Is BEER the answer?—non-immunotherapeutic targeted maintenance treatment of chemotherapy-responsive advanced biliary tract cancers

Biliary tract cancer (BTC) represent a heterogeneous class of malignant tumours of the biliary tree [termed cholangiocarcinoma (CCA)] or of the gallbladder or its associated cystic duct (gallbladder carcinoma; hereafter GBC). Unfortunately, most patients with BTC will present at, progress to, or recur with an advanced [metastatic or locally advanced (aBTC)] tumour stage, where a curative strategy is not feasible and life-extending systemic therapy is recommended. The chemotherapy backbone of aBTC has traditionally comprised of six months of gemcitabine-based doublet therapy with a platinum agent, as established in the UK-based ABC-02 (1) and Japan-based BT22 (2) trials published in 2010. More recently, the addition of immune checkpoint inhibition (ICI) with durvalumab (3) or pembrolizumab (4) to this backbone has shown significant benefits to overall survival (OS), and this chemoimmunotherapy approach should now be considered the standard of care (SOC) in the management of aBTC in the first-line setting. With the advent of immunotherapy, in patients with disease control at 4–6 months, maintenance immunotherapy has become SOC in patients deriving benefit with the combined chemo-immunotherapy approach. This has opened a window to explore the role of maintenance therapies in aBTC.

The majority of patients with aBTC will progress on first-line chemotherapy and there remains clinical equipoise regarding SOC in the second-line setting (5). Data from the recent UK-based ABC-06 (6) trial showed modest improvement in median OS with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) therapy when compared with active symptom control alone in patients who have progressed on first-line gemcitabine-cisplatin. Use of more targeted antineoplastic therapies is another promising area of exploration. Overexpression of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) has been observed in BTC, and therapeutic blockade of the former (7), latter (8), or a combination approach (9) has shown a promising and well-tolerated effect in aBTC previously.

The BEER-BTC trial was a dual center, randomized, phase II study conducted in India among patients with locally advanced or metastatic CCA or gallbladder cancer (10). All patients initially received six months of gemcitabine-based chemotherapy achieving treatment response or disease stabilization before randomization. The investigators assigned 49 subjects to each arm; the interventional arm comprising of maintenance bevacizumab (targeting VEGF A) and erlotinib (an EGFR inhibitor) therapy or the control arm involving post-chemotherapy active surveillance. The study successfully reached its primary end point which was an improved progression-free survival (PFS) of 5.3 months [95% confidence interval (CI): 3.53–7.04] with bevacizumab-erlotinib combination (hazard ratio, 0.51; 95% CI: 0.33–0.74; P=0.0013) and 3.1 months (95% CI: 2.47–3.64) in the control group. The study also demonstrated an excellent safety profile with no treatment related deaths, where the most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash (2%) and oral stomatitis (2%) with erlotinib and bleeding (2%) with bevacizumab. The study is now transitioning into phase III to assess whether patients on the post-chemotherapy maintenance regimen can achieve improved OS outcomes compared with patients under active surveillance.

We commend the investigators for conducting this prospective study in a challenging patient population offering several benefits in the current clinical context. The study design provides patients a chemotherapy-free interval after six months of standard treatment to help obviate significant side-effects associated with chemotherapy, along with the financial burden of continued expensive chemotherapy in resource limited settings. Although a molecularly driven treatment management strategy is increasingly favoured owing to recent development of efficacious targeted agents for BTC, only 40% of BTC patients harbour an actionable mutation (11). Hence, a molecularly unselected treatment design utilizing chemotherapy might be a more prudent approach for most patients. Additionally, a chemotherapy driven treatment paradigm is also more relevant for application in emerging markets as they may offer clinical benefit in such specific scenarios until availability of more economical in-house genomic profiling tests and locally manufactured generic targeted agents to address issues surrounding financial toxicity in this clinical population.

The reduced number of adverse events owing partially to the use of a lower dose of erlotinib combined with the lack of difference in quality-of-life (QOL) scores between interventional and observational groups highlights the notion that maintenance therapy is not increasingly taxing for BTC patients than compared to patients off treatment in the surveillance cohort. The excellent safety profile and extension of PFS highlights the added benefit of maintenance targeted agents after chemotherapy where this treatment sequencing would permit retention of good performance status and preserved quality of life. These are essential factors to qualify a challenging patient population for further treatment in clinical trials or as part of SOC treatment later in the course of their disease.

However, it is prudent to acknowledge the limitations of this study with respect to the clinical trial design. We appreciate the recognition of study limitations by the authors, such as the fact that maintenance therapy with ICI is now SOC for BTC management but its application is limited in resource restricted settings mainly due to the high cost of treatment. However, this notion limits the broader application of study findings due to a significant compromise to the SOC arm. Moreover, the proposed targeted agents may also be associated with cost implications and the biological rationale for offering such treatment combination is debatable.

For instance, although the authors provide pre-clinical evidence to substantiate the use of EGFR inhibitors and anti-angiogenic agents in the study protocol, these studies were primarily conducted in non-BTCs. Additionally, the investigators specified previous phase I-II studies utilising these agents in non-BTCs, but the current study seems to be predicated by a single phase II clinical trial evaluating bevacizumab plus erlotinib in unresectable/metastatic BTCs (9). We also note the presence of a relatively suboptimal control group in the BEER-BTC trial employing a watch-and-wait approach in patients with aBTC. Given poor outcomes in aBTC, we would be inclined to consider the use of local therapy such as radiation in patients with a limited disease burden after chemotherapy. Similarly, patients with previous locally advanced disease experiencing adequate tumour regression after six months of chemotherapy would be more amenable to surgery. European Society for Medical Oncology (ESMO) guidelines suggest that treatment management decisions should be based upon individual patient toxicity, tolerability and tumour response following six months of chemotherapy in a first line setting for advanced or metastatic disease (12). An alternative study design involving the use of a continuous chemotherapy control arm instead of a surveillance control group would have been more clinically informative, especially given the younger patient population (median age =52 years in the control arm) who would better tolerate this regimen (10). This is informed by previous studies (13,14) providing evidence of an improved PFS and OS in BTC patients who continue maintenance chemotherapy versus those who terminate systemic treatment after six months of initial chemotherapy and achieve disease stabilization or treatment response to this regimen. The aforementioned issues are important limiting factors in understanding the biological and clinical rationale for the current study and appropriate application of these findings in the relevant clinical population.

Secondly, there is limited global generalisability to the BEER-BTC trial findings. This was a small study of less than 100 participants, conducted in two centres within one country. The ability to adequately match characteristics in small studies is limited, as evidenced by proportionally more female patients seen in the treatment arm of this trial. Also, the SOC elsewhere in the world (with ICI) could not be implemented in this care setting. Furthermore, given the fact that gallbladder cancer (forming 80% of the study population) has a geographical preponderance in India and South America, one may infer that the clinical benefit reflected in this study may apply only to regional populations with similar phenotypic demographics.

Thirdly, some methodological particulars must be highlighted. Included patients had been treated previously with heterogeneous gemcitabine-based chemotherapy regimens. Physical examination review was more frequent in the intervention arm (three-weekly) compared to the control arm (eight-weekly), which may reflect real-world practise but risks introducing a care bias whereby some participants have more frequent contact with and support from their healthcare provider. We also note variability in the imaging modality selected [either enhanced computed tomography (CT) or fluorodeoxyglucose positron emission tomography (PET) CT] to assess radiological response, when it is known that these scans carry differing sensitivities and specificities and are not the gold-standard to assess progression in BTC (12). Similarly, re-staging scans were performed every two months, which contradicts what is stated in the associated protocol supplement (pages 32 and 34) and may not be sufficiently frequent to assess true response when PFS is of the order of three to five months. One should also be aware that this study was non-blinded and radiologic responses were not standardized by central review, which predisposes outcomes to observer bias. Four unspecified patients in the intervention arm (8%) did not have documented response evaluation by radiologic criteria, with no reason or data given for this apparent patient attrition.

Fourthly, appropriate post-protocol care is important in a challenging patient population such as BTC. Despite progressive disease after protocol therapy in both arms, 27–39% patients did not receive subsequent second line chemotherapy for reasons that were not clarified by the investigators. It is plausible that a proportion of these subjects might have had a decline in performance status, thus obviating the need for further therapy or were lost to follow-up. Although these explanations are speculative in nature, we hope future follow-up studies will elaborate on patterns of treatment change after protocol therapy.

Additionally, the BEER-BTC trial reported a higher rate of radiographic response in the maintenance arm (15.5%) than the active surveillance arm (2.1%). However, data regarding the duration of these treatment responses is lacking. Early estimates of treatment efficacy via use of metrics such as radiographic response or PFS may not always translate into an improvement in OS which remains to be evaluated in the Phase III component of the trial. Additionally, further investigations into factors influencing long-term outcomes would also be essential to re-evaluate the prospect of including a maintenance targeted regimen to standard chemotherapy.

A final major limitation of the BEER-BTC trial is the lack of a translational element which is a key component of clinical trials in current times. It would have been ideal to interrogate radiographic responses with respect to patients with underlying sensitivity to EGFR inhibitors. Additionally, an assessment of changes in the tumour microenvironment performed before, during and after protocol treatment would have been biologically informative. The authors highlight a variable degree of EGFR overexpression in BTC ranging from 8% to 93%. Availability of correlative data identifying associations between treatment response and PFS based on baseline EGFR expression levels would have helped identify ideal candidates who would benefit from maintenance therapy using the protocol stipulated regimen.

The recent advent of liquid biopsies continues to shape the clinical management of patients with gastrointestinal malignancies. Liquid biopsies can serve as an effective and serially repeatable method for BTC screening, treatment monitoring and identification of genomic alterations following treatment recurrence. For instance, recent investigations suggest the practical utility of using this minimally invasive and cost-effective technique for diagnosing CCA in high-risk populations (with primary sclerosing cholangitis) and the prognostic stratification of patients with CCA (15). Incorporation of circulating tumour DNA (ctDNA) based correlative studies in future trials is pivotal to aid with identification of molecular drivers of resistance. Such techniques can also aid clinical trial design involving combination therapies where consideration of treatment sequencing is involved. For instance, it would be important to delineate whether the type and duration of upfront specific systemic agents can increase sensitivity or promote development of acquired resistance to EGFR inhibitors prior to initiation of maintenance therapy using the BEER-BTC regimen. Treatment adjustment with current treatment paradigms typically involves a reactionary approach where treatment is altered after a patient experiences disease progression or adverse events. Future trials should adopt a proactive approach involving individualization of dynamic treatment schedules. In this instance, ctDNA can be beneficial while assessing patient response and to adjust treatment accordingly, as evidenced by the recent success of the CHRONOS trial using panitumumab in metastatic colorectal cancer (16). The integration of minimally-invasive and cost-effective liquid biopsy in SOC practice is vital in strategizing the selection and sequence of therapies to optimize patient clinical outcomes.

It is clear that future work is needed to identify the optimal maintenance strategy for chemotherapy-sensitive aBTC. We suggest the following avenues of pursuit. One approach to consider is whether maintenance treatment with ICI (alone or in combination with extended chemotherapy) shows similar benefit to that demonstrated by the more affordable, targeted approach used in this study. More judicious use of anti-EGFR therapy, guided by tumour expression levels and (in non-Indian populations) at appropriately higher doses may maximise the benefit seen. Given the favourable QOL profile seen in the interventional arm of this study, there may be a role for targeted therapy alone in the first-line setting of aBTC for patients with poor performance status. Additionally, with the advent of molecularly-driven treatment approaches in other gastrointestinal tumours, adequate consideration should be given to the assessment of maintenance BTC therapies against targets other than immune checkpoint molecules, such as the HER2 receptor, IDH1 mutant enzymes, and FGFR2 fusions proteins, which have demonstrated promising efficacy with an excellent safety profile both in clinical trials (17) and in real-world settings (18). Ultimately, it stands to be seen whether the modest PFS benefit demonstrated by combined EGFR-VEGF maintenance blockade in this study will translate into an OS benefit, when compared to active surveillance alone, in the follow-on phase III study proposed by the authors.

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-24-158/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-158/coif). K.K. reports that he is the UK’s Chief Investigator of the Phase 3 LAPIS trial for FibroGen Inc. The other authors have no 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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