The impact of genomic alterations on response rate and survival outcomes in advanced BTC patients who receive cisplatin/gemcitabine plus durvalumab in clinical practice

The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with cisplatin/gemcitabine in patients with advanced biliary tract cancer (BTC), but no data about the prognostic impact of genetic alterations in real-world setting are already available.

A real-world population of advanced BTC patients who were studied by a 324-gene next generation sequencing (NGS) panel was considered for the present analysis. Patients were treated with cisplatin/gemcitabine plus durvalumab as first-line treatment at 11 Italian centers. The aim of the present analysis was to investigate the potential impact in terms of progression free survival (PFS) and overall survival (OS) of the most frequent genomic alterations. Moreover, a comparative genomic analysis between responding patients and non-responding patients was performed.

From February 2022 to November 2022, 51 patients were enrolled and studied with a 324-gene NGS panel. After a median follow up of 6.2 months (95% CI 4.3-10.9), the median OS was not reached, whereas the median PFS was 8.5 months (95% CI 6.3-8.9). Most frequently altered genes were: ARID1A (29.5%), CDKN2A/CDKN2B (21.5%), MLL2 (17.5%), BAP1 (15.5%), BRCA2 (15.5%), PBRM1 (15.5%), TP53 (14%), IDH1 (12%), KRAS (12%) and MTAP (12%). Several other genes were reported to be altered in 10% of the patients, including ATM, MDM2, MSH3, PIK3CB and SMAD4. Of interest, 37% of the patients showed alterations in genes involved with the BRCAness phenotype. No genetic alterations were reported to have an impact on PFS or OS in our population. Overall, 47 patients were included in the response rate analysis. The investigator-assessed confirmed objective response rate (ORR) was 34%, and the disease control rate (DCR) was 80.9%. From the genetic point of view, a statistically significant difference in terms of prevalence of PBRM1 mutation was highlighted between responders and non-responders, since a higher prevalence of PBRM1 mutated patients was observed in the responders’ group compared to non-responders’ group (31% Vs 6.5%).

The present work reported the first genomic analysis on a cohort of patients who received cisplatin/gemcitabine plus durvalumab as first-line treatment in a real-world setting. Data presented are consistent with those reported in the TOPAZ-1 genomic analysis, which were presented at ESMO ASIA 2022. Further investigation on larger number of patients are needed.

The authors.

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L. Rimassa: Honoraria (self): Lecture fees: Bayer, Eisai, Gilead, Incyte, Ipsen, Merck Serono, Roche, Sanofi, Servier; Advisory / Consultancy: AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; Research grant / Funding (institution): Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks; Travel / Accommodation / Expenses: AstraZeneca. M. Niger: Honoraria (self): Editorial collaboration: Incyte, Servier, Medpoint SRL, Sandoz, Speaker: Incyte; Advisory / Consultancy: Incyte, Servier, Taiho, Astrazeneca; Travel / Accommodation / Expenses: Astrazeneca. All other authors have declared no conflicts of interest.