Erlotinib + bevacizumab improves PFS over erlotinib alone for EGFR+ NSCLC
Patients with EGFR-positive non-squamous non-small-cell lung cancer (NSCLC) had greater progression-free survival (PFS) when treated with erlotinib plus bevacizumab rather than erlotinib alone, according to an interim analysis of the phase III NEJ026 trial.
In this multicentre trial conducted in Japan, 228 patients aged ≥20 years with EGFR-positive stage IIIB–IV or recurrent non-squamous NSCLC with ECOG performance status ≤2 and who were chemotherapy-naïve and without Thr790Met mutations were randomized to receive oral erlotinib (150 mg/day) alone or plus intravenous bevacizumab (15 mg/kg every 21 days; n=114 in each arm). Two-step dose reduction (down to 50 mg/day) was permitted for erlotinib but not bevacizumab. Patients were followed up for a median 12.4 months.
PFS favoured patients in the erlotinib plus bevacizumab arm compared with those on erlotinib monotherapy (median, 16.9 vs 13.3 months, hazard ratio, 0.605, 95 percent confidence interval, 0.417–0.877; p=0.016). [Lancet Oncol 2019;doi:10.1016/S1470-2045(19)30035-X]
Objective response rate was comparable between erlotinib plus bevacizumab and erlotinib monotherapy recipients (72 percent vs 66 percent; p=0.31), with disease control achieved by 95 and 96 percent of patients in these respective groups (p=0.52).
Grade ≥3 adverse events (AEs) occurred more frequently among patients on erlotinib plus bevacizumab compared with those on erlotinib monotherapy (88 percent vs 46 percent), with rash the most common grade 3–4 AE (21 percent of patients in each group). Serious AEs occurred in eight and four percent of patients in the erlotinib plus bevacizumab and erlotinib monotherapy arms, respectively, the most common of which were grade 4 neutropenia (two patients on erlotinib plus bevacizumab) and grade 4 hepatic dysfunction (one patient in each group). There were no treatment-related deaths.
Hypertension, proteinuria, and non-pulmonary haemorrhage occurred more often in erlotinib plus bevacizumab compared with erlotinib monotherapy recipients (46 percent vs 10 percent, 32 percent vs 5 percent, and 26 percent vs 3 percent, respectively).
Bevacizumab-related discontinuation occurred in 33 patients, mostly due to proteinuria, haemorrhage, and hepatic dysfunction. Forty-three and 41 percent of erlotinib plus bevacizumab and erlotinib monotherapy recipients, respectively, required erlotinib dose reductions with erlotinib discontinuation most often due to rash (7 percent in each group).
Combined with its anti-angiogenic ability, bevacizumab may “normalize blood flow in tumour blood vessels … improving drug delivery” or “help restore apoptosis”, suggested the researchers, though the actual mechanism of action of the combination in improving PFS is undetermined.
“The addition of bevacizumab to erlotinib therefore seems to be a promising strategy to improve PFS in patients with EGFR-positive NSCLC,” they said, highlighting the potential of this combination as a standard of care for EGFR-positive NSCLC if overall survival and quality of life data are also positive.
Study limitations included the large proportion of patients with ECOG performance status of 0 (~60 percent) and the exclusion of patients with EGFR Thr790Met mutations (which can lead to EGFR TKI* resistance), which could have contributed to the improved PFS, said Professor James Yang Chih-Hsin who was not affiliated with the study, in a commentary. [Lancet Oncol 2019;doi:10.1016/S1470-2045(19)30085-3]