Real world evidence reveals improved survival outcomes in biliary tract cancer through molecular matched targeted treatment

Patient characteristics

In our analysis, we included patients with biliary tract cancer and available comprehensive molecular characterization data from five Austrian cancer centers. The data cut-off date was September 2022 (Fig. 1).

Figure 1
figure 1

Trial design: Flow chart depicting patient allocation.

In total, the molecular profile of 159 patients with biliary tract cancer was available. For further analysis, 19 patients were excluded due to incomplete clinical follow-up data, and 13 patients were excluded because they were still in the curative setting.

Therefore, 127 patients received at least one line of systemic treatment. The description of the molecular landscape of extrahepatic (eCC) and gallbladder cancer (GBC) vs. intrahepatic biliary tract cancer (iCC) was based on this cohort (Fig. 2A,B).

Figure 2
figure 2

Distribution of genetic alteration according to primary tumor location.

The three most prevalent altered genes, TP53 (32.6% for eCC vs. 22.2% for iCC; p = 0.21), KRAS (19.6% for eCC vs.17.3% for iCC; p = 0.81), and CDKN2A (15.2% for eCC vs. 18.5% for iCC; p = 0.81), were evenly distributed. Whereas in iCC alterations in genes dedicated as ESCAT I/II (FGFR2 fusion, BRAF-V600E mut., Her2neu amplification, IDH1 mut., MSI and NTRK Fusion) according to the latest ESMO guidelines for molecular testing in biliary tract cancer were more frequent than in eCC (27.5% vs. 10.5%; p = 0.0093) (Fig. 2A,B; Supplementary Table).

The treatment patterns across lines of therapy are depicted in Fig. 3. 62.2% of patients with advanced unresectable or metastatic biliary tract cancer proceeded to 2nd line treatment and 32.2% received at least 3rd line therapy. Reasons not proceeding to 2nd line were in most cases deterioration of ECOG performance status (N = 22; 17.3%) or death while on first line treatment (N = 17; 13.4%).

Figure 3
figure 3

Sankey plot characterizing treatment patterns across lines of therapy.

After failure of first line strategy, 36 patients who received a matched targeted treatment beyond the first line were compared in terms of efficacy outcomes with 43 patients treated with cytotoxic chemotherapy (Fig. 1).

Patients who received targeted treatment were significantly younger than those who received chemotherapy alone; 61.9 vs. 67.6 years (p = 0.012). However, this age difference became insignificant when patients not suitable for second-line therapy were excluded (61.9 vs 64.6 years; p > 0.05). The description of the group differences between matched targeted treatment (TT) and non-targeted therapy (NTT) versus non-targeted therapy, including only patients with second-line treatment (NTT2), is depicted in Table 1. The male patient rate was consistent between the groups (TT 69.4%; NTT 56%; NTT2 65.1%; p > 0.05). The ECOG performance status was also balanced between the groups. We observed a higher proportion of iCC in the group of patients who were eligible for matched targeted treatment than in the chemotherapy group (TT 83.3% vs. NTT 56% vs. NTT2 55.8; p = 0.0041; p = 0.026). No significant difference in tumor stage distribution was detected between the two groups. Patients with targeted treatment were more often prone to primary tumor resection 41.7% vs. 33% vs. 34.9%; p = 0.412; p = 0.643) and ablative therapy (27.8% vs. 15.4% vs. 18.6%; p = 0.133; p = 0.422) during the course of the disease (Table 1).

Table 1 Characteristics of patients and systemic treatment lines included in the trial.

Most patients received a platinum-based combination as the first-line systemic treatment (80.6% vs. 84.6% vs. 90.7%; p = 0.602; p = 0.214). Second-line chemotherapy consisted mostly of irinotecan or platinum-based chemotherapy. In addition, in the targeted group, 47.2% of patients were already suitable for the matched targeted approach. In total, patients in the matched targeted treatment group received a median of one treatment line more (three vs. two lines; p = 0.023) than the chemotherapy group suitable for at least second-line therapy (Table 1).

Activity of targeted treatment

In the matched targeted treatment group, the most prevalent target genes were FGFR (36.1%), BRAF (11.1%), HER2neu (11.1%) and MSI (11.1%). Tier I/II alterations were found most frequently in our cohort (23 patients, 63.9%). Among these, FGFR2-Fusion (30.4%), BRAF V600E mutation (13%), Her2neu amplification (17.4%), high PDL-1 expression (17.4%), and high MSI (17.4%) were reported. Tiers III/IV consisted of alterations in FGFR2/3 (38.5%), BRCA1/2 (23.1%), PIK3CA (15.4%), EGFR (15.4%), or BRAF non V600E (7.7%) (Fig. 2A,B; Supplementary Table).

In most patients (N = 17 or 47.2%), matched targeted treatment was initiated as second-line therapy, and 36.1% received it as 3rd line (Table 1).

The overall response (ORR) rate was 39%, with two complete responses (CR) in patients harboring MSI and 12 patients with partial remissions (PR). 6 patients (16,7%) achieved stable disease (SD). The disease control rate (DCR) defined as CR + PR + SD was 55.6% (Fig. 4B).

Figure 4
figure 4

Activity of matched targeted treatment in terms of response rates and improvement of mPFS ratios. Pie chart depicting response rates of matched targeted treatment (B). Paired scatter plot describing mPFS of targeted treatment compared to previous chemotherapy according to ESCAT tiers (C,D) and among MSI and FGFR2 fusion patients (A).

To further assess the clinical activity of this targeted approach, we compared the PFS of the targeted approach with that of the previous treatment. For Tier I/II alterations, we observed a modified PFS ratio (PFStargeted/PFSpre-chemotherapy) of 1.86 that was borderline significant (p = 0.059) (Fig. 4C). We further showed that FGFR2 fusion and MSI patients had the greatest benefit, with an mPFS ratio of 2.66 (p = 0.0186) (Fig. 4A). The mPFS ratio for ESCAT III/IV alterations was 0.77 (p = 0.946) with only 4 patients having a mPFS ratio greater than 1 (Fig. 4D).

Efficacy of targeted treatment

Most of the patients received platinum-based first-line therapy. The time to failure of the first-line strategy was not different between the two groups and was 4.76 months (95% CI 2.926–9.436) for the targeted group vs. 6.51 months (95% CI 4.997–8.449) in the chemotherapy group (HR 1.26; 95% CI 0.777–2.038; p = 0.35; Fig. 5C).

Figure 5
figure 5

Kaplan–Meier plots comparing matched targeted treatment with chemotherapy.

OS in the overall cohort was 22.32 months (95% CI 14.663- 29.195) in the targeted group (N = 36) vs. 11.74 (95% CI 8.153–16.636) in the chemotherapy group (N = 91). HR of 0.45 (95% CI 0.275–0.722; p = 0.001; Fig. 5A).

Further comparison of patients who received at least two lines of therapy showed a significant OS benefit of almost 5 months for the targeted treatment group (22.32 months; 95% CI 14.663–29.195; vs. 17.49 months; 95% CI 11.74–19.79). This resulted in HR 0.58 (95% CI 0.335–0.994; p = 0.048) (Fig. 5B).

After adjusting for factors such as sex, ECOG status, primary tumor resection, localization and stage in a multivariate analysis, the OS difference remained significant (p = 0.018) with a HR of 0.45 (95% CI 0.234–0.871; Fig. 6).

Figure 6
figure 6

Forest plot showing potential factors with influence on outcome parameters as depicted in univariate or multivariate analysis.

After the start of second-line treatment, OS was 12.36 months (95% CI 7.792–19.167) in the matched targeted treatment group and 8.48 months (95% CI 4.405–10.422) in the chemotherapy group (HR 0.54; 95% CI 0.309–0.926; p = 0.025; Fig. 5D). Statistical significance remained in the multivariate analysis (HR 0.44; 95% CI 0.229–0.854; p = 0.015).

Efficacy of targeted treatment according to variant classification systems in precision oncology

Subdividing the targeted group according to the level of evidence for each group showed an OS benefit after first-line failure for ESCAT I/II compared to chemotherapy patients 12.43 months 95% CI 6.148–NR) vs. 8.48 months (95% CI 4.405–10.422 HR of 0.44; 95% CI 0.219–0.866; p = 0.018) (Fig. 7). Comparable results were obtained from NCT m1A/B classified variants; OS was 14.96 months 95% CI 6.15–NR) (Supplementary Figure).

Figure 7
figure 7

Kaplan–Meier plots of overall survival after failure of first line strategy stratified by ESCAT tiers, FGFR2 Fusion + MSI or chemotherapy.

For ESCAT III/IV alteration, OS was only numerically different with 12.36 months 95% CI 7.364–19.167; HR 0.78 95% CI 0.396–1.555; p = 0.47 compared to the chemotherapy group (Fig. 7).

Among ESCAT I/II alterations, FGFR2 fusion-positive tumors treated with Pemigatinib and MSI tumors treated with checkpoint inhibitors showed the greatest benefit (N = 11; OS NR; 95% CI 9.863-NR) (Fig. 7).

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