Valle, Juan W.

Abstract Background TOPAZ-1 demonstrated durvalumab + gemcitabine and cisplatin (GemCis) superiority over GemCis in first-line treatment of advanced biliary tract cancers. Real-world data from US patients and patients excluded from TOPAZ-1 (patients with autoimmune conditions [AICs] who did not receive immunotherapy) are lacking. We report real-world data for patients with cholangiocarcinoma treated with durvalumab + GemCis. Methods This retrospective, observational study enrolled adult patients diagnosed with cholangiocarcinoma in the US from the International Cholangiocarcinoma Patient Registry (ICPR) treated with first-line durvalumab + GemCis between 2021–2023. De-identified medical records from ICPR were obtained directly from consenting patients/caregivers. Patient demographics and tumor characteristics (primary objective; assessed at initial diagnosis), comorbidities, second-line treatment modalities, median real-world overall survival (mrwOS), and median real-world time to next treatment (mrwTTNT; initiation of first-line treatment and last activity in the database or death) are reported. Results Seventy patients received first-line durvalumab + GemCis: 13 (18.6%) had AIC(s) and 57 (81.4%) did not. Patient demographics, clinical characteristics, and comorbidities are shown (Table). Median (quartile 1–3) time from diagnosis to start of first-line treatment was 1.0 (0.7–1.7) months; median follow-up from first dose of first-line treatment was 7.0 (3.7–12.1) months. The mrwOS (95% CI) was 15.5 (15.1–not evaluable [NE]) months. mrwTTNT (95% CI) was 10.8 (10.4–15.7) months overall and was 20.8 (10.4–NE) months in patients who died without receiving subsequent treatment (censored at date of last activity). Among patients with AIC(s), <5 received second-line therapy (all received chemotherapy alone). Among patients with no AICs, 15 received second-line treatment; 11 (73.3%) received targeted therapy alone and <5 received chemotherapy alone. Conclusions This dataset demonstrates patients with AIC(s) are treated with durvalumab + GemCis in clinical practice. The mrwOS for durvalumab + GemCis in this patient population is consistent with TOPAZ-1 and global real-world studies.

Abstract Background & Objectives Based on the TOPAZ-I study, durvalumab combined with gemcitabine and cisplatin (GemCis) is now supported as a standard of care treatment for cholangiocarcinoma. Patients with extrahepatic cholangiocarcinoma (eCCA) often have underlying autoimmune conditions (AICs) which could restrict immunotherapy use. Treatment patterns in patients with eCCA with AICs and non-autoimmune conditions (NAICs) are reported. Method This retrospective observational analysis of adult patients diagnosed with eCCA in the United States enrolled in the International Cholangiocarcinoma Patient Registry between 2019 and 2023, focused on those treated with durvalumab. The registry contains de-identified data from medical records obtained directly from consenting patients and caregivers. Patients were followed from index date (date of eCCA diagnosis) until the last activity in the database or death. Demographics, clinical characteristics, biomarkers, treatment patterns, and adverse events (AEs) are reported. Results Overall, 135 patients with eCCA were enrolled: 24 (17.8%) had 2:1 AICs and 111 (82.2%) had NAICs. Baseline demographics were comparable between groups: the median (quartile [Q]l-Q3) age at diagnosis was 63.0 (55.0-70.0) years, the mean number of comorbidities in the overall population was 10.1, and 50.4% of patients were female. PD-Ll positivity was noted in 12.6% of patients and HER2 positivity in 10.4%. Of 91 patients with eCCA who received first-line therapy, 34 (37.4%) received GemCis alone, 27 (29.7%) chemotherapy alone (non-GemCis +/- nab-paclitaxel), 9 (9.9%) GemCis plus nab-paclitaxel, 7 (7.7%) durvalumab plus GemCis, 7 (7.7%) durvalumab monotherapy or in combination, and 7 (7.7%) other regimens. Treatment patterns by autoimmune comorbidity status are also reported (Table). Overall, 129 patients (95.6%) had ≥1 AE; fatigue was the most common (71.1%). Conclusion More patients with eCCA received a first-line durvalumab-based regimen post-March 2022 vs the full study period. The use of durvalumab as first-line treatment in this subgroup may suggest that AICs do not restrict its use.

Abstract Background Eligibility criteria for clinical trials are crucial for maintaining safety and study integrity. However, overly restrictive criteria can result in unrepresentative trial populations, leading to gaps in understanding real‐world treatment efficacy. Addressing potentially modifiable exclusions (PMEs) could enhance trial accessibility and participation without compromising safety. Methods The authors retrospectively analyzed screen‐failed patients with biliary tract cancer or pancreatic cancer between August 2019 and November 2024 at The University of Texas MD Anderson Cancer Center. Screen‐failed patients were those who provided informed consent but did not participate for any reason. Clinical data were obtained from screening logs and electronic health records. PMEs were identified and validated by two independent medical oncologists. Results Of 585 screen‐failed patients from 18 trials, 509 were analyzed (367 with pancreatic cancer and 142 with biliary tract cancer) after excluding 76 because of incomplete data. Leading causes of screen failure were declined participation (19%), comorbidities (12%), suboptimal organ function (11%), absence of a biomarker (10%), and insufficient biospecimens (7%). Reasons for declining included preference for standard care (23%), travel (22%), and competing trials (5%). The authors identified 69 patients (13.6%) who had PMEs (primarily borderline laboratory abnormalities), including liver function (23%), kidney function (20%), platelet count (12%), hemoglobin (7%), and white blood cell count (6%) abnormalities. Other PMEs included previous or concurrent malignancies (9%) and viral hepatitis (4%). PMEs were evenly distributed across trials. Conclusions Rigid eligibility criteria exclude stable patients who might benefit from investigational treatments. Easing criteria related to incidental or asymptomatic laboratory abnormalities could broaden trial accessibility and improve enrollment in populations that are more representative of real‐world use.

Objective: To establish comprehensive recommendations on the management of perihilar cholangiocarcinoma (pCCA) and to identify areas in need of future investigation. Summary Background Data: The lack of consensus in management of pCCA across institutions worldwide impairs optimal patient care and best-achievable oncological outcome. A holistic and critical assessment of the body of evidence and collaborative guidance are required. Methods: The Consensus4pCCA conference developed unbiased consensus using the Zurich-Danish model. An impartial and multidisciplinary jury adopted comprehensive recommendations grounded on the work of eight expert panels answering predefined clinical questions and considering the best-quality evidence through a systematic review. The development of recommendations complied with GRADE and SIGN50 methodologies. Results: Seventy-one international experts considered 570 studies. Ten jury members concluded 71 recommendations covering definition and diagnosis, preoperative assessment and optimization, surgical resection, liver transplantation, and outcome reporting for pCCA patients. The consensus underscored that making patients amenable to high-quality curative resection and reducing its associated morbidity must be of highest priority. As such, multidisciplinary expertise and centralized care at all stages of disease management are critical to ensure both safety and oncological adequacy. To overcome the evidence-gap for rare diseases like pCCA, the jury urged large-scale registries to address open questions across the disease continuum and highlighted priorities for future investigation. Conclusion: The Consensus4pCCA represents an unprecedented commitment to collectively harmonize global treatment strategies for pCCA. This collective effort bridges the gap between expert opinions and clinical evidence and holds great promise to improve patient outcomes in the future.

e23011 Background: Eligibility criteria for clinical trials are crucial for maintaining safety and study integrity. However, they often exclude patients due to medical conditions that are not relevant, leading to gaps in understanding the real-world effectiveness of treatments. Addressing potentially modifiable exclusions (PMEs) could enhance accessibility and participation in trials without compromising safety, particularly given the low rates of enrollment. Methods: We retrospectively analyzed ‘screen-failed’ patients (those who were excluded after providing consent because they did not meet the eligibility criteria or other protocol requirements) with biliary tract (BTC) or pancreatic cancer (PDAC) between August 2019 and November 2024. Screening logs and electronic health records provided clinical data. PMEs were identified and validated by two independent medical oncologists. Results: Of 585 screen-failed patients from 18 trials, 76 were excluded due to incomplete data. Among the 509 patients analyzed (367-PDAC, 142-BTC), the leading causes of screen failure were declined participation (99, 19%), comorbidities (59, 12%), suboptimal organ function (56, 11%), absence of biomarker (49, 10%), and insufficient biospecimens (36, 7%). Among patients declining participation, reasons included preference for standard care (23%), travel (22%), competing trials (5%), adverse event concerns (4%), financial issues (3%), and unknown reasons (43%). Of the 509 patients deemed ineligible for study entry at screening, we identified 69 patients (13.6%) with PMEs, primarily related to borderline laboratory abnormalities: liver function (16, 23%), kidney function (14, 20%), platelet count (8, 12%), hemoglobin (5, 7%), and white blood cell count (4, 6%). Other PMEs included previous or concurrent malignancies (6, 9%) and viral hepatitis (3, 4%). PMEs were evenly distributed across trials. Notably, all screen-failed patients proceeded to receive standard therapy. Conclusions: This analysis underscores the potential for rigid eligibility criteria to exclude stable patients who might benefit from investigational treatments. Easing specific criteria, particularly those related to laboratory abnormalities, could broaden trial accessibility. Furthermore, examining the reasons for declined participation and addressing PMEs could help develop strategies to enhance trial enrollment.

TPS3171 Background: Genetic alterations in fibroblast growth factor receptors 2 and 3 ( FGFR2/3 ) occur in nearly all cancer types. FGFR2 fusions and rearrangements occur in up to 10-15% of intrahepatic cholangiocarcinomas (iCCA) and alterations in FGFR3 occur in 15-30% of urothelial cancers. The clinical benefit from currently approved FGFR inhibitors (FGFRi) is often curtailed by development of acquired resistance, which may arise through on-target mutations in the FGFR2/3 kinase domain. Additionally, off-tumor effects on FGFR1 by pan-FGFRi can lead to hyperphosphatemia and consequently to dose reductions or dose holds. Thus, there is an unmet clinical need for a selective FGFR2/3 inhibitor that has clinical efficacy against activating alterations and resistance mutations without causing FGFR1-mediated hyperphosphatemia. CGT4859 is an orally bioavailable, ATP-competitive, reversible inhibitor of FGFR2/3, with potency against clinically relevant FGFR2/3 kinase domain mutations. In addition, CGT4859 demonstrates >140 fold selectivity over FGFR1, and shows robust efficacy in target altered in vivo tumor models without increases in serum phosphorus. Nonclinical pharmacokinetics (PK) and safety data support evaluating CGT4859 in a first-in-human, open-label, dose-escalation and signal-seeking Phase I/II study (NCT06777316). Safety, tolerability, PK, pharmacodynamics, and antitumor activity of CGT4859 will be assessed in adults with histologically confirmed unresectable or metastatic iCCA or other solid tumors with FGFR2/3 alterations. Methods: CGT4859 will be administered orally continuously in 28-day cycles to patients (N=~50) at a starting dose of 1 mg QD, and dose escalation will not exceed 40 mg QD as determined using a Bayesian optimal interval design with backfill (BF-BOIN). This approach will be used to guide dose escalation and establish the maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D). BF-BOIN enables backfilling of participants to doses that are cleared for safety during the dose escalation, generating additional data on safety and tolerability below the MTD. Objective response rate (ORR) and disease control rate will be determined based on investigator assessment using RECIST v1.1. Phase II will enroll up to 4 cohorts, each enrolling ~15 patients. Proposed cohorts will include participants who have iCCA and are either FGFRi-naïve or FGFRi-exposed. Two additional cohorts with other advanced solid tumors harboring FGFR2/3 alterations may be included based on signals detected in dose escalation. The primary efficacy endpoint for Phase II is ORR per RECIST v1.1. The preclinical data support the study of CGT4859 in this patient population with solid tumors harboring FGFR2 and/or FGFR3 genetic alterations. The phase I dose escalation study is currently enrolling at sites in the United States. Clinical trial information: NCT06777316 .

4009 Background: Survival outcomes are historically poor in patients (pts) with advanced/metastatic iCCA, with median overall survival (mOS) times of approximately 1 year with first-line gemcitabine plus cisplatin and approximately 6 months with second-line chemotherapy. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, demonstrated efficacy with durable responses in pts with iCCA harboring FGFR2 fusion/rearrangements in the pivotal FOENIX-CCA2 phase 2 study (NCT02052778). At the primary analysis of this trial (data cutoff: October 1, 2020), an objective response rate (ORR) of 41.7% was observed, with a median duration of response (mDOR) of 9.7 mo. Here, we report updated efficacy (including mature OS data) and safety data from the final analysis with an additional 8 mo of follow-up. Methods: FOENIX-CCA2 was a single-arm phase 2 study that enrolled pts with advanced/metastatic iCCA with FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; including gemcitabine plus platinum-based chemotherapy). Pts received futibatinib 20 mg once daily until PD/intolerability. The primary endpoint was ORR per RECIST v1.1 by independent central review. Secondary endpoints were DOR, disease control rate (DCR), progression-free survival (PFS), OS, safety, and patient-reported outcomes. Results: At the time of the final data cutoff (May 29, 2021), median follow-up was 25.0 mo, and 96/103 pts (93%) had discontinued tx. The median number of tx cycles was 13.0 for a median tx duration of 9.1 mo. The confirmed ORR was 41.7% (43/103) and thereby the same as of the primary analysis, as was the DCR (at 82.5%). The ORR was consistent across pt subgroups. The mDOR was 9.5 mo, and 74% of responses lasted ≥6 mo. mPFS was 8.9 mo, with a 12-mo PFS rate of 35.4%. Mature mOS was 20.0 mo, with a 12-mo OS rate of 73.1% . No new safety signals were identified. Common tx-related adverse events (TRAEs) included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). TRAEs resulted in tx discontinuation in 4 pts (4%). No tx-related deaths occurred. Quality of life was maintained from baseline to tx cycle 13. Conclusions: Findings from the final analysis of FOENIX-CCA2 confirm the results of the primary analysis and reinforce the durable efficacy and continued tolerability of futibatinib in previously treated pts with advanced/metastatic iCCA harboring FGFR2 fusion/rearrangements. Mature OS data were consistent with data from the primary analysis and far exceed historical data in this patient population. Clinical trial information: NCT02052778.

Abstract Background FGFR2 fusions occur in ~15% of patients (pts) with iCCA, a rare cancer with a poor prognosis. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown activity across tumor types, including iCCA, in a phase 1 study. The pivotal phase 2 FOENIX-CCA2 trial (NCT02052778) is evaluating futibatinib in iCCA harboring FGFR2 fusions/rearrangements. Here, we report the first efficacy, safety, and quality of life (QoL) data for the complete FOENIX-CCA2 population. Methods Eligible pts had unresectable/metastatic iCCA with an FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; excluding FGFR inhibitors). Pts received futibatinib 20 mg QD until PD/intolerability. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central review (target ORR: 20%). Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and patient-reported outcomes (PROs). Subgroup analyses were performed by pt characteristic and molecular alteration. Results Among 103 pts (56% female), 53% had received ≥2 prior tx. FGFR2 fusions were present in 78% (23% had FGFR2-BICC1 fusions) and FGFR2 rearrangements in 22%. At data cutoff (Oct 1, 2020), 72 pts (70%) had discontinued tx. The study met its primary objective with a confirmed ORR of 41.7% (43/103). Responses were durable, with a median (m) DOR of 9.7 mo and 72% of responses ≥6 mo. DCR was 82.5%. mPFS was 9.0 mo; mOS was 21.7 mo, with a 12-mo OS rate of 72%. ORR was consistent across pt demographic subgroups (≥65 y: 65.2%; 2 prior tx: 38.7%). Common tx-related AEs (TRAEs) were hyperphosphatemia (85%), alopecia (33%), and dry mouth (30%). The most frequent grade 3 TRAE, hyperphosphatemia (30%), resolved with adequate management (median 7 d). Retinal disorders (all grade 1-2) were reported in 8% of pts. TRAEs were managed with dosing interruptions (50%)/reductions (54%); 2 pts discontinued tx due to TRAEs. No tx-related deaths occurred. ORRs were consistent in pts with dosing interruptions (40.2%) or reductions (46.8%). PROs were stable through 11.0 mo of tx. In exploratory biomarker analyses, ORR was consistent in pts with FGFR2 fusions (43.8%) and other FGFR2 rearrangements (34.8%) and in pts with BICC1 (41.7%) and non-BICC1 (44.6%) fusion partners. Notably, no obvious differences in ORR were observed in pts with co-occurring genetic alterations, including TP53 comutations (ORR, 38.5% [5/13]). Additional biomarker data will be presented. Conclusions Futibatinib resulted in frequent, durable objective responses in pts with iCCA harboring FGFR2 fusion/rearrangements, regardless of pt baseline characteristic, molecular alteration, or comutation. AEs were manageable with dosing modifications that did not impact response. QoL was maintained. Citation Format: Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Chigusa Morizane, Juan W. Valle, Thomas B. Karasic, Thomas A. Abrams, Robin Kate Kelley, Philippe Cassier, Junji Furuse, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Yoshito Komatsu, Kunihiro Masuda, Daniel Ahn, Yaohua He, Nital Soni, Karim A. Benhadji, John A. Bridgewater. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT010.