Anlotinib plus toripalimab as a first-line treatment in patients with advanced gastric cancer and performance status 2: the phase II APICAL-GC trial

Abstract

Evidence-guided regimens for advanced gastric cancer (AGC) in patients with performance status 2 (PS 2) are limited. Here, we proposed a structured therapeutic framework termed "performance status-matched strategy", and further conducted the APICAL-GC trial (NCT04278222). This open-label, single-arm phase II study evaluated the efficacy and safety of anlotinib combined with toripalimab among 24 treatment-naïve AGC patients with PS 2. The primary outcome was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety profile. This trial met its prespecified endpoints, demonstrating an ORR of 58.3% (95%CI 36.6-77.9) with a DoR of 12.1 months (range: 1.43-48.5), and a DCR of 95.8% (95%CI 78.9-99.9). Median PFS reached 7.33 months (95%CI 3.83-17.1), while median OS was 15.9 months (95%CI 7.73-23.2). Treatment-related adverse events (TRAEs) of any grade occurred in 21 patients (87.5%), with grade-3 TRAEs observed in 7 patients (29.2%). No grade-4/5 TRAEs were reported. These findings provide a rationale for anlotinib plus toripalimab as a promising chemotherapy-free option for the first-line treatment of AGC patients with PS 2 under the performance status-matched strategy, showing comparable anticancer activity and a lower occurrence rate of TRAEs.

Fig. 1. A performance-matched strategy for advanced gastric cancer.

A schematic of outcomes by treatment intensity strategy stratified by PS in AGC patients.

Fig. 2. APICAL-GC study design.

The clinical trial profile of this study. 40 Patients with AGC with PS 2 were screened and 24 patients were enrolled and treated.

Fig. 3. Tumor response and survival outcomes.

Waterfall plot showing the maximum percent change in tumor-targeted lesion size from baseline in each patient as measured by the Response Evaluation Criteria in Solid Tumors (A). The upper dashed line indicates a 20% increase in the tumor burden (PD), and the lower dashed line indicates a 30% decrease in the tumor burden (PR). Asterisks indicate the presence of a new lesion. The Kaplan–Meier curve for progression-free survival (PFS) (B) and overall survival (OS) (C). The data cut-off date for clinical activity was August 20, 2024, and the median follow-up interval was 33.3 months. Vertical lines denote censored patients. The blue area shows the 95% confidence intervals (CI) for the PFS and OS curves. Source data are provided as a Source Data file.

Fig. 4. Clinical activity endpoints analysis stratified by age.

A Overall response rate (ORR), B progression-free survival (PFS), and C overall survival (OS) stratified by older patients (>65 years, n = 17) and younger patients (≤65 years, n = 7). P value, two-sided Fisher exact test for ORR analysis; log-rank test for PFS and OS analysis. Source data are provided as a Source Data file.

Fig. 5. Prespecified exploratory analysis.

Oncoprint of concomitant mutation in 21 treatment-naïve advanced gastric cancer patients in ITT (A). The association between FAT4 mutation, and clinical benefit from anlotinib plus toripalimab (B). P value, two-sided Fisher exact test for ORR analysis; log-rank test for PFS and OS analysis. Source data are provided as a Source Data file.