Is there room for nal-IRI in biliary tract cancer?

The prognosis of biliary tract cancer (BTC) remains dismal. Recently, the phase 3 randomized TOPAZ-1 trial has established a novel standard of care as first line, demonstrating a survival prolongation when the anti-programmed death-ligand 1 (PD-L1) durvalumab is added to the gemcitabine plus cisplatin backbone. FOLFOX is considered the recommended second-line treatment, based on the results of the ABC-06 trial. Recent studies investigated the activity of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV), providing conflicting results. In the final analysis results of the phase IIb NIFTY trial, the combination of nal-IRI + 5-FU/LV demonstrated longer median PFS (4.2 versus 1.7 months, p=0.004), OS (8.6 versus 5.3 months, p=0.02) and objective response rate (ORR; 12.5 versus 3.5%) compared to 5-FU/LV alone in patients who progressed to first-line gemcitabine plus cisplatin (21, 22). Results of the phase II NALIRICC trial have been presented at the ESMO Congress 2022. In previously treated BTC patients the addition of nal-IRI to 5-FU/LV failed to improve PFS (2.64 versus 2.30 months) and OS (6.90 versus 8.21 months). We performed a meta-analysis aiming to evaluate survival outcomes and response rates in these two randomized trials investigating the activity of nal-IRI in previously treated BTC patients.

We retrieved all potentially relevant results through PubMed/Medline, Cochrane library and EMBASE and abstracts presented at the main international oncological meetings. Hazard Ratio (HR) and 95% Confidence Intervals (95%CI) for progression-free survival (PFS) and overall survival (OS), and Odds Ratio (OR) and 95% CIs for objective response rate (ORR) were extracted.

Results from two studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. A total of 274 BTC patients were available for the meta-analysis. 137 patients received the combination therapy and 137 received 5-FU/LV alone. The combination therapy significantly decreased the risk of progression (HR 0.70; 95%CI 0.50-0.97) compared with 5-FU/LV alone. Furthermore, longer OS (HR 0.84; 95%CI 0.53-1.31) and higher ORR (RR 3.15; 95%CI 1.20-.25) were observed in the doublet arm.

FOLFOX is considered the optimal option in the all-comer BTC patients in the second-line setting. However, the control arm of the pivotal arm was the active symptom control alone. Furthermore, not all patients are eligible to this therapy and not all benefit from it. Our meta-analysis supports the role of nal-IRI plus 5-FU/LV in the second-line setting in BTC patients. Further studies are warranted in order to find the best place for this promising combination therapy.

The authors.

Has not received any funding.

All authors have declared no conflicts of interest.