Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
Masafumi Ikeda , Makoto Ueno , Masayuki Furukawa , Chigusa Morizane , Tetsuo Takehara , Tomohiro Nishina , Akiko Todaka , Naohiro Okano , Kazuo Hara , Yousuke Nakai , Kazuyoshi Ohkawa , Takashi Sasaki , Kazuya Sugimori , Naoyuki Yokoyama , Kouji Yamamoto , Junji Furuse
Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells leading to aggressive proliferation and lymphatic metastases. LAT1 sustains energy resources by supplying essential amino acids to the TCA cycle in chemotherapy-resistant cancer cells. LAT1 is a documented marker of poor prognosis. In a placebo-controlled, randomized trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) compared to placebo. Subgroup analysis was conducted to determine whether the level of expression of LAT1 affects nanvuranlat efficacy. Methods: Patients with four different subtypes of advanced BTC were enrolled: intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder and ampulla of Vater cancers. All were refractory to or intolerant of standard chemotherapy and other investigational medicines. Our analysis compared efficacy and safety in the subgroup with high LAT1 expression and all patients group. LAT1 expression was immunohistochemically evaluated in tumor specimens of BTC patients at baseline, as defined by Yanagisawa N, et al. (Cancer Med 2014). Results: At data cut-off (Feb 28, 2022), 211 BTC patients consented at 14 centers in Japan, and 104 patients were randomized (2:1) to nanvuranlat (n = 69) or placebo (n = 35) as the full analysis set (FAS) population. Among the samples immunohistochemically evaluable for LAT1, 62.5% had high LAT1 expression. There was no significant difference in background demography between all patient group and the high-LAT1 subgroup. Nanvuranlat met its primary endpoint (FAS by the blinded independent central review (BICR)), demonstrating a statistically significant improvement in PFS by BICR in comparison with the placebo group. The hazard ratios were further improved with nanvuranlat versus placebo, on analysis of the high-LAT1 subgroup of patients in both PFS and OS. Safety was comparable between nanvuranlat and placebo, on analysis of the high-LAT1 subgroup. Conclusions: This subgroup analysis indicates that the efficacy of nanvuranlat in PFS and OS is enhanced in BTC patients with high LAT1 expression, when compared with placebo. Safety profiles were similar for nanvuranlat- and placebo-treated patients in this subgroup analysis. Clinical trial information: UMIN000034080.
Nanvuranlat vs Placebo | Subgroup of Patients with High LAT1 (n=65) | All Patients (n=104) | |
---|---|---|---|
PFS | Hazard Ratio1 | 0.439 | 0.557 |
95% CI (lower - upper) | 0.2254 - 0.8535 | 0.3435 - 0.9029 | |
p value2 | 0.0131 | 0.0164 | |
OS | Hazard Ratio1 | 0.670 | 0.849 |
95% CI (lower - upper) | 0.3463 - 1.2954 | 0.5308 - 1.3574 | |
p value2 | 0.2313 | 0.4934 |
1 Stratified Cox proportional-hazard model, 2 Stratified log-rank test.
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Abstract Disclosures
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