Varlitinib Misses Primary Endpoint in Frontline Gastric Cancer Trial

Mark McHale, MD

Frontline varlitinib (ASLAN001) added to mFOLFOX6 was not found to significantly reduce tumor size after 12 weeks of therapy compared with mFOLFOX6 alone in patients with HER1/HER2 co-expressing advanced or metastatic gastric cancer, missing the primary endpoint of a phase II study, according to ASLAN Pharmaceuticals, the company developing the pan-HER inhibitor.

Results showed that patients who received varlitinib and mFOLFOX6 had an average tumor shrinkage of 22.0% after 12 weeks versus 12.5% in those who received mFOLFOX6 alone, which did not reach statistical significance. Following review of 17 progression-free survival (PFS) events to date, data showed a trend toward an improvement in PFS in the varlitinib arm.

“Whilst we are disappointed by the study findings, we are encouraged by the positive safety data and remain confident that varlitinib's potent pan-HER inhibition has the potential to yield benefits in biliary tract cancer where HER family expression is known to be high,” said Mark McHale, MD, chief operating officer, ASLAN Pharmaceuticals, in a press release. "We look forward to presenting the upcoming data in first-line biliary tract cancer at [the 2019 Gastrointestinal Cancers Symposium] later this week and delivering topline data from our pivotal TreeTopp study in second-line biliary tract cancer, which is expected in the second half of 2019."

Varlitinib is a highly potent, oral, reversible, small molecule pan-HER inhibitor designed to target HER1, HER2 and HER4. The agent is currently being studied in gastric, biliary tract, breast and colorectal cancers. The FDA granted varlitinib an orphan drug designation in gastric cancer and cholangiocarcinoma in June 2016 and April 2015, respectively, and was granted orphan drug designation for the treatment of patients with biliary tract cancer by the Ministry of Food and Drug Safety in South Korea in February 2017.

In the international, multicenter, placebo-controlled, double-blind, randomized trial (NCT03130790), investigators evaluated the safety and efficacy of varlitinib in combination with mFOLFOX6 or mFOLFOX6 alone in approximately 50 patients with HER1/HER2 co-expressing gastric cancer. A pre-planned phase III portion of the trial was expected to recruit 350 more patients.

Patients received either placebo and mFOLFOX6 or oral varlitinib at 300 mg twice daily for 2 weeks and mFOLFOX6, which consisted of concurrent oxaliplatin at 85 mg/m² and leucovorin at 400 mg/m² intravenously (IV) in 500 ml 5% dextrose water over 120 minutes on day 1, 5-flurouracil bolous at 400 mg/m² IV on day 1, followed by continuous infusion at 2400 mg/m² over 46 hours starting on day 1 every 2 weeks.

The primary endpoints were percentage change in tumor size, which was defined as the percentage change from baseline in the sum of longest diameters of target lesions as assessed by independent central review and defined by RECIST v.1.1 criteria, and overall survival (OS) in the phase III portion. Secondary endpoints in the phase II portion were objective response rate, PFS, time to response, duration of response, disease control rate, OS, and pharmacokinetics.

To be eligible for enrollment in the phase II portion, patients must have had histologically confirmed inoperable locally advanced, recurrent, or metastatic adenocarcinoma of the stomach or gastroesophageal junction cancer, expression of HER1/HER2, have radiographically measurable disease defined by RECIST v1.1, an ECOG performance status of 0 or 1, an estimated life expectancy of ≥4 months, and adequate organ and hematological function.

Patient characteristics were overall balanced between the 2 arms, with the exception of baseline ECOG performance status, ASLAN Pharmaceuticals noted in the press release. There was a greater proportion of patients with an ECOG performance score of 0 on the control arm (46.2%) compared with varlitinib arm (19.2%).

Regarding safety, the combination of varlitinib and mFOLFOX6 was found to be well tolerated; 73.1% of patients on varlitinib experienced a grade ≥3 adverse event compared with 88.5% of patients on the mFOLFOX6-alone arm.

ASLAN Pharmaceuticals stated that it will continue to analyze data from this phase II study and work with study investigators to publish the full findings in the future.

“First-line gastric cancer is a very challenging indication to treat and the majority of patients present with advanced disease at initial diagnosis,” McHale added in the press release. “To date, no targeted therapies have been approved to treat gastric cancer with low HER-family expression.”

The company’s multicenter phase Ib/II trial (NCT02992340) of varlitinib in combination with gemcitabine and cisplatin in the first-line setting for patients with biliary tract cancer will be presented at the 2019 Gastrointestinal Cancers Symposium.

ASLAN Pharmaceuticals Announces Study Results from Phase 2 Study of Varlitinib in First-line Gastric Cancer. Aslan Pharmaceuticals. Published January 14, 2019. https://bit.ly/2stwaIZ?rel=0" . Accessed January 14, 2019.