Exploring the impact of Durvalumab on biliary tract cancer- insights from real world clinical data

doi:10.21203/rs.3.rs-4840712/v1

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Research Article

Exploring the impact of Durvalumab on biliary tract cancer- insights from real world clinical data

https://doi.org/10.21203/rs.3.rs-4840712/v1

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Introduction

This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the Topaz-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes.

Methods

A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies.

Results

Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in Chromatin Remodeling or Homologous Recombination Repair genes were not predictive of survival benefit (HR 0.45; p=0.851 and HR 1.63; p=0.26, respectively). Patients with molecular-informed second-line therapy showed a trend towards survival benefit (HR 0.23, p=0.052).

Conclusion

This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups

DNA Damage Repair

homologous recombination repair (HRR)

biliary tract cancer

molecular informed therapy

BRCAness

precision oncology

Biliary tract cancer (BTC) constitutes a heterogeneous group of malignancies arising from various parts of the biliary system. This collective term includes carcinomas of the gallbladder/cystic duct (GBC) and cholangiocarcinomas (CCA). CCAs can be further divided into three subtypes: intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA), depending on their exact anatomical origin.(1,2)

Although, BTCs are quite rare, accounting for less than 1% of all malignant tumours, recent data have shown an increase in global incidence(2–4). Prognosis remains poor with 5-year overall survival rates of approximately 5–15%. (5,6) This is attributed to several reasons, primarily: 1) about two thirds of all patients are diagnosed with advanced/metastatic disease and 2) patients undergoing potentially curative resection for localized tumours suffer from a high relapse rate.(7)

Palliative treatment in advanced BTCs was studied intensely over the past decades. However, after gemcitabine was first established as a valid treatment option in 1996, many subsequent trials with different treatment approaches yielded disappointing results.(7,8) Progress was not achieved until the ABC-02 trial in 2010. This phase III study investigated gemcitabine in combination with cisplatin against gemcitabine alone and showed a statistically significant advantage in median overall survival (mOS) of 11.7 vs. 8.1 months (Hazard ratio [HR] 0.64; 95% Confidence interval [CI] 0.52–0.80; P < 0.001), thereby establishing a new standard of care for advanced/metastatic BTCs.(9) The nest milestone in BTC treatment was reached when the results of TOPAZ-1 trial were published, reporting improved mOS (12.8 vs. 11.5 months; HR 0.80, 95% CI 0.66–0.97; P = 0.021) and median progression-free survival (mPFS) in patients treated with gemcitabine/cisplatin/durvalumab over gemcitabine/cisplatin.(10) Thus, this combined chemo-immunotherapy is currently considered standard of care as first line treatment in patients with BTCs.(2)

Specifically, BTCs (biliary tract cancers) seem to be excellent candidates for molecularly guided treatment strategies. Notably, nearly half of the patients with BTC might be eligible for therapies based on molecular diagnostics (20, 21). Molecular targeted therapies have the second-line treatment, as strongly recommended by the ESMO guidelines providing an overall survival benefit.(20,21). For some of these alterations approved therapies are already available.

Recently ClarIDHy led to the approval of Ivosidenib in isocitrate dehydrogenase 1 (IDH1) mutant BTCs showing an improvement in mPFS. (11)

Further studies on targetable alterations such as FGFR2 fusions (FIGHT-202 trial), HER2 amplification/overexpression (MyPathway trial), BRAF mutations (ROAR trial) and NTRK fusions (ALKA-372-001, STARTRK-1, and STARTRK-2 trial) opened up new second line treatment options and are validated by multiple real-world cohorts.(12–21)

However, despite recent progress in palliative treatment many questions remain unanswered: 1) There is paucity of real-world clinical data on the efficacy of first line gemcitabine/cisplatin/durvalumab. 2) Predictive biomarkers highlighting patients, who benefit most from the addition of durvalumab are currently pending. 3) the majority of previously mentioned studies on targeted therapies in second line did not employ gemcitabine/cisplatin/durvalumab as first line therapy. Current clinical data are therefore urgently needed to address this gap.

2.1 Patients

We conducted a retrospective analysis involving 102 patients with histologically confirmed biliary tract cancer (BTC) treated with durvalumab, platin and gemcitabine at five cancer centers in Austria and one comprehensive cancer center in Germany. The initial diagnoses were made between 2022 and January 2024.

Written informed consent for molecular analysis was obtained from all patients as part of routine clinical workflow. The study protocol received approval from local committees on human research (21-10239-BO, Essen, Germany; Ethics Committee, Land Oberoesterreich, 1100/2023; and Ethics Committee of the City of Vienna, EK-1099/2021), ensuring compliance with the ethical guidelines of the 1975 Declaration of Helsinki.

Clinical data were retrieved from the patients' electronic records system, encompassing demographics, clinical history, surgical interventions, local therapeutic approaches, chemotherapy, targeted therapies, response to targeted treatment, molecular pathology diagnostics, and survival status up to March 2024. Decisions regarding individual molecular-matched therapeutic options were based on contemporary scientific and clinical knowledge, the availability of clinical trials, and approved agents at the time. Disease stages were defined according to the TNM 8th edition (Citation). Patients with distal CCAs, perihilar tumours and carcinomas of the Ampulla Vateri were pooled under the term extrahepatic cholangiocarcinoma (eCCA).

2.2 Molecular Profiling and Classification of Mutations

DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) samples from core tumor biopsies or surgical samples. Sequencing was conducted using customized NGS panels: TruSight Tumor 170, TruSight Oncology 500 (Illumina Inc., San Diego, CA, USA), GeneRead DNAseq Custom Panel V2 (QIAgen, Hilden, Germany), Oncomine Comprehensive V3, Ion AmpliSeq Cancer Hotspot Panel v2 (Thermo Fisher Scientific, Waltham, MA, USA) and FoundationOne CDx hybrid-capture NGS service platform (324 genes for both mutations and fusions) Foundation Medicine, Inc, Cambridge, MA in the Austrian centers, and PACAP Panel (DNA-based customized NGS panel, 20 genes), CCP3 Panel (DNA-based customized NGS panel, 20 genes)(MiSeq platform, Illumina Inc., San Diego, CA, USA)- in the German center. All platforms were used according to the manufacturers´ instructions. For RNA sequencing FusionPlex CTL Panel, Archer (Illumina Inc., San Diego, CA, USA) was used.

Additionally, data on defective mismatch repair (dMMR)/microsatellite instability (MSI) status, PD-1 or PDL-1 and HER2neu (IHC) were collected when reported. Genes associated directly or indirectly with Homologous Recombination Repair (HRR) were the following: ARID1A, BRCA1, BRCA2, PALB2, BARD1, ATR, ATRX, ATM, BAP1, RAD51C, RAD51D, BRIP1, NBN, CHEK1, CHEK2, FANCA, FANCC, and MRE11.(22,23) Genes thought to be associated with chromatin remodeling comprised: ARID1A/B, ARID2, ASXL1, ATRX, CREBBP, DAXX, DNMT1, DNMT3A, EP300, EZH2, H3F3A, HIST1H3B, IDH1/2, KDM5C, KDM6A, MEN1, MLL2/3, NCOR1, PAX5, PBRM1, PRDM1. SETBP1, SETD2, SMARCA4, SPOP, TET2, WT1.(24,25)

Identification of pathogenic mutations was based on the effect of the gene alterations (including nonsense, frameshift, start/stop codon alterations and splice site mutations) on the function of the corresponding proteins. These gene changes were then verified for their clinical relevance by querying the following databases: ClinVar, Catalogue of Somatic Mutations in Cancer (COSMIC), Varsome and Alamut Visual Plus (Sophia Genetics).(26–29).

For annotation of targetable mutations, two variant classification systems were implemented: ESCAT, as a framework for the actionability of molecular targets, and the National Center for Tumor Diseases (NCT) Heidelberg variant classifier.(30,31) Both were used to rank the clinical evidence for the matched molecular informed therapies. The pathogenicity of mutations was evaluated according to ACMG-AMP (American College of Medical Genetics and Genomics the Association for Molecular Pathology) criteria. (32)

2.3 Study end points

Our primary objectives were to assess the time to progression on first line therapy and overall survival of patients treated with platinum plus gemcitabine in combination with durvalumab in first line therapy. PFS was defined as the time from the start of the first-line chemotherapy until radiologically proven progression, untreatable toxicities or death from any cause, whichever occurred first. The response to treatment was assessed for each therapy line using a combination of clinical response and imaging findings, including computed tomography and magnetic resonance tomography. Radiological response was classified in accordance with the RECIST V1.1 criteria.

OS was defined as the time from the starting date of first-line palliative chemotherapy to the date of death; patients without documented death on the cut-off date were censored on the date the patient was last known to be alive. Median follow up was calculated by reverse Kaplan-Meier method.

2.4 Statistics

Descriptive statistics were used to summarize the baseline clinical data of all patients and the results of molecular testing.

Survival analysis was conducted for patients who received a first-line platinum-based chemotherapy doublet consisting of platinum and gemcitabine combined with durvalumab.

Time-to-event endpoints were estimated using the Kaplan-Meier method and log-rank test for statistical comparison. Cox proportional hazards models were used to obtain hazard ratios with 95% confidence intervals. Multivariate Cox models were used to calculate HR with 95% CIs while adjusting for potential confounders (age, ECOG performance status, sex, primary tumor location, primary tumor resection and stage at diagnosis).

P-values were two-sided. All statistical analyses were performed using Stata software package (Stata. version 18.0).

3.1 Patient characteristics

From 2022 to January 2024, we identified a total of 104 patients with a histologically confirmed diagnosis of biliary tract cancer treated with platinum/gemcitabine and durvalumab. Patient allocation is depicted in Figure1.

The study included a total of 102 eligible patients, comprising 44 females (43.1%) and 58 males (56.9%). The median age of the participants was 65.18 years, ranging from 25.57 to 83.84 years, with 53 patients (52%) being older than 65 years. The majority of patients (n=94, 92.2%) were assessed with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The breakdown of BTC subtypes included 62 patients (60.8%) with iCCA, 14 patients (13.7%) with dCCA, 13 patients (12.7%) with gallbladder cancer, 11 patients (10.8%) with perihilar tumours, and 2 patients (2.0%) with carcinoma of the Ampulla Vateri. 24 patients (23.5%) had metachronous metastatic disease, with initial curative intended surgical resection; of these 18 patients (17.6%) received adjuvant therapy. The median Body Mass Index (BMI) was 26.2 kg/m². Metabolic liver disease was present in 16 patients (15.7%), and a history of viral hepatitis was noted in only three individuals.

3.2 Molecular characterization

Comprehensive molecular characterization was performed for 90 patients of the cohort. Of these, 18 patients (20%) exhibited no detectable genetic alterations. Tumor Mutational Burden (TMB) was evaluated in 23 patients, with a median value of 2.61 mutations per megabase (mut/Mb), (95%CI 2.4-4.62). Microsatellite status was assessed in 68 patients (75.6% of those characterized), identifying only one patient with Microsatellite Instability (MSI). The most frequently mutated genes were TP53 (29%), KRAS (18%), and CDKN2A (11%). Alterations in Chromatin Remodeling genes were identified in 18 patients, with the most common alterations occurring in ARID1A/B (9%) and IDH1/2 (10%). HRR genes were altered in 26 patients, with the highest prevalence seen in BAP1 (9%), BRCA1/2 (9%), and ARID1A (8%).

In terms of therapeutic relevance, ESCAT (ESMO Scale for Clinical Actionability of molecular Targets) Level I/II alterations were found in 20 patients, and level III/IV alterations were observed in 15 patients. The most prevalent actionable alterations were in BRCA1/2 (9%), IDH1 (8%), ERBB2 (6%), and PIK3CA (5%). FGFR2 alterations were noted in 4% of patients, including three cases of FGFR2 fusion.

3.3 Efficacy of durvalumab + platinum based doublet regarding PFS in first line and OS.

For the survival analysis, data were collected from a cohort of 102 patients undergoing first-line treatment with a combination of platinum-based chemotherapy and Gemcitabine, plus durvalumab. The majority of patients (94.1%) received Cisplatin as the chemotherapeutic backbone, with a smaller number receiving Carboplatin (4.9%) and one patient (1%) treated with oxaliplatin. The median follow-up period was 9.34 months, with a 95% CI of 6.575 to 11.178 months. At the data cut-off, 36 patients (35.3%) were still receiving their first-line treatment.

The observed disease control rate was 71.57%, and the overall response rate was 35.11%. The median PFS was 6.51 months (95% CI: 4.767-7.266), and the OS was 13.61 months (95% CI: 11.277-21.633). Overall survival for patients showing response (CR or PR) to durvalumab and platinum based doublet was 14.14 months 95%CI(13.545-NR) vs patients with stable disease 12.2 months 95%CI(10.521-NR) vs patients with progressive disease (PD) 8.52months 95%CI(5.458-NR). HR for patients with at least a PR compared to non-responders was 0.29 95%CI(0.119-0.719), P=0.007.

A comparative analysis between cisplatin-based and non-cisplatin-based chemotherapeutic regimens showed no statistically significant difference in OS, with the cisplatin group showing an OS of 13.84 months (95% CI: 12.197-21.633) versus 10.32 months (95% CI: 2.959-NR) for the non-cisplatin group (p=0.3).

In the multivariate analysis including localization of primary tumor (iCCA vs non-iCCA), resection of primary tumor (yes vs no), ECOG performance status (0 vs higher), sex (m vs w), age (below 65 vs above 65), prior adjuvant therapy (yes vs no) and metabolic liver disease (yes vs no) only age below 65y was found to be an independent prognostic factor.

3.4 Clinical outcome of distinct molecular subgroups

Comprehensive molecular profiling was available for 90 patients. We subsequently aimed to determine if the response to and efficacy of combined therapy were associated with mutations in specific genes or pathways. The distribution of clinically relevant pathogenic variants associated with tumor response and survival outcomes is shown in Supplementary Table 1. No single gene alteration could show was associated with a better outcome.

26 patients receiving platinum based doublet plus durvalumab were HRRm. ORR for HRRm patients was 30.77% vs 32.81% P=0.851, DCR was 76.92% vs 71.88% for nonHRRm; P=0.624. PFS was 6.44months 95%CI(2.959-7.496) vs 7.13months 95%CI(4.767-7.595), HR 1.33 95%CI(0.739-2.388); P=0.343. OS was 13.55 95%CI(6.805-NR) vs 13.84months 95%CI(11.277-21.633), HR 1.63 95%CI(0.696-3.810); P=0.26.

As a recent study demonstrated that loss-of-function mutations in chromatin remodeling genes may be associated with longer survival in patients with BTCs receiving chemo-immunotherapy, we also evaluated this potential predictive biomarker in our study. (24,25) For patients with alterations in genes involved in chromatin modification DCR was 77.78% vs 72.22%, P= 0.634, ORR was 50% vs. 27.78%; P=0.71. PFS was 6.44 vs 7.04months 95%CI, HR 1.21.95%CI(0.668-2.180); P=0.533. OS was 14.14 vs 13.61months; HR 0.45 95%CI(0.167-1.218); P=0.851.

20 patients had ESCATI/II Alterations. DCR was 75% vs 72.86%, P=0.848; ORR was 35% vs. 31.43, P=0.763. PFS was 7.17 vs 6.38months, HR was 0.88 95%CI(0.485-1.609); P=0.684. OS was 14.99 vs 13.55; HR was 0.45 95%CI(0.167-1.218); P=0.116. 15 patients received matched molecular therapy in 2^nd or later lines. Median OS was not reached 95% CI (14.992-NR) vs 13.55 95% CI (11.211-21.633) months. HR 0.23 95% CI (0.054-1.011). P=0.052. Most frequent targeted alterations were IDH1 (N=5), ERBB2 Amplification (N=2), FGFR2 Fusion (N=2) and MET Amplification (N=2).

For patients not prone to targeted therapy, we analyzed 24 patients who received 2^nd line chemotherapy. 12 patients each received FOLFOX or FOLFIRI. OS from start of 2^nd line was 8.52 months 95% CI (3.419-NR) for FOLFOX vs 4.18 95% CI (2.63-NR) months for FOLFIRI, HR 0.47 95% CI (0.142-1.55); P=0.213.

This real-world analysis investigating durvalumab in combination with platinum based chemotherapy doublet in 102 patients with BTC was able to confirm the positive results of the TOPAZ-1 trial. In our cohort, median OS was 13.6 months which is consistent with the median OS of 12.8 months reported by the TOPAZ-1 trial. Accordingly, median PFS (6.5 vs. 7.2 months), disease control rate (DCR; 71.6% vs 85.3%) and overall response rate (ORR; 35.1% vs. 26.7%) were comparable across the two studies.(10,33,34) These results are also in line with data from the recently published KeyNote-966 study testing pembrolizumab as checkpoint inhibitor.(35)

A retrospective analysis from Italy previously reported a prolonged PFS in patients with underlying viral hepatitis B and/or hepatitis C infection treated with gemcitabine/cisplatin/durvalumab.(36) While the TOPAZ-1 trial registered approximately 20% of patients with a history of viral hepatitis, our cohort comprised only 3 patients with this diagnosis. The difference in prevalence may explain the slightly lower mPFS observed in our study. Additionally, the shorter follow-up time (9 vs. 16.8 months) and the higher proportion of Caucasian patients in our cohort may explain the worse PFS compared to the registration trial, in which the Asian population exhibited a prolonged PFS.(10) Moreover, in our cohort, 4.9% of patients received Carboplatin and 1% of patients received oxaliplatin instead of cisplatin. We did not observe a statistically significant difference between the non-cisplatin and the cisplatin group (10.3 vs. 13.8 months). Therefore, in selected cases with compromised renal function cisplatin might be substituted by other platinum compounds without losing efficacy.

In our multivariate analysis of OS including established clinically relevant parameters, only the covariate age below vs. above 65 years was statistically significant, while other potential confounders did not reach statistical significance. This is contrast to TOPAZ-1 and we suspect that one reason is that in our cohort double as many patients aged below 65y received palliative 2^nd line chemotherapy.

In a smaller recently published analysis by Rimini et al., patients were clustered according to molecular and genomic alterations. Participants with alterations in RTK/RAS pathway and cell-cycle apoptosis showed worse response rates compared to patients with alterations in the chromatin modification pathway.(37) In our cohort, for patients with alterations in chromatin remodelling genes (n=18) ORR, PFS and OS did not differ significantly and results need to be interpreted with care due to the small sample size.

Deficiency in homologous recombination repair (HRR) is associated with increased sensitivity to DNA damaging agents, e.g. platinum agents. BTC’s are not typically grouped as HRD associated cancers, such as breast, prostate, pancreas or ovarian cancer, and numerous trials showed inconsistency concerning increased sensitivity to cisplatin in first line when alterations in HRR associated genes occurred in the background of a biliary tract phenotype. Our data is first in describing the effect of adding IO to standard platinum doublet on HRRm BTC’s. In short we could not delineate an enhanced sensitivity of HRRm compared to non-HRRm BTC’s. Therefore, HRD in BTC still needs more refinement especially when it comes to the choice of maintenance therapy, including mono-immunotherapy or chemotherapy.(22,23)

NGS testing has become mandatory in the treatment landscape of BTCs, especially when it comes to selection of 2^nd line therapy. Targeted therapies have become increasingly important in the last years and due to intensive research various treatment options are currently available in second line BTC.(7) However, available studies on targeted therapies in BTC were performed primarily in immunotherapy naïve patients.(11,12,14,17) We therefore lack data on targeted treatment options following chemoimmunotherapy. In our cohort, 88.2% of patients underwent molecular profiling and actionable targets were found in 22.2% of patients. In line with previous research, most targetable alterations were quite rare.(20) Therefore, we pooled all patients with ESCAT level I/II alterations, as addressing these targets provided the greatest benefit as recently shown by Verdaguer et al..(20) This group comprised 20 individuals and did not show any statistically significant difference in terms of OS, PFS, ORR and DCR compared to the other participants. However, PFS and OS were numerically higher in ESCAT I/II patients. Overall, 15 patients received targeted therapies in 2^nd or later lines, which resulted in prolonged OS (NR vs. 13.6 months), showing a trend towards statistical significance (HR 0.23; P=0.052). Despite the relatively small size of this cohort, response to chemoimmunotherapy was not influenced by actionable alterations, despite 1 patient with MSI high status, who confirmed as a long term responder. No single genetic alteration could be delineated to be predictive for enhanced benefit by addition of durvalumab; a finding which is largely consistent with biomarker analysis of Topaz-1 and large real world cohorts. (38,39)However, further research with larger cohorts is required to identify new predictive biomarkers.

Our data is first in investigating efficacy of 2^nd line after failure of durvalumab + platinum based doublet. In our trials in non targetable BTCs re-challenge with a platinum compound (FOLFOX) showed a numerically better outcome compared to FOLFIRI, though statistical significance was not reached.

This study has several limitations, including the relatively small sample size and the comparatively short follow-up time. Further, due to the multicentre nature of our work, different assays were used to determine genetic alterations. Moreover, since this study was conducted as a retrospective analysis, subsequent therapies were not predefined and a few participants received targeted therapy only after the second line.

In conclusion, treatment with platinum based chemoimmunotherapy showed promising results in our analysis of a real-world cohort, supporting the results from the TOPAZ-1 trial and establishing durvalumab + platinum doublet as a new first line standard- with efficacy across prominent subgroups. Our data further confirm current concepts of early integration of molecular informed therapies at least in second line, and could reiterate FOLFOX as the preferred 2^nd line in patients without a targetable alteration. Furthermore, use of targeted therapies beyond first line chemoimmunotherapy resulted in numerical OS prolongation compared to chemotherapy, highlighting the importance of conducting genetic profiling as early as possible.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors of this research paper have directly participated in the planning, execution, or analysis of the study.

P.R. and B.D. : writing original draft; B.D., P.R., T.W., H.R.: Conceptualization; B.D., P.R.: Data curation and formal analysis; IM.A, H.T., G.S., D.M., M.B., EM.S., S.M., A.D., G.W.P: Data curation; All authors: review and editing

Data Availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committees Essen (21-10239-BO, Essen, Germany), Land Oberoesterreich (1100/2023, Upper Austria, Austria), and Vienna (EK-1099/2021, Vienna, Austria).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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No competing interests reported.

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Exploring the impact of Durvalumab on biliary tract cancer- insights from real world clinical data

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Abstract

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1 Introduction

2 Materials and Methods

2.1 Patients

2.2 Molecular Profiling and Classification of Mutations

2.3 Study end points

2.4 Statistics

3 Results

Discussion

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References

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