p = .005). However, EGFR-TKIs maintenance still produced a reduction of 19 % in the risk of progression over placebo (HR = 0.81, p = .02). Furthermore, EGFR-TKIs added to chemotherapy as first-line treatment resulted in an improvement of PFS over chemotherapy alone in such wild-type EGFR patients (HR = 0.82, p = .03). In overall survival (OS) analysis, only EGFR-TKIs single agent was inferior to chemotherapy in EGFR wild-type patients (HR = 1.13, p = .02). No statistically significant difference in terms of OS was observed in any other subgroup analysis. CONCLUSIONS: For EGFR mutant patients, EGFR-TKIs therapy produced a prominent PFS benefit in all settings. Among EGFR wild-type patients, EGFR-TKIs were inferior to chemotherapy both for first-line treatment and for second/third-line treatment. However, EGFR-TKIs maintenance and addition of EGFR-TKIs to chemotherapy could provide additive benefit over chemotherapy alone in such EGFR wild-type patients.

EGFR-TKIs combined with chemotherapy versus EGFR-TKIs single agent as first-line treatment for molecularly selected patients with non-small cell lung cancer.

EGFR-TKIs added to chemotherapy and EGFR-TKIs single agent have been used as first-line treatment for advanced non-small cell lung cancer patients with and without EGFR mutations. However, direct head-to-head comparison between them is still lacking. We performed indirect comparisons to assess the treatment effects of EGFR-TKIs added to chemotherapy versus EGFR-TKIs alone via common comparator of standard chemotherapy in both subgroups. A comprehensive literature search was undertaken. Finally, 12 randomized controlled trials enrolling more than 2,160 patients with EGFR mutation analysis met the inclusion criteria. We found that EGFR-TKIs combined with chemotherapy did confer an additive PFS advantage over standard chemotherapy both for patients with mutant EGFR tumors (HR 0.54, 95 % CI [0.30, 0.95], P = 0.03) and for patients with wild-type EGFR tumors (HR 0.82, [0.68, 0.98], P = 0.03), but no survival difference between the treatments in both subgroups. When using standard chemotherapy as common comparator, indirect comparison indicated that addition of chemotherapy to EGFR-TKIs did confer an additive PFS benefit (HR 0.38, [0.32, 0.46], P < 0.001) and survival benefit (HR 0.75, [0.66, 0.85], P < 0.001) over EGFR-TKIs alone in patients with wild-type EGFR, but showed a PFS disadvantage (HR 1.35, [1.03, 1.77], P = 0.03) and a marginal trend toward survival disadvantage (HR 1.16, [0.99, 1.35], P = 0.06) compared with EGFR-TKIs alone in patients with mutant EGFR tumors. In summary, addition of chemotherapy to EGFR-TKIs as first-line treatment did confer an additive benefit over EGFR-TKIs alone in patients with wild-type EGFR tumors, but was inferior to EGFR-TKIs alone in patients with mutant EGFR tumors.

Bortezomib and lenalidomide as front-line therapy for multiple myeloma.

The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p < 0.001). On the other hand, the addition of lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p < 0.001) for bortezomib and 0.48, 95% CI [0.42, 0.55]; (p < 0.001) for lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p < 0.001), peripheral neuropathy (RR, 3.59 [1.89, 6.83], p < 0.001) and gastrointestinal effects (RR, 2.19 [1.37, 3.50], p = 0.001) among patients receiving bortezomib, and gastrointestinal effects (RR, 2.36 [1.33, 4.17], p = 0.003) and thromboembolic events (RR, 2.55 [1.48, 4.38], p < 0.001) among patients receiving lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p < 0.001). In summary, bortezomib improved OS, and both lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy.