1. Fuerst, Mark L.

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The LAT1 inhibitor nanvuranlat significantly improves progression-free survival (PFS) over placebo in heavily pretreated advanced refractory biliary tract cancer patients. The L-type amino acid transporter, LAT1, transports large neutral amino acids across the membrane. Biliary rectal cancer patients with high LAT1 expression show significantly lower overall survival compared to patients with low LAT1 expression. Nanvuranlat is a selective LAT1 inhibitor.

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In a dose-escalation and Phase I trial conducted in patients with solid cancers, including biliary tract, colorectal, pancreas, esophagus, and breast cancers, nanvuranlat showed the highest disease control rate in patients with biliary tract cancers. Based on this result, Japanese researchers set biliary cancer as the target patient disease in a randomized Phase II trial. NAT2 patients with nonrapid phenotype were selected to maximize the clinical benefit of nanvuranlat.


"Nanvuranlat, a LAT1 inhibitor, demonstrated a statistically significant PFS benefit in patients with pretreated advanced refractory biliary tract cancer. Treatments in later lines of chemotherapy for biliary tract cancer are very limited. Nanvuranlat may help improve survival in patients with biliary tract cancer that is refractory to standard treatments," said lead author Junji Furuse, MD, PhD, of Kanagawa Cancer Center in Yokohama, Japan, at the 2023 ASCO Gastrointestinal Cancers Symposium.


Study Details

In this Phase II study, 104 patients were randomized to receive nanvuranlat (69 patients) 25 mg/m2 daily for 5 days, followed by 9 days of rest, or placebo (35 patients). The primary endpoint was PFS (Abstract 494). Demographics and the baseline characteristics were balanced in the two arms.


"Almost half of patients had a primary resection, and metastatic disease was seen in almost 90 percent or more in each arm," said Furuse.


Intrahepatic cholangiocarcinoma was seen in 40 percent of nanvuranlat patients and 50 percent of placebo patients. Individuals in the nanvuranlat arm were more likely to be older than age 65 years (65%) compared with patients in the placebo arm (46%).


"There were statistically significant improvements in PFS with nanvuranlat compared to placebo (HR: 0.557)," Furuse noted. "PFS was demonstrated in favor of nanvuranlat in every subgroup, especially in extrahepatic cholangiocarcinoma and gallbladder cancer."


The secondary endpoint of disease control rate was higher in the nanvuranlat arm (24.6%) compared to the placebo arm (11.4%). One patient in the nanvuranlat arm had a partial response and 16 patients had stable disease. Four patients in the placebo arm had stable disease. Also, extrahepatic cholangiocarcinoma gallbladder cancer had a very high disease control rate (31.3%) with nanvuranlat, she noted. In terms of adverse events, there were no significant differences between nanvuranlat and placebo, but there were some serious adverse events, including cholangitis (nine patients), with nanvuranlat.


"This is the first uncontrolled clinical trial in which nanvuranlat, a LAT1 inhibitor, demonstrated statistically significant PFS improvement over placebo," Furuse said. "A PFS benefit of nanvuranlat was present across mostly predefined biliary tract cancer subgroups. Nanvuranlat demonstrated a clear safety profile compared to that of the placebo group."


ASCO expert in gastrointestinal cancers Cathy Eng, MD, Professor of Medicine at Vanderbilt University Medical Center, commented: "LAT1 is a transporter of L-type amino acid and its expression is associated with poor prognosis. This Phase II trial demonstrates that nanvuranlat, a promising LAT1 inhibitor, improved PFS compared to best supportive care in patients with refractory biliary tract cancer and may offer a new treatment option. However, these findings will likely need to be assessed in a more diverse patient population, which will allow validation of efficacy and treatment-related toxicities."


Mark L. Fuerst is a contributing writer.