First-generation EGFR-TKI plus chemotherapy versus EGFR-TKI alone as first-line treatment in advanced NSCLC with EGFR activating mutation: a systematic review and meta-analysis of randomized controlled trials

Abstract

The aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with chemotherapy (CT) compared to EGFR-TKI monotherapy as first-line treatment in advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutation.A systematic literature search of randomized controlled trials using Cochrane Library, PubMed, Embase, and Web of Science, was performed up to Jan. 7 th , 2020. A total of eight randomized trials involving 1,349 advanced NSCLC patients with sensitive EGFR mutation were included in the meta-analysis. All patients in both groups received first-generation TKI as first-line treatment. The pooled HR of PFS and OS was 0.56 (95% CI=0.50-0.64; P < 0.00001) and 0.70 (95% CI=0.54-0.90; P=0.005), respectively. Subgroup analysis showed significantly higher OS advantages in patients receiving doublet CT (P=0.02) and concurrent therapy (P=0.002). The ORR in the EGFR-TKI plus CT group was significantly higher than in the EGFR-TKI monotherapy group (RR = 1.18, 95% CI = 1.10-1.26). The combination regimen showed a higher incidence of chemotherapy-induced toxicities. Subgroup analysis indicated that doublet chemotherapy rather than single-agent chemotherapy significantly increased incidence of grade 3 or higher leukopenia, neutropenia and anemia. In conclusion, compared with EGFR-TKI monotherapy, the combination of first-generation EGFR-TKI and CT, especially when applying concurrent delivery of platinum-based doublet chemotherapeutic drugs, significantly improve ORR and prolong PFS and OS in first-line treatment for advanced EGFR-mutated NSCLC, yet at the price of increasing incidence of chemotherapy-induced toxicities that is well tolerated and clinically manageable.

A meta-analysis of adjuvant EGFR-TKIs for patients with EGFR mutation of resected non-small cell lung cancer

“…The meta-analyze may support these results, showing that TKIs plus chemotherapy, the first-line therapy, significantly increase ORR while improving OS and DFS for advanced NSCLC cases with EGFR mutation. [ 18 ]…”

“…The meta-analyze may support these results, showing that TKIs plus chemotherapy, the first-line therapy, significantly increase ORR while improving OS and DFS for advanced NSCLC cases with EGFR mutation. [18] EGFR-TKIs have been recommended as first-line therapies for patients with EGFR-mutant NSCLC, and patients tend to benefit from adjuvant EGFR-TKI treatment in terms of DFS and OS. The ability of adjuvant EGFR-TKI treatment, however, remains unsatisfactory.…”

Detection of an EML4-ALK fusion mutation secondary to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer: a case report

“…However, most patients develop drug resistance at around 9-14 months after administration of first-line treatment with firstor second-generation EGFR-TKIs. The most common mechanisms for acquired drug resistance include secondary point mutations (e.g., T790M mutation), bypass activation (e.g., c-MET amplification), human epidermal growth factor receptor 2 (HER2) mutation, and histological type transformation (2,3). The T790M mutation is the most common mechanism for acquired drug resistance (4), occurring in around 60% of cases.…”

Minimal residual disease in EGFR-mutant non-small-cell lung cancer

“…The TAKUMI trial randomised sixty-two patients who had developed T790M resistance mutation after first line EGFR-TKI therapy to either osimertinib with combination carboplatin-pemetrexed versus osimertinib alone and found that there was no significance difference in median PFS (35). In regards to safety, a metaanalysis of combination chemotherapy with first-generation TKIs found overall increased toxicities most notably myelosuppression and gastrointestinal side effects (36). As well, no specific pattern of toxicity leading to dose modification or discontinuation was observed, although one patient discontinued study treatments due to pneumonitis (37).…”