Efficacy and Safety of Gefitinib in Combination with Chemotherapy vs. Chemotherapy Alone in the Treatment of Advanced NSCLC

Analyzed Studies and Evaluated Patient Population

The meta-analysis included 7 randomized controlled trials (2 of which were double-blind and placebo-controlled) published between January 2000 and June 2019 in PubMed, Embase, and the Cochrane database. A total of 1,418 patients with advanced NSCLC verified histologically or cytologically were evaluated. They were treated either with a combination of gefitinib (a selective epidermal growth factor receptor tyrosine kinase inhibitor − EGFR) + chemotherapy, or chemotherapy alone (carboplatin + paclitaxel, cisplatin/carboplatin + pemetrexed, or carboplatin + gemcitabine). Primary endpoints were progression-free survival (PFS) and overall survival (OS), with overall response rate (ORR) and safety of treatment also assessed.

Findings

Patients receiving gefitinib combined with chemotherapy showed significant improvement in PFS (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.43–0.82; p = 0.001). Sequential therapy (chemotherapy followed by gefitinib treatment; HR 0.67; 95% CI 0.57–0.79; p < 0.00001) proved to be the most beneficial. However, two studies did not show improvements in patients with adenocarcinoma (HR 0.79; 95% CI 0.41–1.53; p = 0.48) and EGFR mutation (HR 0.49; 95% CI 0.12–1.96; p = 0.31).

No significant improvement in OS (HR 0.92; 95% CI 0.71–1.20; p = 0.54) or ORR (HR 0.98; 95% CI 0.67–1.44; p = 0.93) was observed during treatment.

Side effects such as leukopenia, neutropenia, anemia, nausea, fatigue, and constipation were reported with similar incidence in both groups. However, the risk of rash (odds ratio [OR] 3.82; 95% CI 2.31–6.31; p < 0.00001) and diarrhea (OR 2.83; 95% CI 1.77–4.52; p < 0.00001) was higher in patients treated with gefitinib in combination with chemotherapy. Additionally, there was a significant difference in the incidence of grade 3/4 rash (OR 7.45; 95% CI 1.70–32.59; p = 0.008) and thrombocytopenia (OR 1.75; 95% CI 1.17–2.63; p = 0.007) between the gefitinib plus chemotherapy group versus the chemotherapy alone group.

Conclusion

Treatment of advanced NSCLC with gefitinib in combination with chemotherapy was associated with extended PFS, but no improvements were observed in OS and ORR parameters. Sequential therapy was found to be the most advantageous for prolonging PFS. This might be due to the antagonistic effects of gefitinib, which arrests the cell cycle in the G1 phase, and cell cycle-dependent chemotherapeutic agents (e.g., paclitaxel is most effective in the M phase).

The meta-analysis demonstrated that the combination of gefitinib + chemotherapy increases the risk of rash, diarrhea, and thrombocytopenia compared to chemotherapy alone as adverse treatment reactions.

The results are limited by the absence of a subgroup analysis by sex, smoking status, TNM classification of NSCLC, and drug dosing.

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Source: Zhao Q., Sun K., Lei X., Cai L. A meta-analysis of the therapeutic effect of gefitinib combined with chemotherapy and chemotherapy alone in treating non-small cell lung cancer. Medicine (Baltimore) 2020; 99 (31): e21490, doi: 10.1097/MD.0000000000021490.