Despite Promising Trial Results, Skeptics Raise Red Flags About Anlotinib's Efficacy in Heavily Treated NSCLC

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The VEGFR/EGFR inhibitor anlotinib prolonged PFS and OS in Chinese patients with NSCLC, but additional studies are needed to determine its benefit in other populations.
The VEGFR/EGFR inhibitor anlotinib prolonged PFS and OS in Chinese patients with NSCLC, but additional studies are needed to determine its benefit in other populations.

Anlotinib, an angiogenesis and proliferative signaling inhibitor, prolonged progression-free (PFS) and overall survival (OS) when used as a third-line treatment in Chinese patients with advanced non-small cell lung cancer (NSCLC), according to results from the phase 3 ALTER 0303 trial.1

Targeted therapies are the standard of care in patients with NSCLC who harbor genetic aberrations such as EGFR mutations orALK rearrangements. The aim of the phase 3 ALTER 0303 trial was to further determine the efficacy and safety of anlotinib following the release of positive PFS results from its phase 2 trial.

Anlotinib is a tyrosine kinase inhibitor (TKI) that targets multiple factors involved in angiogenesis and proliferation signaling, including VEGFR receptors 1 to 3, EGFR, FGFR 1 to 4, PDGF-R α and β, and stem cell factor receptors. Although the TKIs for NSCLC that are currently approved in the United States target EGFRALKROS1, or BRAF, results from recent trials suggest that VEGF inhibition may also provide a benefit in some patients. H. Jack West, MD, the medical director of the Thoracic Oncology Program at the Swedish Cancer Institute in Seattle, Washington, who was not involved in the ALTER 0303 trial, told Cancer Therapy Advisor that “This work on anlotinib, as well as the recent positive results from the IMPower150 trial — specifically in the arm that received carboplatin/paclitaxel/bevacizumab with atezolizumab immunotherapy — highlights the ongoing clinical relevance for VEGF inhibition.” In addition, he noted that the combination of erlotinib plus bevacizumab in a study conducted in Japan also “corroborates the relevance of VEGF inhibition in patients with NSCLC, perhaps particularly in patients with an EGFR mutation.”

ALTER 0303 Results

The multicenter double-blind, phase 3 ALTER 0303 trial randomly assigned 439 Chinese patients with stage IIIB to IV NSCLC 2:1 to receive anlotinib or placebo until disease progression or drug intolerance. Patients with actionable driver mutations were eligible after progression during 1 line of chemotherapy and TKI therapy, or, in patients whose disease did not harbor an actionable mutation, after progression following 2 lines of chemotherapy. The primary end point was OS and the secondary end points included PFS, objective response rate (ORR), disease control rate, and quality of life. 

At baseline, mean patient age was 57 in both arms; approximately one-third of patients were women and 49% were nonsmokers. Approximately 76% of patients had adenocarcinoma and approximately 21% had squamous histology. EGFR mutations and ALK rearrangements were present in 31.6% and 1.6% of patients, respectively.

More patients responded to anlotinib, with an ORR of 9.2% compared with 0.7% with placebo (P<.001). In a similar fashion, the disease control rate was significantly higher in the anlotinib arm compared with placebo: 81% and 37.1%, respectively (P<.001).

Treatment with anlotinib significantly prolonged OS; OS was a median of 9.6 months longer in the anlotinib arm (95% CI, 8.2-10.6 months) compared with 6.3 months in the placebo arm (95% CI, 5.0-8.1 months; hazard ratio [HR], 0.68; 95% CI, 0.54-0.87; P=.001). The OS rate was 27.8% (95% CI, 19.9-35.7%) and 22.7% (95% CI, 14.8-30.7%) at 12 and 18 months, respectively.

The median PFS with anlotinib was 5.4 months (95% CI, 4.4-5.6 months) compared with 1.4 months (95% CI, 1.1-1.5 months) with placebo (HR, 0.25; 95% CI, 0.19-0.31; P<.001).

“The patients in the study overall did better than would be expected, suggesting that many of these patients had indolent disease, low-volume disease, or other factors that makes this study population not clearly representative of a global population of patients with heavily treated NSCLC and no further treatment options,” Dr West commented.

The survival benefit of anlotinib remained in most predefined subgroups, including individuals with or without EGFR mutations, adenocarcinoma or squamous histology, smoking history, and previous exposure to chemotherapy or targeted therapy. The sample size of patients with ALK rearrangements, however, was too small for interpretation.

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