Rethinking maintenance strategies in biliary tract cancers

Biliary tract cancers (BTCs) are a heterogeneous group of aggressive malignancies arising from the epithelial lining of the biliary tract. Owing to a generally insidious onset of symptoms, most patients are diagnosed at advanced stages, where curative intent interventions are no longer feasible (1). For these patients, the recent addition of immunotherapy (IO) to gemcitabine-based chemotherapy represents a modest but clinically meaningful evolution in the treatment paradigm for advanced BTCs (2,3). However, the absence of predictive biomarkers (such as programmed death-ligand 1 or PD-L1 expression, tumor mutational burden, driver alterations, etc.) that may help identify sub-groups of patients most likely to benefit and their limited availability in low- to middle-income countries are some key challenges associated with the use of immune checkpoint inhibitors for the treatment of advanced BTCs at a global level. Here, we review BEER-BTC, a recent clinical trial investigating a novel bevacizumab and erlotinib switch maintenance strategy among patients with chemo-responsive advanced BTCs in the context of the current approach to management of advanced BTCs.

The BEER-BTC trial was a multicenter, investigator-initiated, open-label, randomized phase II/III trial conducted across two institutions based in India. Patients aged 18–75 years with histologically confirmed unresectable or metastatic BTCs (adenocarcinoma of the gallbladder, intrahepatic cholangiocarcinoma, or perihilar cholangiocarcinoma; but not distal cholangiocarcinoma) were eligible for inclusion after receiving 24 weeks of gemcitabine-based chemotherapy (gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemcitabine, gemcitabine-cisplatin-nab paclitaxel, or gemcitabine-capecitabine) with at least stable disease (SD) on response evaluation (clinically and radiologically). Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate organ function prior to inclusion. Patients were randomly assigned 1:1 to active surveillance or to bevacizumab-erlotinib. Patients in the active surveillance group did not receive any cancer-directed therapy until disease progression. Patients in the treatment arm received intravenous (IV) bevacizumab 5 mg/kg once every 21 days and oral dose erlotinib 100 mg once daily. It is important to note that the dose of bevacizumab was lower than the more commonly used 5 mg/kg every 14 days or 7.5 mg/kg every 21 days in other solid tumors. The primary endpoint of the study was progression-free survival (PFS) from time of enrollment as assessed by study investigators (response assessment was not blinded). The secondary endpoints were assessment of adverse events and treatment completion rates. Health-related quality-of-life (HRQOL) assessments were performed at baseline and every 6–8 weeks using the Functional Assessment of Cancer Therapy-Hepatobiliary Cancer (FACT-Hep) version 4 questionnaire. Overall survival (OS) was not reported as it is the endpoint of interest for the follow-up phase III trial.

A total of 98 patients were enrolled and randomly assigned to the active surveillance arm (n=49) or the treatment arms (n=49). Of these, the majority had gallbladder adenocarcinoma (80%) and most patients had received gemcitabine-cisplatin as prior therapy (89%). With a median follow up of 13.4 months, PFS was longer in the bevacizumab-erlotinib group than in the active surveillance group [hazard ratio (HR), 0.51; 95% confidence interval (CI): 0.33–0.74; log-rank test, one-sided P=0.001]. The median PFS in the active surveillance group was 3.1 months (95% CI: 2.47–3.64) and 5.3 months (95% CI: 3.53–7.04) in the bevacizumab-erlotinib group. In a post-hoc analysis, the PFS benefit was particularly notable among patients with metastatic disease (versus locally advanced) and gallbladder adenocarcinoma (versus cholangiocarcinoma), as well as younger patients and those without an elevated cancer antigen 19-9. The investigators also did not record any changes in HRQOL between the two arms. The follow-up phase III randomized clinical trial will further investigate the efficacy of this therapy in terms of the OS (4).

While these phase II results are promising, several important caveats warrant consideration. The BEER-BTC trial did not include the modern chemo-IO backbone to initial treatment of advanced BTCs, which is now the standard of care (SOC) for the management of the majority of patients with advanced/unresectable BTCs. Recent pivotal clinical trials such as TOPAZ-1 (gemcitabine, cisplatin and durvalumab followed by durvalumab maintenance) and KEYNOTE-966 (gemcitabine, cisplatin and pembrolizumab followed by pembrolizumab only or gemcitabine and pembrolizumab maintenance) have firmly established chemoimmunotherapy as the new SOC for frontline therapy among patients with advanced/unresectable BTCs and further delineated a role for maintenance therapy in BTC. These clinical trials demonstrated a significant improvement in OS with the addition of IO to chemotherapy, leading to regulatory approval for use by the US Food and Drug Administration (USFDA). Without incorporation of IO into frontline therapy among patients treated on BEER-BTC, the relevance of the trial’s findings in the current era of chemoimmunotherapy may be limited (2,3).

It is also important to note here that using PFS as the primary endpoint with vascular endothelial growth factor (VEGF)-targeting agents like bevacizumab can be challenging, as PFS benefits do not always translate to OS improvements. This has been seen before among patients with high grade gliomas such as glioblastoma multiforme, where bevacizumab may demonstrate substantial decrease in tumor enhancement on imaging without an actual reduction in tumor volume (5). Additionally, this concern was manifest in the IMBrave151 trial, which demonstrated a PFS benefit with atezolizumab-bevacizumab in combination with gemcitabine-cisplatin among patients with advanced BTCs but failed to show a corresponding OS advantage over atezolizumab-placebo with gemcitabine and cisplatin (6). Furthermore, previous trials of combination erlotinib and bevacizumab have shown an improvement in PFS without a corresponding improvement in OS. Similar outcomes were reported in a trial of patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), where an improvement in PFS with erlotinib and bevacizumab was not associated with an improvement in OS (7,8). These findings underscore the need to weigh the clinical significance of PFS benefits against their impact on long-term outcomes, patient quality of life (QoL), and healthcare costs associated with the use of therapies that may not improve long-term patient outcomes. Moreover, it is also important to acknowledge that prior efforts to incorporate anti-EGFR or VEGF therapies to frontline therapy in BTC did not yield promising results (9,10). The planned phase III BEER-BTC trial will need to address whether the observed PFS improvements will correlate with an improvement in OS. Similarly, erlotinib has demonstrated limited efficacy in other gastrointestinal cancers, such as pancreatic adenocarcinoma where a statistically significant but clinically questionable ten-day improvement in median OS was noted when added to gemcitabine-based treatment (11). It remains to be seen whether the observed PFS improvement with bevacizumab-erlotinib translates into clinically meaningful OS benefits in BTC.

Further, biomarker testing is an increasingly important consideration in the treatment of patients with BTCs. Many notable biomarkers such as microsatellite instability, human epidermal growth factor receptor (HER2), fibroblast growth factor receptor (FGFR) alterations, etc. are of clinical significance due to our ability to use these biomarkers to offer effective targeted therapies. It is important to note that the BEER-BTC trial did not include biomarker-driven patient selection, which could have hindered the ability to identify subgroups more likely to benefit from bevacizumab-erlotinib combination therapy. For example, In the IMBrave151 trial, high VEGFA gene expression emerged as a useful biomarker for predicting response to bevacizumab (6). Similarly, one could hypothesize that EGFR overexpression, which is common in BTCs, may correlate with clinical benefit of bevacizumab and erlotinib maintenance therapy (12). The absence of similar analyses severely limits the ability to optimize patient selection in BEER-BTC.

BEER-BTC also enrolled a majority of patients with gallbladder adenocarcinoma (80%), raising questions about the broad applicability of the findings to other BTC subtypes, such as intrahepatic and extrahepatic cholangiocarcinoma. Additionally, etiological and biological differences in BTC between India and Western populations may also limit the generalizability of the results. For example, gallbladder cancer is far more prevalent in the Indian subcontinent compared to the West, driven by unique environmental and genetic factors (13). As such, future trials should aim to validate these findings in more diverse patient populations.

Nonetheless, the trial highlights some important potential niches for bevacizumab-erlotinib as a maintenance strategy. Bevacizumab-erlotinib could especially serve as an alternative for patients in low- and middle-income countries (LMICs), where IO accessibility may be limited, for those with contraindications to IO or patients who develop serious immune-related adverse events (irAEs), where rechallenge with IO may not be feasible. Additionally, the benefit of bevacizumab-erlotinib maintenance within the cohort of patients with gallbladder cancer in BEER-BTC is in contrast to the subgroup analyses in TOPAZ-1 and KEYNOTE-966, which both did not note an improvement in outcomes among the cohort of patients with gallbladder adenocarcinoma (2,3). Therefore, pending confirmatory phase III data, bevacizumab-erlotinib maintenance may present a meaningful therapeutic option particularly among patients with gallbladder adenocarcinoma.

Beyond BEER-BTC, the emerging concept of biomarker-informed and biology-directed maintenance therapy may represent a promising path forward in advanced BTC. Rational maintenance approaches such as IO continuation, targeted agents (e.g., FGFR or IDH2 inhibitors, HER2-targeted therapy) or anti-angiogenic strategies offer the potential to prolong disease control while minimizing cumulative toxicity from cytotoxic chemotherapy. Future trials should prioritize on developing biomarker-based maintenance strategies that leverage tumor biology and unique therapeutic vulnerabilities for the selection of maintenance strategies rather than the more traditional empiric maintenance regimens.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-40/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-40/coif). T.J.B. receives advisory board fees from Daiichi Sankyo and Incyte. The other author has no conflicts of interest to declare.

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