Dataset Information

Comparative efficacy and safety of second-line treatments for advanced non-small cell lung cancer with wild-type or unknown status for epidermal growth factor receptor: a systematic review and network meta-analysis.

ABSTRACT:

Background

Docetaxel, pemetrexed, erlotinib, and gefitinib are recommended as second-line treatment for advanced non-small cell lung cancer (NSCLC) with wild-type or unknown status for epidermal growth factor receptor (EGFR). However, the number of published randomized clinical trials (RCTs) on this topic is increasing. Our objective was to assess the comparative effectiveness and tolerability of all second-line treatments for advanced NSCLC with wild-type or unknown status for EGFR by a systematic review and network meta-analysis.

Methods

MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov, and the US Food and Drug Administration website, as well as other sources, were searched for available reports up to June 6, 2017. Two reviewers independently selected published and unpublished reports of RCTs comparing any second-line treatments, extracted data and assessed the risk of bias of all included trials. We performed a Bayesian network meta-analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response (ObR), the number of serious adverse events, and quality of life.

Results

We included 102 RCTs involving 36,058 patients (62% male, median age 61 years, 81% with stage IV cancer, 80% smokers, and 92% with performance status 0-1). We revealed a differential reporting of outcomes between efficacy and safety outcomes. Half of the trials reported safety outcomes and less than 20% quality of life. For OS, nivolumab was more effective than docetaxel (hazard ratio (HR) 0.69, 95% credible interval (CrI) 0.56-0.83), pemetrexed (0.67, 0.52-0.83), erlotinib (0.68, 0.53-0.86), and gefitinib (0.66, 0.53-0.83). Pembrolizumab, atezolizumab, and pemetrexed plus erlotinib were also significantly more effective than docetaxel, pemetrexed, erlotinib, and gefitinib. For PFS, erlotinib plus cabozantinib was more effective than docetaxel (HR 0.39, 95% CrI 0.18-0.84), pemetrexed (0.38, 0.18-0.82), erlotinib (0.37, 0.18-0.78), and gefitinib (0.38, 0.18-0.82). Cabozantinib and pemetrexed plus erlotinib were also significantly more effective than the four recommended treatments. For ObR, no treatment was significantly more effective. The effectiveness of the four recommended treatments was similar and they were ranked among the 25 less-effective treatments. For safety, evidence is insufficient to draw certain conclusions.

Conclusions

Nivolumab, pembrolizumab, atezolizumab, and pemetrexed plus erlotinib may be the most effective second-line treatments for NSCLC in terms of OS. The four recommended treatments seem to have relatively poor performance. However, the impact on life expectancy of immunotherapy versus other treatments should be further explored by future analyses, and more trials comparing the novel treatments are needed to reduce uncertainty in these results.

Trial registration

Registration number: PROSPERO ( CRD42015017592 ).

SUBMITTER: Crequit P

PROVIDER: S-EPMC5662096 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Second-line treatment options for advanced/metastatic non-small cell lung cancer (NSCLC) patients are limited. We aimed to evaluate the efficacy and safety of docetaxel/sodium cantharidinate combination vs. either agent alone as second-line treatment for advanced/metastatic NSCLC patients with wild-type or unknown EGFR status. A randomized, open-label, phase III study was performed at 12 institutions. Patients with failure of first-line platinum regimens were randomized to receive either single-agent sodium cantharivsdinate (SCA) or single-agent docetaxel (DOX) or docetaxel/sodium cantharidinate combination (CON). The primary endpoints were centrally confirmed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. A total of 148 patients were enrolled in our study between October 2016 and March 2020. After a median follow-up time of 8.02 months, no significant difference was observed among the three groups in ORR (SCA vs. DOX vs. CON: 6.00% vs. 8.33% vs. 10.00%, respectively; p=0.814) and DCR (74.00% vs. 52.00% vs. 62.50%, respectively; p=0.080). In additional, the mOS was significantly higher in the CON group, compared with the single-agent groups (7.27 vs. 5.03 vs. 9.83 months, respectively; p=0.035), while no significant differences were observed in terms of PFS (2.7 vs. 2.9 vs. 3.1 months, respectively; p=0.740). There was no significant difference in the baseline QoL scores between the three groups (p>0.05); after treatment, life quality in SCA and CON group was significantly better than that in the DOX group (p<0.05). Furthermore, the incidence of adverse events (AEs) in the SCA group was significantly lower (46.00 vs. 79.17 vs. 25.00%, respectively; p=0.038) and the incidence of grade ≥3 AEs was also significantly lower in the SCA group compared with the DOX and CON groups (10.00 vs. 82.00 vs. 30.00%, respectively; p=0.042). Single-agent SCA and single-agent DOX has similar therapeutic efficacy in the second-line treatment of advanced/metastatic NSCLC with wild-type or unknown EGFR status, but single-agent SCA has fewer AEs and better QoL. Also, SCA plus DOX can significantly improve OS and exerted a significant synergistic effect, with good safety and tolerance profile.

Project description:Purpose: Different second-line treatments of patients with trastuzumab-resistant human epidermal growth factor receptor 2 (HER2) positive breast cancer were examined in randomized controlled trials (RCTs). A network meta-analysis is helpful to evaluate the comparative survival benefits of different options. Methods: We performed a bayesian network meta-analysis using R-4.0.0 software and fixed consistency model to compare the progression free survival (PFS) and overall survival (OS) benefits of different second-line regimens. Results: 13 RCTs (19 publications, 4313 patients) remained for qualitative synthesis and 12 RCTs (17 publications, 4022 patients) were deemed eligible for network meta-analysis. For PFS, we divided network analysis into two parts owing to insufficient connections among treatments. The first part involved 8 treatments in 9 studies and we referred it as PFS (#1). Amid the following 8 interventions: pyrotinib + capecitabine, T-DM1 + atezolizumab, pertuzumab + trastuzumab + capecitabine, T-DM1, trastuzumab + capecitabine, lapatinib + capecitabine, neratinib, and capecitabine, we found consistent benefits between the first three interventions; moreover, pyrotinib + capecitabine was most likely to be associated with the best benefits; capecitabine monotherapy was associated with the worst PFS. The second part included 3 treatments in 2 studies and we referred it as PFS (#2): everolimus + trastuzumab + vinorelbine had better PFS benefits versus trastuzumab + vinorelbine and afatinib + vinorelbine. For OS, we analyzed 7 treatments in 7 studies, and observed T-DM1 + atezolizumab, pertuzumab + trastuzumab + capecitabine, and T-DM1 had similar effectiveness, and the first had the highest probability to yield the longest OS; capecitabine or neratinib alone yielded the worst OS benefits. Conclusions: Our work comprehensively summarized and analyzed current available RCT-based evidence of the second-line treatments for trastuzumab-treated, HER2-positive, advanced breast cancer. These results provide clinicians and oncologists meaningful references for clinical drug administration and the development of novel effective therapies.

Project description:ObjectiveTo compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).DesignSystematic review and network meta-analysis.Data sourcesPubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019.Eligibility criteria for selecting studiesPublished and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher.Results18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation.ConclusionsThese results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively.Systematic review registrationPROSPERO CRD42018111954.

Project description:IntroductionAdvanced gastric cancer (AGC) is one of the most common forms of cancer and remains difficult to cure. There is currently no recommended therapy for second-line AGC in the UK despite the availability of various interventions. This paper aims to compare different interventions for treatment of second-line AGC using more complex methods to estimate relative efficacy, fitting various parametric models and to compare results to those published adopting conventional methods of synthesis.MethodsSeven studies were identified in an existing literature review evaluating seven comparators, which formed a connected network of evidence. Citations were limited to randomised controlled trials in previously-treated AGC patients. Evidence quality was assessed using the Cochrane Collaboration's tool. Studies were assessed for the availability of Kaplan-Meier curves for overall survival. Individual patient data (IPD) were recreated using digitisation software along with a published algorithm in R. The data were analysed using multi-dimensional network meta-analysis (NMA) methods. A series of parametric models were fitted to the pseudo-IPD. Both fixed and random-effects models were fitted to explore long-term survival prospects based on extrapolation methods and estimated mean survival.ResultsRelative efficacy estimates were compared to those previously reported, which utilised conventional NMA methods. Results presented were consistent within findings from other publications and identified ramucirumab plus paclitaxel as the best treatment; however, all the treatments assessed were associated with poor survival prospects with mean survival estimates ranging from 5.0 to 12.7 months.ConclusionWhilst the approach adopted in this paper does not adjust for differences in trial patient populations and is particularly data-intensive, use of such sophisticated methods of evidence synthesis may be more informative for subsequent cost-effectiveness modelling and may have greater impact when considering an indication where observed data is particularly immature or survival prospects are more positive, which may then lead to more informative decision-making for drug reimbursement.