EGFR+ NSCLC Treated in the Frontline With Osimertinib/Apatinib Combination Has PFS Improvement

Li Zhang, MD

The combination of apatinib and gefitinib (Iressa) demonstrated the feasibility of dual VEGFR/EGFR inhibition in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC), according to progression-free survival (PFS) results of the phase 3 ACTIVE trial (NCT02824458) that were reported at the ESMO Vritual Congress 2020.

A total of 313 patients enrolled on ACTIVE trial were randomized 1:1 to receive apatinib plus gefitinib (n = 157) or placebo plus gefitinib (n = 156). At median follow-up of 15.8 months, the median PFS in the apatinib arm was 13.7 months compared with 10.2 months with the EGFR inhibitor alone (HR, 0.71; 95% CI, 0.54-0.95; P = .0189).¹

“Apatinib combined with gefitinib is expected to become a new first-line treatment option for EGFR-mutant NSCLC patients,” said Li Zhang, MD, who presented the data as part of the 2020 ESMO Virtual Congress. “Furthermore, this dual oral regimen will definitely provide a more convenient treatment for patients who require long-term administration.” Zhang is a professor of medical oncology, director of Phase I Unit of Sun Yat-Sen University Cancer Centre (SYSUCC), and deputy director of the Lung Cancer Research at SYSUCC.

Patients with detectable EGFR exon 19 deletions (Ex19del) and exon 21 (L858R) mutations were well balanced between the study arms: 51.6% and 47.1% in the apatinib arm versus 53.2% and 46.8% in the placebo arm. Stratified PFS data showed a similar PFS benefit for patients with Ex19del (HR, 0.67; 95% CI, 0.45-0.99) and those with L858R mutations (HR, 0.72; 95% CI, 0.48-1.09).

Secondary end points of the trial included investigator-assessed PFS, objective response, and duration of response. Median PFS via investigator assessment was 13.8 months with apatinib versus 12.0 months with placebo (HR, 0.71; 95% CI, 0.53-0.95; P = .0186). The objective response rates were 77.1% and 73.7%, respectively (P = .5572). Specifically, 1 patient in the apatinib arm achieved a complete response (CR), 120 (76.4%) had a partial response (PR), and 12 (7.6%) had stable disease (SD). No patients achieved a CR in the placebo arm, however, 115 (73.7%) patients had a PR and 22 (14.1%) had SD. The disease control rates were 84.7% and 87.8%, respectively (P = .3466).¹

The depth of response was also evaluated and defined as the best percentage change from baseline in sum of diameters of the target lesions. A reported depth of response of at 30% in change in lesion size was reported for 89.2% of patients treated with apatinib plus gefitinib and 79.5% of patients treated with gefitinib alone (P = .0209). The percentage of patients who had a depth of response of at least 50% were 64.3% and 52.6%, respectively (P = .0238).¹

Duration of response (DOR) was evaluable in 121 patients in the apatinib arm and 115 patients in the placebo arm. The median DOR was 12.9 months (95% CI, 11.2-14.7) and 9.3 months (95% CI, 9.2-11.1), respectively (HR, 0.64; 95% CI, 0.47-0.88; log-rank P = .005).1

Overall survival data were immature at the time of cutoff, with only 29.4% of the predetermined events reached.

Safety

In terms of safety, “no unexpected safety signals were identified beyond the established safety profile of each single agent,” Zhang explained. “As expected, apatinib plus gefitinib increased the risk of treatment-emergent adverse events [TEAEs] compared with placebo plus gefitinib. Roughly 50% of patients in the combination group experienced dose interruption or reduction.”

Grade 3 or higher TEAEs were reported in 84.1% of patients treated in the combination arm versus 37.7% of patients in the placebo arm. In regard to dose interruption and reduction, the rates were 59.9% and 48.4% versus 22.7% and 4.5%, respectively. Further, discontinuation of treatment due to TEAEs was 5.1% with the combination and 3.2% with placebo.

The most common grade 3 or higher TEAEs in the apatinib arm were hypertension (46.5%), proteinuria (17.8%), alanine aminotransferase increase (11.5%), and weight decrease (11.5%). Grade 3 or higher TEAEs were less common in the placebo arm. The most commonly reported were alanine aminotransferase increase (10.4%), aspartate aminotransferase increase (3.2%), hypertension (2.6%), and diarrhea (1.3%).¹

Exploratory Biomarker Analysis

Next-generation sequencing (NGS) performed at baseline and post-progression provided further efficacy indicators in patient subgroups. Biomarker analysis at baseline demonstrated an improved PFS in patients with TP53-mutant disease treated with the apatinib and gefitinib combination (HR, 0.56; 95% CI, 0.31-1.01) compared with those who do not harbor the mutation (HR, 0.92; 95%, 0.50-1.67). More specifically, a PFS benefit was observed in patients with TP53 exon 8 mutations, with a hazard ratio of 0.24 (95% CI, 0.06-0.91) favoring the apatinib group. The hazard ratio was 0.79 (95% CI, 0.41-1.52) in patients without the exon 8 mutation.¹

“Subgroup analysis by baseline p53 mutation status showed that the PFS hazard ratio favored the combination treatment for patients with p53 exon 8 mutation…However, due to the small sample size [N = 18] this benefit will need to be further confirmed by a large-scale clinical study,” said Zhang. Seven patients in the apatinib combination arm harbored the TP53 exon 8 mutation compared with 11 in the placebo arm.

Further, in analysis of patients who experienced progressive disease, 43.7% patients (n = 103) in the apatinib arm and 41.4% patients (n = 111) in the placebo arm provided blood samples for NGS.

A similar resistance pattern was found in both groups in regard to the development of T790M mutation. In total, 37.8% of patients treated with apatinib who experienced progressive disease were T790M-positive compared with 37.0% of patients in the placebo arm.¹

Delaying EGFR-TKI resistance has been an ongoing challenge in the NSCLC treatment landscape. Despite an observed PFS benefit with the EGFR TKI gefitinib in patients following failure of chemotherapy, a majority of patients experience disease progression or relapse within 1 year.²

Apatinib, is a novel small-molecule, multi-targeted TKI, that selectively inhibits VEGFR2. Investigators of the ACTIVE trial hypothesized that simultaneously targeting EGFR and VEGFR pathways may be a feasible therapeutic strategy for patients with EGFR-mutant NSCLC based on early preclinical studies that demonstrated the dual blockade’s efficacy delaying the emergence of resistant tumors.²

Apatinib is currently approved in China for the treatment of patients with advanced gastric cancer following failure of frontline standard chemotherapy following superior observed PFS and OS data over placebo and a manageable safety profile.²

_References

1. _{Zhang L. ACTIVE: apatinib plus gefitinib versus placebo plus gefitinib as first-line treatment for advanced epidermal growth factor receptor-mutant (EGFRm) non-small-cell lung cancer (NSCLC): a multicentered, randomized, double-blind, placebo-controlled phase III trial (CTONG1706). Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract LBA50.}
2. _{Zhang Z, Luo F, Zhang Y, et al. The ACTIVE study protocol: apatinib or placebo plus gefitinib as first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (CTONG1706). Cancer Commun (Lond).2019;39(1):69. doi:10.1186/s40880-019-0414-4}