Meta-analysis of Seven Randomized Control Trials to Assess the Efficacy and Toxicity of Combining EGFR-TKI with Chemotherapy for Patients with Advanced NSCLC who Failed First-Line Treatment

Abstract

Background: Some recent clinical trials have been conducted to evaluate a combination of EGFR-TKI with chemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trials are inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKI and chemotherapy for patients with advanced NSCLC who failed first-line treatment. Materials and Methods: We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library and Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and major toxicity. Results: Seven trails eventually were included in this meta-analysis, covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR 1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR 0.88 [0.68-1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS (HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05-2.21], p=0.03). However, combination therapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improved the ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62-0.88], p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade 3-4 toxicity was found at significantly higher incidence in the combined regimen arm. Conclusions: Continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combination therapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic and predictive factors to find the group with the highest benefit of the combination strategy.

The efficacy and safety of platinum plus gemcitabine (PG) chemotherapy with or without molecular targeted agent (MTA) in first-line treatment of non-small cell lung cancer (NSCLC)

“…Subgroup meta-analysis stratified for each involved pathway was carried out. Among these, 1 subgroup meta-analysis investigating the EGFR inhibitor revealed a significant benefit in PFS with 4 articles involved and ORR with 6 articles involved than PG group which was consistent with previous studies [ 56 – 58 ] in first-line or second-line settings. As for toxicity profile, there were more incidence of grade 3 or 4 rash, anemia, diarrhea, and anorexia in combining EGFR targeted therapy group compared to PG group.…”

The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis

“…The data of ORR was 18% and median PFS was 4.2 months for patients with chemotherapy alone in the previous study, but the hematologic and neurologic adverse effects were much more common in chemotherapy group (22). Considering the efficacy and toxicity, afatinib could be an optional choice compared with chemotherapy alone with much (23)(24)(25). Meanwhile, for advanced EGFRpositive patients with acquired resistance, changing to other 1st generation TKIs seemed to be the inefficient treatment.…”

Oncogenic kinase fusions: an evolving arena with innovative clinical opportunities

“…Of note, a growing number of protocols combining chemotherapy and TKi are currently being tested in both TKF-induced hematological and solid tumors [ 107 , 132 ] [ 133 ], and several trials are evaluating the efficacy of new TKi either alone or in combination with more conventional therapies (NCT02269085; NCT02427620; NCT02315768; NCT01606878; NCT02134912; NCT02511184). Preclinical studies have also demonstrated a substantial advantage of combining classical chemotherapy with TKi: Das and colleagues showed a synergistic effect of Crizotinib and Temozolomide in FIG-ROS1-positive glioblastoma patient-derived cells, paving a route to improve clinical outcome [ 134 ].…”