Adding Bevacizumab to Erlotinib Prolongs PFS in EGFR-Mutated NSCLC

The combination of bevacizumab (Avastin) and erlotinib (Tarceva) is superior to erlotinib alone as upfront treatment for non—small cell lung cancer (NSCLC) harboring EGFR mutations. A preplanned interim analysis of the phase III study known as NEJ026 showed a median progression-free survival (PFS) by independent review (the primary endpoint) of 16.9 months with the bevacizumab/erlotinib combination compared with 13.3 months with erlotinib by itself,¹ said Naoki Furuya, MD, PhD, at the 2018 ASCO Annual Meeting.

The difference represents a 39.5% relative advantage on the primary endpoint favoring the combination (HR, 0.605; 95% CI, 0.417-0.877; P = 0.01573).

“The bevacizumab/erlotinib combination is considered a new standard therapy in patients with untreated EGFR-mutated NSCLC,” he said.

Median PFS with first- or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy for EGFR-mutated NSCLC has been 9.2 to 14.7 months, noted Furuya, from St. Marianna University, School of Medicine, Kawasaki, Japan, representing the North East Japan Study Group. As second-line therapy, the bevacizumab/erlotinib combination did not improve overall survival (OS) compared with erlotinib alone in the intent-to-treat population with advanced stage NSCLC, but a 56% improvement in OS was observed in the subset with EGFR-mutant tumors.²

JO25567 was a randomized phase II study of chemotherapy-naïve patients with nonsquamous stage IIIB/IV NSCLC with activating EGFR mutations (exon 19 deletion or exon 21 L858R) and no brain metastases, and showed a median PFS of 16.0 months with bevacizumab/erlotinib, which was a 46% improvement versus erlotinib alone.³

The NEJ026 phase III study was designed to confirm the phase II results, but also allowed for inclusion of patients with asymptomatic central nervous system (CNS) metastases. A total of 228 chemotherapy-naïve patients with advanced nonsquamous, EGFR-mutant NSCLC were randomly assigned to either 150 mg of erlotinib, or the combination of 150 mg of erlotinib plus 15 mg/kg of intravenous bevacizumab i every 3 weeks. At progression, the doublet of a platinum plus pemetrexed in the combination arm and the triplet of platinum, pemetrexed, and bevacizumab in the erlotinib monotherapy arm were recommended as second-line therapy. The status of EGFR mutations in plasma samples was analyzed routinely during treatment.

The preplanned interim analysis was performed at 117 PFS events using the full analysis set of 224 patients (112 in each arm). Baseline characteristics were well balanced between arms. Median age was 67 to 68 years, about two-thirds were female, more than half were never smokers, and 99% had an ECOG performance status of 0 or 1. Pathology was adenocarcinoma in 222 of the 224 patients. About half of the patients had an exon 19 deletion and half had anexon 21 L858R mutation. About one-third of patients had CNS metastases.

After a median follow-up of 12.4 months, median PFS favored the combination by independent review and at a median follow-up of 12.5 months, by investigator assessment. In the latter analysis, median PFS was 16.6 months in the bevacizumab/erlotinib arm and 12.4 months in the erlotinib monotherapy arm (HR, 0.563; 95% CI, 0.394-0.804; P = 0.00057). Subgroup analysis showed consistent benefit with the combination.

When assessed by EGFR mutation status, median PFS was 16.6 months in the combination arm and 12.4 months in the erlotinib arm (HR, 0.68; 95% CI, 0.41-1.16) in patients with an exon 19 deletion, and 17.4 months and 13.7 months, respectively (HR, 0.57; 95% CI, 0.33-0.97) in patients with an exon 21 L858R mutation.

The objective response rates were 72.3% in the combination arm and 66.1% in the erlotinib monotherapy arm, with 8 complete responses in the combination arm and 4 in the erlotinib monotherapy arm.

Median erlotinib treatment duration was 405 days when used in combination with bevacizumab and 364 days when used as monotherapy. Median treatment duration with bevacizumab was 350 days. Bevacizumab was discontinued in 29.5% of patients due to adverse events (AEs), which occurred at a higher rate compared with erlotinib. Erlotinib was discontinued due to AEs in 18.8% of patients when used in combination with bevacizumab and in 15.2% when used alone.

In the safety analysis (n = 226), the rates of grade ≥3 AEs were 56.3% in the combination arm and 37.7% in the erlotinib arm. Serious AEs occurred in 8.0% and 4.4% of patients, respectively. There were no treatment-related deaths in either arm. Grade ≥3 hypertension occurred in 22.3% of the combination arm and in 0% of the monotherapy arm and the rates of grade ≥3 proteinuria were 7.1% and 0% in the 2 arms, respectively. Low-grade hemorrhage was more common in the combination arm (25.0%) versus monotherapy (2.6%).

Invited discussant Lecia Sequist, MD, MPH, Director, Center for Innovation in Early Cancer Detection, Massachusetts General Hospital, Boston, noted the much higher discontinuation rate for adverse events in the combination therapy arm compared with that of TKI monotherapy in other clinical trials as well as NEJ026.

The premise of a combination of an EGFR TKI plus a vascular endothelial growth factor inhibitor in EGFR-mutated NSCLC is strong, given the signals in this patient subset, she said. However, in the context of today’s landscape, in which osimertinib (Tagrisso) has been approved by the FDA for first-line treatment of metastatic NSCLC with most common EGFR mutations, the bevacizumab/erlotinib combination may be obsolete in the United States, and the data from NEJ026 “do not change the standard of care at this time.”

References

1. Furuya N, Fukuhara T, Saito H, et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. Presented at: 2018 ASCO; June 1-5, 2018; Chicago, IL. Abstract 9006. abstracts.asco.org/214/AbstView_214_212527.html.
2. Herbst RS. Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011;377(9780):1846-1854. doi: 10.1016/S0140-6736(11)60545-X.
3. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-1244. doi: 10.1016/S1470-2045(14)70381-X.