Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer
Status:
Recruiting
Trial end date:
2021-06-01
Target enrollment:
Participant gender:
Summary
Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer
(NSCLC) associated with poor prognosis and rapid deterioration of performance status. The
incidence of LM is increasing, reaching 3.8% in molecularly unselected NSCLC patients, being
more frequent in adenocarcinoma subtype and up to 9% in epidermal growth factor receptor
mutation (EGFRm) lung cancer patients, one-third of patients have concomitant brain
metastasis . This increased incidence may in part be conducive to the increased survival of
patients with EGFRm advanced NSCLC since the introduction of EGFR-tyrosine kinase inhibitions
(TKIs).Currently, no standard therapeutic regimen for LM has been established because of its
rarity and heterogeneity[11], and no approved therapies exists to specifically target LM in
patients with EGFRm NSCLC. TKIs therapy is the first-line treatment of patients with EGFRm of
NSCLC. The leptomeningeal space is a sanctuary site for tumour cells and therapeutic agents
due to the presence of an active blood-brain barrier (BBB), so CSF concentration is an
important factor affecting treatment of LM by TKIs. Standard-dose first- and
second-generation EGFR-TKIs have good systemic efficacy but sub-optimal CNS penetration, as
evidenced by preclinical studies of brain distribution and clinical reports of CSF
penetration[15, 16]. Osimertinib is a third-generation EGFR-TKI, irreversible, oral EGFR-TKI
that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance
mutations, which has demonstrated efficacy in NSCLC CNS metastasis[17-22]. Preclinical, I/II
clinical studies and AURA program (AURA extension, AURA2, AURA17 and AURA3) have shown that
Osimertinib has higher brain permeability than the first- and second-generation.
Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial
growth factor (VEGF), animal studies and autopsy specimens show that VEGF plays an important
role in LM. VEGF and EGFR share many overlapping and parallel downstream pathways. The
biological rationale shows that inhibiting of EGFR and VEGR signaling pathways could improve
the efficacy of antitumor and remove the resistance of EGFR inhibition. Besides, preclinical
researches have shown the similar results. Based on these, numbers of clinical trials have
confirmed that VEGF inhibitors in combination with EGFR-TKI significantly prolong patients'
survival.