Efficacy and safety of treatment modalities across EGFR selected/unselected populations with non-small cell lung cancer and brain metastases: A systematic review and Bayesian network meta-analysis

Objective: To compare the efficacy and safety of treatment modalities across different populations with non-small cell lung cancer and brain metastases. Methods: A comprehensive search for randomized controlled trials was conducted in databases including PubMed, Embase, the Cochrane library, the ClinicalTrials.gov, and major international conferences. The main outcomes of interest were progression-free survival, overall survival, and severe adverse events. Bayesian network meta-analytical techniques were implemented, to compare treatment modalities based on efficacy and safety profiles. The protocol for this study has been registered in the Prospective Register of Systematic Reviews (PROSPERO, CRD42020155330). Results: 15 randomized controlled trials with a total of 1216 patients were analyzed. Network meta-analysis generated six comparisons both in EGFR positive and EGFR unselected populations. For patients harboring EGFR positive mutations, osimertinib appears to significantly increase progression-free survival, compared to 1st generation EGFR-TKI (HR 0.46, 95 %CI 0.38-0.55), 2nd generation EGFR-TKI (HR: 0.59, 95 %CI 0.34-0.99), conventional chemotherapy (HR 0.30, 95 %CI 0.14-0.66), radiotherapy (HR 0.20, 95 %CI 0.14-0.29), and radiotherapy plus 1st generation TKI (HR 0.21, 95 %CI 0.14-0.32). Osimertinib also appears to increase the likelihood of survival and prolong overall survival. For EGFR unselected patients, combined anti-PD1 monoclonal antibody with conventional chemotherapy appears superior to radiotherapy (HR: 0.20, 95 % CI 0.14-0.29), conventional chemotherapy (HR: 0.42, 95 %CI 0.28-0.68), radiotherapy plus conventional chemotherapy (HR: 0.59, 95 %CI 0.32-0.98), radiotherapy plus 1st generation TKI (HR:0.49, 95 %CI 0.25-0.96), and immune checkpoint inhibitors monotherapy (HR:0.44, 95 %CI 0.28-0.69). However, combination therapies are generally more toxic causing an increased number of severe adverse events, particularly when anti-PD1 monoclonal antibody is combined with conventional chemotherapy. Conclusions: Osimertinib appears to be the most effective and safest treatment in NSCLC patients with brain metastases, harboring EGFR positive mutations. The anti-PD1 monoclonal antibody and conventional chemotherapy combination increases survival for NSCLC patients with brain metastases who were not selected according to EGFR mutation, although this increased benefit positively correlates with an increased number of severe adverse events.