Osimertinib Plus Bevacizumab Does Not Improve PFS in EGFR-Mutated NSCLC

Osimertinib (Tagrisso) plus bevacizumab (Avastin) does not produce a superior progression-free survival (PFS) benefit over osimertinib monotherapy in patients with non-squamous non-small cell lung cancer (NSCLC) harboring an EGFR mutation. However, for patients who have a history of smoking or an exon 20 deletion, the combination may prove beneficial, according to new research presented at the 2021 ESMO Virtual Congress.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is the current standard of care for patients with EFGR-mutated NSCLC. Previous studies have suggested that the addition of an anti-vascular endothelial growth factor (VEGF) inhibitor to 1st generation EGFR-TKIs prolongs PFS in patients with EGFR-mutated NSCLC.

The phase 2 WJOG917L study, which was conducted in Japan, enrolled 122 patients with EGFR-mutated NSCLC. All patients were previously untreated, had clinical stage IIIB, IIIC, IV, or recurrent disease after surgical resection, and ECOG score of 0 or 1, and at least 20 years of age. Patients with symptomatic brain metastases were also excluded.

The primary end point of the study is PFS. Secondary end points include overall response rate (ORR), overall survival (OS), and adverse events (AEs).

Patients were randomized 1:1 to receive either osimertinib (80mg, daily) plus bevacizumab (15mg/kg, once every 3 weeks) or osimertinib (80mg, daily) alone. Stratification factors included clinical stage, sex, exon 19 deletion, and L858R mutation.

Sixty-one patients were assigned to each arm. In the monotherapy arm, 60 patients went on to treatment and 58 were evaluable. At data cutoff, 17 patients in this arm remained on study treatment. In the combination arm, all patients received treatment and all 62 were evaluable. At the time off data cutoff, 20 patients remained on study treatment.

The median age of patients in the monotherapy arm was 66 years (range, 29-85), 62.3% were female, and 50.8% of patients had a smoking history. Most patients, 55.7%, had an ECOG score of 0 and 98.4% had a diagnosis of adenocarcinoma. Clinical stages included were III (3.3%), IV (75.4%), and recurrence after surgical resection (21.3%). Fifty-nine percent of patients had an exon 19 deletion and 41% had a Leu858Argmutation.

In the combination arm, the median age was 67 years (range, 41-86), 60.7% were female, and 37.7% had a smoking history. Most patients, 52.5%, had an ECOG status of 0 and 100% of patients had a histopathological diagnosis of adenocarcinoma. Clinical stages included were III (1.6%), IV (78.7%), and recurrence after surgical resection (19.7%). Over half, 57.4%, had an exon 19 deletion and 42.6% had a Leu858Arg mutation.

At the median follow-up of 30.4 months, the median PFS in the monotherapy arm was 20.2 months (95% CI, 11.79 to not evaluable [NE]) versus 22.1 months in the combination arm (95% CI, 19.81-NE). The 1-year PFS rate for the monotherapy arm was 63.7% (95% CI, 49.5%-74.9%) and 73.8% in the combination arm (95% CI, 60.4%-83.3%). The 2-year PFS rate for the monotherapy arm was 44.5% (95% CI, 31.0%-57.2%) and 49.8% (95% CI, 36.1%-62.1 for the combination arm (HR, 0.862; 60% CI, 0.700-1.060) or (95% CI, 0.531-1.397; on-sided P = 0.213).

“In the subgroup analysis, progression-free survival, ever-smokers and patients with exon 19 deletion show a better trend in the osimertinib plus bevacizumab arm,” said presenter Hirotsugu Kenmotsu, MD, PhD, senior staff member in the Division of Thoracic Oncology at the Shizuoka Cancer Center. 

For patients with a smoking history, the median PFS for the monotherapy arm was 13.6 months (range, 7.8-19.9) and 32.4 months (range, 19.8-NE) in the combination arm (HR, 0.481, 95% CI 0.227-1.019). For patients who never smoked, the median PFS was 32.5 months in the monotherapy arm (range, 13.8-NE) and 20.3 months in the combination arm (range, 13.7-32.3) (HR, 1.444, 95% CI, 0.736-2.833).

For patients with an exon 19 deletion, the median PFS was 20.3 months (range, 9.6-NE) in the monotherapy arm and NE in the combination arm (range, 20.1-NE) (HR, 0.622; 95% CI, 0.312-1.240). For patients with a Leu858Arg mutation, the median PFS was 15.7 months (range, 11.5-32.5%) for the monotherapy arm and 20.0 months in the combination arm (range, 8.5-24.4) (HR, 1.246; 95% CI, 0.621-2.502).

The ORR for the monotherapy arm was 86% (95% CI, 77%-96%) and 82% in the combination arm (95% CI, 72%-92%). The median OS for either arm was not reached (HR, 0.970, 95% CI 0.505-1.866). The 1-year OS rate for the combination arm was 98.3% (95% CI, 88.8%-99.8%) versus 90.2% (95% CI, 79.4-99.5) for the combination arm The 2-year OS rate was 76.4% (95% CI, 63.5-85.3%) for the monotherapy arm compared with 81.7% in the combination arm (95% CI, 69.5%-89.5%).

The median duration of treatment in the combination arm was 57.6 weeks (range, 1.4-157.9) and 94 weeks with the combination (range, 1.6-158). Grade 3-5 AEs occurred in 48.3% of patients in the monotherapy arm and 55.7% of patients in the combination arm. AEs lead to discontinuation of 26.7% of patients in the monotherapy arm and 55.7% of patients in the combination arm. AEs led to dose modification in 41.7% of patients in the monotherapy arm and 63.9% of patients in the combination arm. Serious AEs led to treatment discontinuation in 5% of patients in the monotherapy arm 11.5% in the combination arm. AEs led to dose reduction in 4.9% of patients in the combination arm. No treatment-related deaths were reported.

Common AEs in both the combination arm and the monotherapy arm included diarrhea (58.3% vs 57.4%), paronychia (45% vs 67.2%), and white blood cell decrease (47.7% vs 31.1%). All-grade pneumonitis occurred in 18.3% of patients in the monotherapy arm compared with 3.3% of patients in the combination arm.

“This study failed to show the efficacy of osimertinib plus bevacizumab against osimertinib monotherapy with respect to improving progression-free survival in patients with EGFR-mutation positive non-squamous non-small cell lung cancer,” Kenmotsu concluded. “Ever-smoker or patients with exon 19 deletion might benefit to osimertinib plus bevacizumab for this population as first-line treatment.”

_REFERENCE:

_{Kenmotsu H, Wakuda K, Mori K, et al. Primary results of a randomized phase II study of osimertinib plus bevacizumab versus osimertinib monotherapy for untreated patients with non-squamous non-small-cell lung cancer harboring EGFR mutations; WJOG9717L study. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA44.}