Fruquintinib, gefitinib shows promise for EGFR-mutated non-small cell lung cancer

Issue: November 10, 2017

The combination of fruquintinib with gefitinib appeared safe and effective for the first-line treatment of patients with non-small cell lung cancer and EGFR activating mutations, according to results of a single-arm, open-label, multicenter phase 2 study presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

Fruquintinib (HMPL-013, Hutchison Medi Pharma/Hutchison China MediTech) is a potent highly selective oral VEGFR tyrosine kinase inhibitor that has shown safety and efficacy in the third-line setting.

“Promising antitumor effect of fruquintinib monotherapy was shown in a proof-of-concept study last year in NSCLC, which was verified in a phase 3 study of patients with metastatic colorectal cancer at this year’s ASCO Annual Meeting,” Shun Lu, MD, PhD, professor at Shanghai Chest Hospital of Jiao Tong University and chief of Shanghai Lung Cancer Center in Shanghai, China, said during his presentation.

Studies have shown that the simultaneous targeting of EGFR mutations and tumor angiogenesis has synergistic effects in the first-line setting of EGFR-mutated NSCLC. However, these studies have demonstrated increased toxicity, particularly grade 3 or worse hypertension.

Because small molecule TKIs have shorter half-lives, researchers hypothesized that the combination of an EGFR TKI with a VEGFR TKI would demonstrate a more manageable safety profile.

“The high selectivity of fruquintinib and its shorter half-life compared with a VEGF antibody provide a hypothesis for a better safety profile while preserving efficacy,” Lu said.

Lu and colleagues assessed the safety, tolerability and efficacy of fruquintinib plus gefitinib (Iressa, AstraZeneca) in 26 treatment-naive patients (69.2% aged 65 years or older; 50% men; 100% Asian) with NSCLC and an ECOG performance status of 1. Eleven patients had L858R mutations and 15 had exon 19 deletions.

Twenty-six patients in the first stage of the study received 250 mg gefitinib continuously plus 4 mg fruquintinib for 3 weeks followed by 1 week off. In the second stage, six patients received an escalated dose up to 5 mg in subsequent cycles provided no grade 3 or worse adverse events or grade 2 or worse liver dysfunction occurred after the first treatment cycles.

Safety, tolerability and overall response rate served as the primary endpoints. Secondary endpoints included PFS, disease control rate, time to response and duration of response.

As of Oct. 10, the first patients have been treated for more than 250 days. Only one patient discontinued treatment due to grade 3 proteinuria.

The 5-mg dose of fruquintinib led to more frequent dose interruptions, mostly due to liver enzyme elevations. However, a 4-mg dose appeared well tolerated and was recommended for further development, Lu said.

Among 17 evaluable patients, 13 (76.5%) have achieved partial response and four (23.5%) have achieved stable disease. Thus, researchers observed a 100% disease control rate.

Twenty-three patients (88.5%) experienced any treatment-related adverse event, but only eight patients (30.8%) experienced grade 3 or worse toxicity.

The most common adverse events included increased alanine transaminase (46.2%), increased aspartate transaminase (53.8%), increased total bilirubin (38.5%), increased thyroid stimulating hormone (38.5%) and rash (34.6%).

“This is the first study of fruquintinib in combination with gefitinib in the first-line setting for patients with NSCLC and EGFR mutation,” Lu said. “So far, this is also the first combination of two small molecular inhibitors. This combination shows an overall acceptable safety profile, as well as promising efficacy.” – by Alexandra Todak

Reference:

Lu S, et al. Abstract JCSE 01.12. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Oct. 15-18, 2017; Yokohama, Japan.

Disclosures: Lu reports research support or speakers fees from and advisory roles with AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hutchinson MediPharma, Roche and Sanofi. Please see the abstract for a list of all other authors’ relevant financial disclosures.