Anlotinib Extends Time to Brain Progression in Patients with Advanced NSCLC

Apost hocanalysis of the ALTER 0303 trial has found that anlotinib (AL3818), compared with placebo, extended the time patients with advanced non-small cell lung cancer (NSCLC) had before brain metastases developed or existing brain lesions increased in size, reports a recent paper inThe Oncologist.¹

About one-fourth of ALTER’s patients (97 of 437) had brain metastases at baseline. In these patients, anlotinib was associated with longer progression-free survival (PFS; median PFS, 4.17 vs. 1.30 months; Hazard Ratio [HR], 0.29; 95% Confidence Interval [CI], 0.15—0.56) and overall survival (OS; median OS, 8.57 vs. 4.55 months; HR, 0.72; 95% CI, 0.42–1.12). These findings showed improvement similar to what patients without baseline brain metastases experienced in both PFS (HR, 0.33; 95% CI, 0.24–0.45) and OS (HR, 0.67; 95% CI, 0.50–0.91).

Patients with brain metastases who received anlotinib had an intracranial objective response rate (ORR) of 14.3% and a disease control rate of 85.7%. Anlotinib was also associated with longer time to brain progression (TTBP), this study’s primary endpoint (HR, 0.11; 95% CI, 0.03—0.41;P=.001) regardless of any confounding factors. Anlotinib was associated with more neural toxicities (18.4% vs. 8.4% for placebo) and psychological symptoms (49.3% vs. 35.7%). Anlotinib showed no association with either infarction or cerebral hemorrhage.

“Anlotinib can benefit patients with advanced NSCLC with BM [brain metastases] and is highly potent in the management of intracranial lesions,” wrote the authors, led by Shunjun Jiang, MD, of the Guangzhou Institute of Respiratory Health, Guangzhou, People’s Republic of China. “These results suggested that anlotinib has activity in the brain and plays a potential role in tumor control at intracranial sites… Its special effect on BM and cerebral tissue merits further investigation.”

All data in this study were drawn from the ALTER trial (NCT02388919). This phase III randomized, controlled trial was designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC.²

In the current study, the primary outcome of TTBP was defined as the duration between randomization and objective intracranial progression. In evaluating the intracranial ORR, target brain lesions were defined as each patient’s largest lesion that was larger than 1 cm and had not received previous radiotherapy.

Of the 437 patients included in the full analysis, patients were randomized 2:1 in favor of anlotinib (anlotinib n = 294, placebo n = 143). Both baseline and demographic characteristics were well-balanced between arms, including in patients who did and did not have baseline brain metastases.

The authors found no interaction effect between the PFS benefit (P= .69) and OS benefit (P=.79) in patients with and without brain metastases. In the anlotinib group, among the 14 patients with brain metastases at baseline, 2 had partial response (14.3%), 10 had stable disease (71.4%), and 2 had progressive disease (14.3%).

Jiang et al also performed a variety of subgroup analyses and found a trend favoring anlotinib in significantly longer TTBP. These include age over 60 years

(HR, 0.12; 95% CI, 0.02—0.95), EGFR mutation (HR, 0.07; 95% CI, 0.01–0.58), nonsmoker (HR, 0.17; 95% CI, 0.04–0.82), Eastern Cooperative Oncology Group performance status 1 (HR, 0.25; 95% CI, 0.07–0.86), stage IV (HR, 0.31;

95% CI, 0.10—0.94), previous receipt of targeted TKI therapy (HR, 0.12; 95% CI, 0.02–0.74), or surgery (HR, 0.15; 95% CI, 0.03–0.86). “These results indicated that anlotinib improves the intracranial local control in patients with advanced NSCLC,” they wrote.

According to Jiang et al, anlotinib suppressed tumor cell proliferation via inhibition of platelet-derived growth factor receptors α and β, c-Kit, and Ret as well as Aurora-B, c-FMS, and discoidin domain receptor 1, which was a group of newly identified kinase targets involving the tumor progression. “In addition, anlotinib showed antitumor activity against tumor cells carrying mutations in platelet-derived growth factor receptor α, c-Kit, Met, and epidermal growth factor receptor,” they wrote. “There has been no preclinical study indicating that anlotinib could cross the blood-brain barrier; this clinical evidence suggests preclinical study should focus on the mechanism of anti—brain metastatic tumor effect of multitargeted agents.”

In terms of study limitations, the authors note itspost hocnature, plus inherent bias from the relatively small numbers of patients with target brain lesions at baseline. Perhaps of greatest significance is the fact that anlotinib is currently available only in China: “However, it may be a good representation of multitargeted agents, such as sunitinib and sorafenib,” Jiang et al wrote.

References

1. Jiang S, Liang H, Liu Z, et al. The Impact of Anlotinib on Brain Metastases of Non-Small Cell Lung Cancer: Post Hoc Analysis of a Phase III Randomized Control
2. Trial (ALTER0303).The Oncologist. 2020;25:1—5.
3. Han B, Li K, Wang Q et al. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: The ALTER 0303 phase 3 randomized clinical trial.JAMA Oncol. 2018;4:1569—1575.