Despite Poor Prognosis, Anlotinib May Improve PFS in Pre-Treated NSCLC With Liver Metastases in Later Lines

The phase 3 ALTER 0303 trial demonstrated that although patients with non–small cell lung cancer and liver metastases have a worse prognosis than those without, treatment with anlotinib may result in better progression-free survival vs a placebo.

Despite having worse outcomes than patients with no liver metastases, patients with pretreated non–small cell lung cancer with liver metastases may benefit from anlotinib as a third-line or later therapy, according to data from the phase 3 ALTER 0303 trial (NCT02388919) published in the Journal of Cancer Research and Clinical Oncology.

A longer median PFS of 3.0 months (95% CI, 2.0-3.9) was observed with anlotinib vs 0.9 months (95% CI, 0.7-1.1) with placebo (HR, 0.23; 95% CI, 0.12-0.42; P <.0001). The median overall survival (OS) in the anlotinib group was 6.6 months (95% CI, 5.3-7.9) compared 4.0 months (95% CI, 2.2-5.8) in the placebo arm (HR, 0.61; 95% CI, 0.36-1.02; P = .055).

Overall, those without liver metastases had superior PFS of 4.2 months (95% CI, 3.9-4.5) in the anlotinib group vs 2.6 months (95% CI, 2.0-3.3) in the placebo group (HR, 1.83; 95% CI, 1.39-2.41; P <.0001), and a longer median OS of 9.4 months (95% CI, 8.5-10.4) vs 5.6 months (95% CI, 4.3-7.0; HR, 1.92; 95% CI, 1.46-2.53; P <.0001).

A total of 68.4% of patients in the placebo group and 60.3% in the anlotinib group who did not have liver metastases died at data cutoff. In the anlotinib group, the median PFS was 5.5 months (95% CI, 5.0-6.1) vs 1.4 months (95% CI, 1.2-1.6) in the placebo group (HR, 0.25; 95% CI, 0.19-0.33; P <.0001). The median OS in the anlotinib group for those without liver metastases was 10.1 months (95% CI, 8.8-11.4) vs 7.0 months (95% CI, 5.0-9.0) in the placebo group (HR, 0.69; 95% CI, 0.53-0.91; P = .008).

A total of 440 patients enrolled, of whom 437 were randomized and included in the efficacy analysis. Of these patients, 17.8% had liver metastases. Among individuals with liver metastases, 66.7% received anlotinib and 33.3% received placebo. Moreover, 3.8% of patients had liver metastases alone and 96.2% had more than 1 metastatic site. Additionally, 50 patients had over 3 metastases, 63 had adenocarcinoma, and 15 had squamous cell carcinoma. EGFR mutations were observed in 28.2% of patients and 1.3% had ALK mutations. A total of 39.7% of patients who had liver metastases received previous targeted therapy.

By data cutoff, 88.5% of patients with liver metastases in the placebo group and 82.7% in the anlotinib group had died. The objective response rate for those in the anlotinib group was 6.3% vs 0% in the placebo (P = .548), and the disease control rate was 77.1% vs 19.0% (P <.0005), respectively.

The univariate analysis showed similar outcomes for those with liver metastases and different tumor histologies with regard to both PFS (P = .841) and OS (P = .619). Investigators also reported that number of metastases was not predictive of PFS (P = .068) or OS outcomes (P = .198) outcomes. Additionally, EGFR mutations did not favor better survival in terms of PFS (P = .066) or OS (P = .694).

Subsequent treatment was given in 42.3% of patients in the anlotinib group vs 50% in the placebo group (P >.05) following disease progression. In total, 23.1% vs 30.8% of patients in either arm received chemotherapy, 17.3% vs 26.9% received targeted therapy, 9.6% vs 11.5% received radiotherapy, 3.8% vs 3.8% received traditional Chinese medicine, and 3.8% vs 0% received immunotherapy (all P >.05).

Treatment with anlotinib was more associated with hand-foot syndrome (7.7% vs 0%), serum thyroid-stimulating hormone rise (7.7% vs 3.8%), hypertension (3.8% vs 3.8%), prolongation of QTc interval (3.8% vs 3.8%) vs the placebo group.; adverse effects (AEs) did not differ significantly between groups (P >.05), with the aforementioned AEs being no more than grade 3.


Shen Y, Lu J, Hu F, et al. Effect and outcomes analysis of anlotinib in non-small cell lung cancer patients with liver metastasis: results from the ALTER 0303 phase 3 randomized clinical trial. J Cancer Res Clin Oncol. Published online April 28, 2022. doi:10.1007/s00432-022-03964-9