Clearing the bar: adding anti-VEGF therapy to chemoimmunotherapy for biliary tract cancer

In 2010, the ABC-02 trial demonstrated significant survival benefit for first-line treatment with gemcitabine cisplatin (GC) over gemcitabine alone in patients with advanced biliary tract cancer (BTC) (1). The bar was set, and for the next decade, GC remained the mainstay of first-line treatment, with multiple novel agents and treatment strategies failing to improve on the clinical efficacy of first-line GC therapy. Over the past 5 years, however, the advent of molecular profiling and immune checkpoint inhibitors (ICIs) has rapidly changed the treatment landscape for advanced BTC. Two pivotal phase III trials (TOPAZ-1 and KEYNOTE-966) have now established GC chemotherapy in combination with either anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed cell death-ligand 1 (anti-PD-L1) ICIs as the new standard first-line therapy (2,3). However, despite both of these trials being the first in more than a decade to show a statistically superior regimen over GC alone, the clinical overall survival (OS) benefit of adding an ICI to GC appears modest, with the addition of approximately 1.5 months of median OS benefit (2,3).

It is thus apparent that only a fraction of patients benefit from the addition of ICI treatment, with most BTCs still immunologically cold, permeated by a desmoplastic and immunosuppressive tumor microenvironment (TME) (4). A key regulator of an immunosuppressive TME is upregulated vascular endothelial growth factor (VEGF), which is overexpressed in approximately half of BTCs (5). However, the addition of anti-VEGF to GC did not confer a survival advantage over GC alone in two different phase 2 trials (6,7). As such, perhaps combining anti-VEGF with ICI is warranted. This combinatorial strategy has been shown in pre-clinical models to augment ICI anti-tumor activity. Moreover, it has also demonstrated clinical activity and is now part of standard-of-care treatment of multiple solid tumors, including hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), to name a few (8-10).

IMbrave151 was a global, randomized, double-blind, placebo-controlled, two-arm phase II trial designed to assess whether the addition of an anti-VEGF monoclonal antibody (bevacizumab) to ICI (atezolizumab, anti-PD-L1) + GC improves outcomes vs. ICI + GC alone (11). In this study, 162 untreated patients with advanced, recurrent, or metastatic BTC, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer (GBC), were randomized 1:1 to either the bevacizumab arm (bevacizumab + atezolizumab + GC) or the placebo arm (placebo + atezolizumab + GC). The primary endpoint was investigator-assessed progression-free survival (PFS) with secondary endpoints as OS, objective response rate (ORR), duration of response, disease control rate, and safety. A total of 162 patients were enrolled and randomized, with 44% of patients accrued in Asia, 55% with iCCA, and 80% having metastatic disease.

Although the study’s primary endpoint was met, the benefit of the addition of bevacizumab was modest, with the median PFS of 8.3 months in the bevacizumab arm vs. 7.9 months in the placebo arm [stratified hazard ratio (HR), 0.67; 95% confidence interval (CI): 0.46 to 0.95]: a difference of 0.4 months. The prespecified 90 PFS events only provided 68% power to detect a statistically significant HR, so the hypothesis testing on the primary endpoint was not adequately powered. As such, although the HR and separation of curves may suggest clinical benefit, this was not statistically significant. Ultimately, an improvement in OS is the ‘measuring stick’ for an increase in median PFS that contributes to a clinically meaningful survival benefit (12). Unfortunately, there was no meaningful difference in secondary outcomes of OS and ORR, with nearly identical median OS (14.9 months in the bevacizumab and 14.6 months in the placebo arm) and ORR (26.6% in the bevacizumab arm and 25.5% for the placebo arm) for both arms. These results were comparable to those observed in TOPAZ-1 and KEYNOTE-966 and suggest that the addition of bevacizumab does not appear to provide additional benefit and that ICI + GC remains the standard first-line treatment for advanced BTC.

The disappointing results of IMbrave151 portend the resurgence of a familiar theme in BTC first-line trials: are we to wait another decade for the next breakthrough? We certainly hope not, and if anything, IMbrave151 demonstrated that well-done randomized trials in rare/uncommon cancers can be accomplished. IMbrave151 was the first randomized study to evaluate combination ICI + VEGF blockade in advanced BTC, and despite the relatively rare prevalence of BTCs, this global study accrued rapidly across multiple countries. Similarly, another recently completed randomized first-line study, S1815, completed accrual of 450 patients in 2 years, demonstrating the motivation from both academia and industry to address this significant unmet need for novel therapeutics in this patient (13). Despite negative results from intention-to-treat (ITT) analysis, studies like these present valuable insights from biomarker and subgroup analyses that may allow for appropriate patient selection and fine-tuning of therapies for subsequent trials. This is especially relevant to BTCs, where variation in tumor biology and molecular profile can have a significant effect on therapeutic outcomes (14).

A specific exploratory biomarker assessed by IMbrave151 was VEGFA gene expression. Transcriptome analysis from 95 baseline tumor samples suggested that high VEGFA gene expression (median expression score) appeared to be associated with improved PFS (HR, 0.44; 95% CI: 0.23 to 0.83) and OS (HR, 0.65; 95% CI: 0.31 to 1.37) for the bevacizumab arm vs. the placebo arm. These results suggest a subgroup of BTCs that may benefit more with the addition of bevacizumab to ICI + GC, but these data need to be interpreted with caution due to the post-hoc exploratory analysis in a limited patient cohort. A key finding in these subgroup analyses was that VEGFA gene expression was higher for iCCA and GBC vs. eCCA. Notably, iCCA and GBC were the subgroups that appeared to have greater PFS with the addition of bevacizumab. These results highlight once more the impact of the biologic heterogeneity amongst BTC anatomic subsets and the potential impact it has on therapeutic response.

Further subgroup analyses of response-associated outcomes reveal further granularity in the seemingly identical ORRs between the study arms. As opposed to patients in the placebo arm, patients in the bevacizumab arm had a numerically higher 6-month PFS rate (78% vs. 63%) and a higher 12-month PFS rate (33% vs. 20%). More strikingly, the percentage of patients with an ongoing response for 1 year was higher in the bevacizumab arm (47.8%) vs. the placebo arm (9.6%). A post-hoc analysis to evaluate the association of ORR and PFS also suggested PFS benefit in the patients who responded to bevacizumab vs. placebo (HR, 0.32; 95% CI: 0.13 to 0.76). The investigators inferred that the prolonged duration of response in the bevacizumab arm likely accounts for the trend of PFS improvement in patients who were able to achieve an objective response. Unfortunately, analysis of response-based outcomes was not reported according to BTC anatomic subsets or VEGFA expression. However, when looking at VEGF expression in analyzable baseline samples, high VEGF expression appears to be associated with improvement of PFS vs. placebo (HR, 0.44; 95% CI: 0.23 to 0.83), but not OS (HR, 0.65; 95% CI: 0.31 to 1.37).

As these subgroup analyses were not powered to conclusively determine the impact of anatomic subsets or high VEGFA expression on the benefit of bevacizumab in the treatment of BTCs, we are left to mere speculation as we encounter another recurring theme in BTC trials: heterogeneity of outcomes between subsets of a rare/uncommon cancer. This is evident in the evolution of patient populations included in BTC trials over the years. The ABC-02 trial, for instance, included ampullary carcinoma as a BTC and had GBC as the most common anatomic subtype (1). In contrast, more contemporary studies like TOPAZ-1, KEYNOTE-966, and S1815 have a majority iCCA population, with GBC as a minority, and ampullary carcinoma excluded. The situation becomes even more complex when we consider the various molecular subsets within each rare anatomic subtype and the variation in biology and prognosis. As such, conducting biomarker-selected first-line randomized prospective trials for a specific BTC subtype with molecular stratification remains an elusive “holy grail”. These challenges are illustrated by the recent termination of three randomized phase III trials of fibroblast growth factor receptor 2 (FGFR2) inhibitors in the first-line treatment of FGFR2 fusion cholangiocarcinoma (NCT03773302, NCT03656536, and NCT04093362). Despite the impressive activity and clinical benefit demonstrated by these inhibitors in small phase II studies, accruing a population that accounts for only 5% of BTCs and splitting this pool amongst three separate trials with their own control arms is a daunting task and unrealistic goal (15). Novel and innovative study design, including the potential use of circulating tumor DNA as early read-outs or synthetic control arms, may be some strategies that can help address some of these challenges (16,17). Modeling strategies such as the longitudinal tumor growth inhibition and OS (TGI-OS), which was conducted on samples from IMbrave151, may also provide insightful predictions on treatment benefit and should be considered for future trial development and inform go/no-go decisions (18).

We may also need to re-examine the role of anti-VEGF therapy and its putative biomarkers in the specific context of BTC. Although the authors indicate anti-VEGF + ICI is a rational combination strategy and that this strategy has conferred clinical benefit in cancers like HCC and RCC, the biliary context may be fundamentally different. To illustrate, HCC and RCC are highly vascular tumors that are enhanced more uniformly on the arterial phase during cross-sectional imaging. In contrast, BTCs are less vascular and arterially enhance more at the periphery with “rim-like” enhancement, with a central hypo-enhancing desmoplastic core (19). Several HCC studies have suggested how tumors with lower levels of enhancement are associated with lower responses to anti-VEGF treatment and poorer prognosis (20). In fact, HCCs that demonstrate the typical BTC pattern of “rim-like” enhancement are less likely to respond to anti-VEGF therapy. This radiographic phenotype may explain why anti-VEGF agents do not appear to be as active in BTCs as they are in HCC or RCC. In fact, not a single anti-VEGF agent is Food and Drug Administration-approved for the treatment of BTCs despite multiple investigations. This is in stark contrast to HCC and RCC, where anti-VEGF agents dominate the treatment landscape. Moreover, although IMbrave151 demonstrated how VEGFA expression may be a useful marker for bevacizumab benefit, prospective validation in the context of the different BTC subtypes will be challenging. Clinical feasibility is another challenge, given that sufficient tissue is not always readily available, and transcriptomic analysis is not clinically available.

Lastly, even if we were able to validate a predictive anti-VEGF biomarker and a definitive subset who would benefit with the addition of bevacizumab, challenges remain. Multiple mechanisms of anti-VEGF have been elucidated, including activation of alternative angiogenic pathways, recruitment of pro-angiogenic cells in the TME, and selection of hypoxia-resistant clones (21). It is also unclear whether there is indeed true synergy between anti-VEGF therapy and ICI treatment or whether this interaction is merely additive and potentially at the cost of added toxicity. It may be reasonable to hypothesize that escalating the ICI arm of front-line combinations with dual blockade of PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or other novel ICIs may confer added benefit based on preclinical data (22). However, a recent study done with the combination of durvalumab, tremelimumab, and bevacizumab in a small cohort of BTC did not suggest a significant added benefit of adding anti-CTLA4 to durvalumab and bevacizumab (23). The ARTEMIDE-Biliary02 (NCT07221253) is an ongoing front-line BTC study evaluating GC in combination with either durvalumab or an anti-T cell immunoreceptor with Ig and ITIM domains (anti-TIGIT)/anti-PD-L1 bispecific antibody, rilvegostomig.

Although IMbrave151 did not “clear the bar” to demonstrate a significant clinical survival benefit of adding an anti-VEGF agent to the standard of GC + ICI, the study provided valuable insights into our understanding of angiogenesis inhibition in BTC and laid out the groundwork on how we can potentially overcome these challenges. Bevacizumab is only one of a myriad of anti-VEGF agents, and other anti-VEGF therapies may warrant further evaluation in biomarker-enriched populations that are more likely to show clinical benefit. IMbrave151 identifies the potential for VEGF expression as a biomarker for benefit, and further studies should consider using this as an integral biomarker in prospective studies in BTC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-885/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-885/coif). G.K. reports institutional research grant funding from Iterion Therapeutics, Genentech, Omega Therapeutics, and Bayer; and consultant role in AstraZeneca, Ipsen, Tempus, Jazz, and Pfizer. V.S. reports institutional research grant funding from Actuate Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Elicio, Esanik, Jazz, Ipsen, NCI, PanCAN, Cornerstone (previously Rafael), Relay, Repare, RevMed, Servier, SystImmune, Transthera, and Verastem; consultant role in AstraZeneca, Civala, Delcath, Elevar, HistoSonics, Incyte, Ipsen, Jazz, MitoPhilix, RevMed, Servier, Tallac, and TransThera; royalty fees from AI Metrics; and receipt of data/material from Cornerstone (previously Rafael). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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