Central nervous system activity of ramucirumab + osimertinib in patients with advanced T790M-positive EGFR-mutant non-small-cell lung cance

Paz-Ares et al. are conducting an ongoing, open-label, multicentre phase 1 study on treatment with ramucirumab plus osimertinib in patients with EGFRm T790M-positive NSCLC [4]. Outcomes suggest potential anti-tumour activity in the CNS with the combined treatment, and a similar safety profile in patients with and without CNS metastasis.

Osimertinib is a novel EGFR TKI with demonstrated systemic and CNS efficacy [5]. Ramucirumab is a human IgG1 VEGFR2 mAb. Treatment with a VEGF mAb plus an EGFR TKI has shown promising results in EGFR-mutant NSCLC [6]. This study’s primary objective was the safety and tolerability of ramucirumab + osimertinib in patients with T790M-positive EGFR-mutant (Ex19del or L858R) NSCLC.

Eligibility criteria included relapse after 1L EGFR TKI therapy, asymptomatic and stable CNS metastasis (with or without prior radiotherapy), or no CNS metastasis. Enrolled patients (n=45) had an ECOG performance status of 0-1. Ten patients had CNS metastasis at enrolment. Of this group, 7 patients had prior radiotherapy and 3 had no radiotherapy. Median follow-up was 7.23 months. Fifteen patients remained on study treatment (5 with CNS metastasis, 10 without).

Investigator assessed treatment-emergent AEs (e.g. headache, vomiting, nausea) were comparable in the groups with and without CNS metastasis. One patient suffered cerebral haemorrhage (grade 1). It was related to CNS metastasis, not study treatment. Approximately 7 weeks after the last dose of ramucirumab, another patient with CNS metastasis developed a treatment-emergent AE of grade 5 subdural haemorrhage. It was unrelated to CNS metastasis. One patient with measurable CNS metastasis had tumour shrinkage (24%), with a best response of stable disease. The other 9 patients had non-measurable CNS lesions; 1 had a CNS complete response, with a systemic best response of stable disease. Sixty-seven percent (67%) of those with non-measurable CNS metastasis had prior CNS radiation. CNS response in the rest of the patients (n=25) was non-complete and non-progressive. One patient had CNS progression due to new CNS lesions. Her CNS best response was stable disease. Twelve-month PFS was 48.9 months in all patients, 33.3 months in those with CNS metastasis, and 60 months in those without CNS metastasis. Ramucirumab plus an EGFR TKI is being assessed in an ongoing phase 3 study (RELAY, NCT02411448).