Valle, Juan W.

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

348 Background: The proportion of females in medicine is increasing (approx. 50% in medical school/workforce), but disparities in female authorship in oncology research publications exist; female corresponding authorship reportedly ranges from 7.2-39.1% in oncology clinical trials (Ludmir et al 2019). This study aimed to describe and assess factors associated with female first and senior authorship in later phase systemic clinical trials in BTC and to identify any changes over time. Methods: Embase/Medline were used to identify final primary trial publications in BTC (2000-2020) (excluding phase I (PI) (expected to move to later phase), mixed tumour site trials, reviews, editorials and trial-in-progress publications). Gender was determined by inspection of names, google search and author communication. Chi-square tests and log regression were used to assess factors associated with female first and senior authorship, including changes over time (STATA16). Results: Of 501 publications, 163 met inclusion criteria; 80% single-arm PII and 15% and 5% randomised PII and PIII respectively; 73% enrolled ≤50 patients. Tumour primary sites were all BTC: 86%, cholangiocarcinoma: 8%, gallbladder cancer: 6%; 80% involved chemotherapy, 13% targeted therapy and 5% localised/systemic combinations; 65% were in first-line (1L) advanced setting, 17% post 1L, 13% advanced non-specified and 5% neo-adjuvant/adjuvant. Forty-eight percent received industry funding and 65% met primary end-point. Sixty-four percent were published post ABC-02 (Valle et al 2010). Publication impact factor (IF) was ≤5 in 50% and >20 in 12%. Median number of authors in all publications was 11. Geographic location of all first and senior authors were Asia (42%/42%), Europe (29%/29%), USA (24%/22%) and other (4%/6%), respectively. Median individual trial female author representation was 25%; there were no female authors in 12% of trials. Overall, female first and senior author representation was 21% and 11%, respectively. Median position of first female author was second. In publications with IF ≤20 and >20, there were 22% and 16% female first and 13% and 0% female senior authors, respectively. The phase of trial, journal IF, industry funding, or whether met primary end-point did not impact female first or senior author representation (all P>.05). There were more female senior authors associated with “other” geographic locations (40% in 10 trials) (P=.016) vs Asia (7%), Europe (8%) and USA (14%). There were no significant changes in female first or senior author representation over time (‘00-05: 21%/18%, ‘06-10: 27%/5%, ‘11-15: 15%/15%, ‘16-20: 22%/9%, P=.738, and P=.508 respectively). Conclusions: Female first and senior author representation in later phase systemic clinical trial publications in BTC is low and has not changed significantly over time. The underlying reasons for this imbalance need to be better understood and addressed.

266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20–40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1–9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1–3 (inappropriate) and greater than 2 (>2) ratings of 7–9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4–33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as “appropriate” or “maybe appropriate” based on a patient’s bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.

TPS600 Background: Pts with adv CCA have poor survival outcomes, and chemotherapy offers limited survival benefit (5-year survival rates, 5–10%; median overall survival [OS], 8–12 months). FGFR2 gene rearrangements are known to be early drivers of oncogenesis in ~15% of pts with intrahepatic (i) CCA. Futibatinib, an oral, highly selective, irreversible FGFR1-4 inhibitor has shown antitumor activity against a broad spectrum of FGFR-deregulated tumors in preclinical studies. In a previous study, futibatinib demonstrated clinical activity and tolerability in heavily pretreated pts with adv CCA harboring FGFR2 gene rearrangements. This phase 3 trial (FOENIX-CCA3) is designed to evaluate futibatinib vs gem-cis as 1L therapy for pts with adv iCCA harboring FGFR2 rearrangements. Methods: FOENIX-CCA3 is a multicenter, open-label, randomized phase 3 study that will be conducted in pts with metastatic or unresectable iCCA harboring FGFR2 rearrangements (assessed at screening by a central laboratory). Pts must have an ECOG performance status of 0 or 1 and should not have received previous systemic anticancer therapy for adv disease (adjuvant/neoadjuvant therapy ≥6 mo prior to randomization is permissible). Pts with clinically-significant alterations in calcium-phosphorus homeostasis or ectopic mineralization/calcification will be excluded. Approximately 216 pts will be randomized (1:1 ratio) to receive 20 mg futibatinib once daily until disease progression or other discontinuation criteria are met or gem-cis (on days 1 and 8 of a 21-day cycle) for 8 cycles or until disease progression, whichever occurs first. Pts will be stratified by prior surgical excision (yes vs no), geographic region, and locally adv vs metastatic disease. The primary endpoint is progression-free survival (PFS) assessed by independent central review (ICR). Secondary endpoints include objective response rate and disease control rate based on ICR, OS, PFS per investigator assessment, and safety. The anticipated start date is in April, 2020.

TPS592 Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10–16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1–3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ≤1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ≥2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.

PURPOSE To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population. RESULTS Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria. RECOMMENDATIONS Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

TPS468 Background: Intrahepatic cholangiocarcinoma (iCCA) is a cancer arising from the intrahepatic bile duct. Standard treatment of unresectable, recurrent, or metastatic iCCA is with cytotoxic chemotherapy. FGFR2 gene fusions have been identified as oncogenic drivers in 10–20% of iCCA tumors, but no targeted agents have been established to date. TAS-120 is an investigational irreversible FGFR1–4 inhibitor in development as a once-daily oral treatment for iCCA. Based on initial studies in multiple tumor types expressing FGFR abnormalities, iCCA was identified as a tumor type with potential susceptibility to FGFR inhibition and high unmet need. A phase I portion of the trial with an iCCA expansion cohort demonstrated tolerability and preliminary evidence of clinical efficacy with TAS-120 as a continuous, once-daily oral treatment in patients with iCCA. The most common AEs in the phase I portion of the trial were hyperphosphatemia, a mechanism-based on-target side effect, cutaneous AEs, and gastrointestinal AEs. The phase I portion of the study is continuing to enroll, and final results are anticipated in early 2019. Based on preliminary findings, a phase II portion of the study (FOENIX-101; clinicaltrials.gov registration NCT02052778) has been initiated. Methods: The phase II portion of the trial is a global, single-arm study of TAS-120 in patients with iCCA harboring FGFR2 gene rearrangements. The study will enroll approximately 100 adult patients with locally advanced or metastatic iCCA that progressed after ≥ 1 systemic therapies and with an ECOG PS of 0 or 1. Prior systemic therapy must include gemcitabine plus platinum-based chemotherapy. Screening for FGFR2 gene rearrangements will be performed at a central laboratory. The primary endpoint is objective response rate based on RECIST v1.1. Secondary endpoints include duration of response, disease control rate, overall survival, progression-free survival, safety, and health-related quality of life. Clinical trial information: NCT02052778.

TPS462 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR genetic alterations is implicated in many cancers, including cholangiocarcinoma (CCA). FGFR2 translocations with fusion partners occur in ≈10% to 20% of intrahepatic CCA tumors. Pemigatinib is a selective oral inhibitor of FGFR-1, 2, 3. Preliminary data from the ongoing phase 2 study show efficacy and tolerable safety in patients (pts) with CCA with FGFR2 translocations. We present the design for a phase 3, open-label, randomized trial investigating pemigatinib monotherapy versus gemcitabine plus cisplatin chemotherapy in the first-line treatment of pts with advanced/metastatic or unresectable CCA with FGFR2 rearrangement. Methods: Eligible pts (target, N = 432) are ≥ 18 years (≥ 20 years for Japanese pts) and have ECOG performance status ≤ 1 and histologically confirmed advanced (locally advanced, metastatic, or recurrent) CCA with a documented FGFR2 rearrangement. Key exclusion criteria include prior systemic therapy, excluding adjuvant/neoadjuvant treatment completed ≥ 6 months before enrollment; current evidence of clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues; and known, untreated CNS metastases or history of uncontrolled seizures. Pts are randomized 1:1 and stratified by geographic region and tumor burden into 2 treatment groups: pemigatinib starting dose 13.5 mg once daily continuously on a 3-week cycle; or gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) administered intravenously on days 1 and 8 of every 3-week cycle for up to 8 cycles until disease progression or unacceptable toxicity. Crossover to pemigatinib may be allowed once progressive disease is confirmed. The primary endpoint is progression-free survival (based on independent central review using RECIST v1.1). Secondary endpoints include overall response rate, overall survival, duration of response, disease control rate, safety and tolerability, and impact on quality of life. Clinical trial information: NCT03656536.