The therapeutic landscape of FGFR2-rearranged iCCA has been significantly reshaped by the advent of FGFR inhibitors [5,6,7]. However, the initial promise of these targeted agents is often tempered by the eventual emergence of acquired resistance, necessitating clear strategies for continued management. This case report highlights the intriguing potential and inherent complexities of sequential FGFR inhibition, culminating in a radiographic partial response (PR) to a third-line FGFR inhibitor, tasurgratinib, after progression on both pemigatinib and futibatinib. To our knowledge, this report represents the first documented instance of a radiographic PR to a third-line FGFR inhibitor after sequential failure of two prior FGFR-targeted agents in iCCA. This offers a unique glimpse into the largely uncharted territory beyond second-line FGFR-targeted therapy and serves as a crucial, practical data point for clinicians navigating a field where consensus on optimal sequencing is notably absent.

The Evolving Rationale for Sequential FGFR Inhibition: Navigating Resistance and Pharmacological Diversity

The core rationale for sequential targeting lies in the distinct pharmacological profiles of available FGFR inhibitors and the diverse mechanisms of acquired resistance. Our clinical decision to use futibatinib, an irreversible, covalent FGFR1–4 inhibitor, after progression on the reversible inhibitor pemigatinib was based on the principle that its distinct mechanism could overcome resistance mutations arising from prior ATP-competitive agents [2, 3]. Our case aligns with this, where futibatinib was introduced after pemigatinib failure, although resistance eventually developed to futibatinib as well. The subsequent response to tasurgratinib, a novel FGFR1–3 inhibitor with a purported distinct binding mode and preclinical efficacy in models resistant to other FGFR inhibitors [1], is particularly compelling. Specifically, tasurgratinib (E7090) was designed to form a unique hydrogen bond interaction with the hinge region of the FGFR kinase domain. This distinct binding mode is thought to contribute to its potent activity against certain gatekeeper mutations, such as V564F in FGFR1 and V565F in FGFR2, which are known to confer resistance to some ATP-competitive FGFR inhibitors. This outcome suggests that even after multiple lines of targeted therapy, tumors can retain dependency on the FGFR pathway, and that subtle differences in drug design may offer tangible clinical benefits by overcoming previously selected resistance mechanisms. The lack of complete cross-resistance observed across these three structurally distinct FGFR inhibitors in our patient strongly underscores the biological plausibility and potential clinical utility of a carefully considered sequential inhibition strategy [2]. However, this optimistic view must be balanced by the real-world clinical challenge of identifying which specific inhibitor will overcome which specific resistance mechanism(s), especially in the absence of routine post-progression molecular profiling.

Acquired resistance to FGFR inhibitors is a complex and multifaceted challenge, posing a significant hurdle to durable responses. On-target secondary FGFR2 kinase domain mutations (e.g., gatekeeper, molecular brake mutations) are common [4, 8,9,10,11], but the activation of bypass signaling pathways, which render the tumor less dependent on the FGFR axis, also plays a significant role. These off-target mechanisms include the activation of the MET pathway. Preclinical studies have demonstrated that MET amplification can confer resistance to FGFR inhibitors in FGFR2-fusion cholangiocarcinoma models, a resistance that could potentially be overcome by combination therapies [12]. Furthermore, a comprehensive analysis of clinical samples from patients with FGFR2-altered cholangiocarcinoma who developed resistance to various FGFR inhibitors has confirmed MET amplification as an important acquired resistance mechanism observed in the clinic [13]. Other implicated bypass pathways include the EGFR cascade [14]. Furthermore, the PI3K/AKT/mTOR pathway, a key downstream effector of FGFR signaling [8, 15], is also a critical axis in acquired resistance. Mutations in this pathway, such as in PIK3CA, are known to occur in a subset of iCCA [8] and, importantly, have been detected in post-progression samples from patients treated with FGFR inhibitors, highlighting their potential role as a bypass mechanism [16]. The fact that our patient responded to a third FGFR inhibitor could imply several non-mutually exclusive scenarios: (i) tasurgratinib effectively targeted a specific FGFR2 alteration that conferred resistance to pemigatinib and futibatinib; (ii) the intervening non-FGFR-directed therapies (GC plus durvalumab, S-1) altered the clonal landscape, potentially re-sensitizing a dominant clone to FGFR inhibition by a different agent; or (iii) the tumor harbored heterogeneous resistance mechanisms, and tasurgratinib was able to inhibit a still-FGFR-dependent subclone. Without serial molecular data, these remain speculative but highlight critical areas for future research.

The Uncharted Waters of Third-Line FGFR Inhibition and Beyond: A Call for Evidence and Consensus

The durability of response to third-line FGFR inhibition is a critical question. In our case, the patient has derived a sustained clinical benefit, maintaining SD for over 7 months on tasurgratinib, which is a clinically meaningful outcome in a heavily pretreated setting. This prolonged disease control, characterized by the slow growth of existing lesions without the development of new ones, suggests that continued FGFR pathway inhibition can effectively temper the pace of disease progression even if a complete or deep response is not achieved. While successful futibatinib treatment following prior FGFR inhibitor therapy, such as pemigatinib or other ATP-competitive inhibitors, has been highlighted in case reports and small series (e.g., individual cases have reported prolonged clinical benefit [17] or robust responses after specific prior inhibitors like pemigatinib [18]). Notably, the first successful post-approval use of tasurgratinib in a patient with FGFR2-rearranged iCCA was recently reported by Maruki et al., providing an important benchmark for this agent’s activity, although this was not in a third-line FGFR inhibitor setting [19]. However, the evidence for later-line therapies, particularly regarding favorable outcomes with third-line FGFR inhibitor therapy, is limited, and such reports are virtually non-existent in published literature. Our case, therefore, provides an important, albeit anecdotal, piece of evidence suggesting that continuing FGFR-targeted therapy beyond two lines can be clinically meaningful in appropriately selected patients. This directly challenges the current “evidence vacuum” and calls for a more systematic investigation into later-line targeted strategies.

A critical point of discussion, and an area where international consensus remains notably absent, is the role of intervening non-FGFR-directed therapies. In our patient, courses of gemcitabine/cisplatin with durvalumab and subsequently S-1 were administered between FGFR inhibitor lines. This clinical course aligns with the principles of adaptive therapy, a strategy wherein treatment breaks or switches to non-cross-resistant therapies are used to manage resistance [20]. The underlying theory posits that in the absence of targeted pressure from an FGFR inhibitor, drug-sensitive clones may repopulate and outcompete resistant clones, which often carry a fitness cost [9, 20, 21]. This dynamic could potentially re-sensitize the overall tumor to a subsequent FGFR-targeted agent. While direct evidence in iCCA is lacking, preclinical models and clinical experiences in other cancers, such as melanoma, have shown that intermittent dosing strategies can delay the onset of resistance [20]. Goyal et al. reported that polyclonal secondary FGFR2 mutations often arise during FGFR inhibitor therapy, leading to acquired resistance [9]. The dynamic interplay between different treatment modalities and clonal evolution is a fascinating but poorly understood aspect of managing refractory iCCA [21]. Could these “breaks” from direct FGFR pressure reset the evolutionary clock, or at least shift the balance of subclones? This remains a controversial yet highly relevant question for designing future sequencing trials.

Furthermore, the efficacy differences observed between pemigatinib (reversible, selective FGFR1–3), futibatinib (irreversible, FGFR1–4), and tasurgratinib (novel binding, FGFR1-3) in this single patient likely stem from a complex interplay of their distinct pharmacological properties, the specific resistance mechanisms at play at each progression, and the evolving tumor biology. The argument that “not all FGFR inhibitors are created equal” in the face of resistance is gaining traction, but translating this into evidence-based, personalized sequencing decisions is the current frontier [1, 3, 4, 8].

The Impact of Co-altered Genes: More Than Just Passengers?

Beyond direct FGFR pathway alterations, the broader genomic context, including co-occurring mutations such as the truncating ARID1A mutation and RAD21 amplification observed in our patient, introduces further layers of complexity to the treatment response equation [18, 21, 22]. ARID1A mutations are frequently found in iCCA, as demonstrated by several multigene mutational profiling studies [18, 21, 22]. These alterations can influence genomic instability and DNA damage response. Furthermore, they can potentially shape the tumor immune microenvironment, thereby affecting responses to therapies such as immune checkpoint blockade, where ARID1A alterations have been associated with longer progression-free survival [23, 24]. RAD21 amplification, though less characterized in iCCA, may contribute to chromosomal segregation defects, given the critical role of the RAD21-containing cohesin complex in sister chromatid cohesion which is essential for proper chromosome segregation [25]. Furthermore, impaired cohesin function, potentially affected by RAD21 amplification, could lead to genomic instability through defective DNA damage repair, as RAD21 itself has been shown to play a crucial role in DNA damage repair processes and affect cancer cell responses to therapies targeting this pathway [26, 27]. While these were not directly targeted, their impact on the overall treatment course and response to sequential FGFR inhibition cannot be dismissed and represents an area of growing interest. For instance, could ARID1A status predict a differential benefit from intervening chemotherapy or immunotherapy, thereby indirectly influencing the success of subsequent FGFR inhibitor therapy? This remains speculative but highlights the need for a more holistic genomic understanding beyond just the primary driver alteration.

The Imperative of Molecular Monitoring and Future Therapeutic Directions

The mixed radiological response observed in our patient—with slow growth in some lesions while others remained controlled and no new lesions appeared—is a clinical manifestation of intrapatient tumor heterogeneity. This heterogeneity highlights a key limitation of our report, as pointed out by the reviewer: the lack of serial genomic monitoring. While no additional molecular studies, such as post-progression biopsies or ctDNA sequencing, have been performed to date, this clinical course strongly argues for their future necessity. For instance, a re-biopsy of a growing lesion or analysis of ctDNA would be invaluable to elucidate the specific resistance mechanisms emerging in different metastatic sites and to guide subsequent treatment decisions. Therefore, while our hypotheses on clonal evolution remain speculative because of this lack of molecular evidence, this case serves as a powerful clinical example underscoring the imperative of implementing such monitoring in practice. This case underscores the critical need for serial genomic monitoring (e.g., ctDNA or repeat biopsies) to understand evolving resistance mechanisms and guide subsequent therapeutic choices [16, 28]. Although not performed in this instance, such an approach could have provided invaluable insights into why pemigatinib and futibatinib failed and why tasurgratinib was effective. Implementing routine, real-time molecular monitoring in clinical practice is not just a research goal but is becoming a clinical necessity for truly personalizing sequential targeted therapies. Establishing a consensus on the optimal timing, methodologies, and clinical integration of such molecular monitoring is a critical unmet need for advancing personalized sequential therapies.

Looking ahead, beyond the currently approved agents in Japan (which now includes tasurgratinib for iCCA post chemotherapy), other FGFR inhibitors like infigratinib (FDA-approved for previously treated FGFR2-fusion/rearrangement iCCA) [6] and erdafitinib (FDA-approved for urothelial carcinoma, with pan-FGFR activity and preclinical iCCA data) [8] may expand the clinician’s therapeutic armamentarium internationally. The availability of a broader range of FGFR inhibitors with differing profiles could offer more options for sequencing but will also demand more sophisticated strategies for their optimal deployment. Furthermore, novel approaches such as next-generation highly selective FGFR2 inhibitors (e.g., lirafugratinib/RLY-4008) [29], agents targeting specific resistance mutations, or combination strategies (e.g., FGFR inhibitors with MET inhibitors, immunotherapy, or chemotherapy) [8, 10, 13, 26] are under active investigation and hold promise for overcoming resistance and improving outcomes.

Beyond monotherapy sequencing, rational combination therapies are crucially being explored to prevent or overcome resistance and improve outcomes. The development of effective immunotherapy combination strategies, for example, is a major focus in oncology [30], and systematic reviews highlight various combinations of targeted therapies or immunotherapies being investigated in advanced solid tumors [31]. Investigating FGFR inhibitors combined with chemotherapy, other targeted agents (e.g., MET inhibitors [13, 14] or, as suggested by recent research, EGFR inhibitors to counteract bypass signaling [14]), or immunotherapy [30, 31] holds significant promise for patients with FGFR2-rearranged iCCA.

However, systematically evaluating these new agents and sequencing strategies, especially in rare and molecularly selected patient populations like FGFR2-rearranged iCCA that has progressed on multiple lines, presents significant challenges to traditional clinical trial designs. Innovative trial designs, such as master protocols including basket and umbrella trials, guided by robust molecular rationale are needed to address these challenges in rare, molecularly defined patient populations [32].

A Balanced Perspective and Call for Rational Strategies

While this case provides a compelling example of successful third-line FGFR inhibition, it is essential to maintain a balanced perspective. The arguments for pursuing sequential FGFR inhibition are rooted in the potential for sustained disease control in a highly aggressive cancer with limited options. However, this must be weighed against the risks of cumulative toxicity, the financial burden, and the current lack of robust predictive biomarkers to guide such later-line choices. The decision to continue with further lines of targeted therapy should be highly individualized, involving shared decision-making with the patient and, ideally, enrollment in clinical trials designed to address these unanswered questions. A purely empirical “trial-and-error” approach, while sometimes necessary in refractory settings, is not a sustainable long-term strategy for the field.