Integrative molecular profiling and response to chemotherapy on the COMPASS trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 188-188 ◽  
Author(s):  
Grainne M. O'Kane ◽  
Sandra Fischer ◽  
Rob Denroche ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Chemotherapy Resistance ◽  
Predictive Biomarker ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Strongly Correlated ◽  
First Line ◽  
Tumor Biopsy ◽  
Response To Chemotherapy

188 Background: Predictive mutational and transcriptional features in advanced PDAC are needed for improved patient stratification and treatment selection. Methods: Patients (pts) on the COMPASS trial with advanced PDAC are prospectively recruited prior to first-line chemotherapy for WGS and RNAseq. Tumor tissue undergoes enrichment by laser capture microdissection with genomic analyses available within eight wks. Tumor responses and clinical outcomes in this maturing cohort were correlated with molecular characteristics. Results: 157 pts underwent a tumor biopsy between Dec 2015 and Jul 2018 with over 95% success in achieving results. 141 genomes have been reported in pts planned to receive chemotherapy; the median time from biopsy to report was 35.5 days. In the ITT population,118 pts are summarised for first-line response. The median age was 63 yrs (29-81), 55% were male, and 16% had locally advanced disease. 66 (56%) received modified FFX as first-line treatment. 25 (21%) tumors displayed the Moffitt basal-like RNA signature which associated with chemotherapy resistance, with tumor shrinkage mainly observed in the classical RNA subtype (p = 0.002). GATA6 expression (log10 scale) clearly separated Moffitt subgroups with classical tumors exhibiting high expression (p < 0.0001). GATA6 in situ hybridization strongly correlated with RNAseq, (r = 0.89, p < 0.001) with strong correlation also seen with GATA6 IHC. The median overall survival (OS) in the classical group was 8.5 mths vs. 6.6 mths in the basal-like group (HR 0.53, 95% CI 0.32-0.89 p = 0.015). In those treated with mFFX, median OS was 10.1mths in classical versus 6.6mths in the basal-like subtypes, (HR 0.32, 95% CI 0.16-0.63, p=0.001). 30% of pts had potentially actionable genetic alterations including BRAF variants (n = 4) and an NTRK3-EML4 fusion in KRAS WT tumors (8%). Signatures of homologous recombination deficiency (HRD) were found in seven pts; two additional pts with BRCA germline variants did not exhibit somatic HRD hallmarks. Conclusions: Subsets of pts with advanced PDAC have actionable variants including those with HRD signatures and patients with KRAS WT tumors. GATA6 is a putative predictive biomarker of transcriptomic subgroups which should be incorporated in clinical trials. Clinical trial information: NCT02750657.

Harnessing biomarkers of response to improve therapy selection in esophago-gastric adenocarcinoma

2021 ◽  
Author(s):  
Caroline YK Fong ◽  
Ian Chau
Keyword(s):  
Patient Outcomes ◽  
Tumor Heterogeneity ◽  
Systemic Treatment ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Molecular Characteristics ◽  
Precision Oncology ◽  
First Line ◽  
Clinical Strategies ◽  
Line Chemotherapy

Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.

FGFR-altered, advanced urothelial carcinoma (UC) and response to chemotherapy prior to receiving erdafitinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4542-4542
Author(s):  
Andrea Necchi ◽  
Arlene O. Siefker-Radtke ◽  
Bob Zhong ◽  
Parthiv Jasvant Mahadevia ◽  
Ademi E. Santiago-Walker ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Response Rates ◽  
First Line ◽  
Open Label ◽  
Response To Chemotherapy ◽  
Open Label Phase ◽  
Prior Systemic Therapy ◽  
Advanced Urothelial Carcinoma ◽  
Post Hoc

4542 Background: FGFR-altered, advanced UC has predominantly a luminal 1 subtype, which is associated with lower response rates to immunotherapy and possibly also to chemotherapy. Objective response rates (ORR) for first-line cisplatin-based regimens, such as gemcitabine-cisplatin (gem/cis) and methotrexate-vinblastine-doxorubicin-cisplatin (MVAC), historically range between 45-60% and for gemcitabine-carboplatin (gem/carbo) 35-45%. However, the ORR on chemotherapy for the ~20% of patients with FGFR-altered tumors is unknown. Methods: BLC2001 (NCT02365597) is an ongoing global open-label phase 2 study of the pan-FGFR inhibitor erdafitinib in patients with locally advanced or metastatic UC with specific FGFR2/3 gene alterations. Patients who had received first-line (1L) or second-line (2L) chemotherapy for advanced UC were identified. Investigator-reported ORR (complete + partial responses) and median time to progression (TTP) on these pretreatments were analyzed. Results: Of 210 patients treated with erdafitinib in BLC2001, 191 had received prior systemic therapy including 184 and 83 patients who had received 1L and 2L chemotherapy, respectively. ORR were 29.3% (54/184; 95% CI 22.8%, 35.9%) to 1L chemotherapy and 24.1% (20/83; 95% CI 14.9%, 33.3%) to 2L chemotherapy. 1L therapy consisted of gem/cis in 94 patients, gem/carbo in 59 patients, and MVAC in 22 patients, with ORR (95% CI) of 35.1% (25.5%, 44.8%), 25.4% (14.3%, 36.5%), and 22.7% (5.2%, 40.2%), respectively. In the 2L setting, of 46 patients who had received a regimen containing a taxane (paclitaxel or docetaxel) or vinflunine, 8 patients (17.4%; 95% CI 6.4%, 28.3%) achieved an objective response. Median TTP was 7.16 mo (95% CI 6.18, 7.49) after 1L chemotherapy (7.6 mo for gem/cis, 6.3 mo for gem/carbo, and 5.3 mo for MVAC) and 4.35 mo (95% CI 3.3, 5.5) after 2L chemotherapy (3.6 mo for taxane or vinflunine). Conclusions: In this post-hoc analysis, the overall ORR to prior 1L chemotherapy was lower, but within the range expected based on historical data. Further investigation into the response to chemotherapy in FGFR alteration positive patients is warranted and may be useful for the development of 1L trials of combination therapy. Clinical trial information: NCT02365597.

BRCA mutations in metastatic colorectal cancer (mCRC) and response to chemotherapy.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 235-235
Author(s):  
Sophie Feng ◽  
Laith Al-Showbaki ◽  
Monika K. Krzyzanowska ◽  
Rebecca M. Prince ◽  
Tracy Stockley ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Series ◽  
Molecular Characteristics ◽  
Small Subset ◽  
Chemotherapy Response ◽  
First Line ◽  
Brca Mutations ◽  
Response To Chemotherapy ◽  
Brca 1 ◽  
The Impact

235 Background: Mutations in BRCA 1/2 are typically associated with breast, ovarian, pancreatic and prostate cancers. BRCA mutations have been reported in colorectal cancer in sporadic case series. Unlike other cancers, the significance of BRCA mutations in mCRC is not known. We report the prevalence and molecular characteristics associated with BRCA 1/2 mutations in mCRC, and investigate the impact of these mutations on chemotherapy response since both oxaliplatin (OX) and irinotecan (IRI) interfere with DNA repair pathways. Methods: The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) database was queried to identify mCRC patients (pts) harbouring BRCA 1/2 mutations. BRCA 1/2 mutations were detected using panel-based next generation sequencing (NGS) on archival tumour tissue. Clinical and molecular variables were collected, together with treatment outcomes. Results: Of 279 mCRC pts within the OCTANE database as of March 2019, 9 pts with BRCA 1/2 mutations were identified (3.2%): 4 BRCA 1 and 5 BRCA 2 mutations. Each patient had a unique variant with 8/9 missense mutations and 1/9 splicing error. Allele frequency ranged from 0.11 to 0.57. RAS or BRAF mutations were present in 67%. Common co-mutations included TP53 (56%), APC (56%), TSC1 (44%), ROS1 (33%) and ATM(33%). 2 pts were mismatch repair deficient. Median age was 48.5 years (range: 31-69 years), 56% males. 5 pts presented with de novo metastatic disease. First line OX-containing chemotherapy was administered to 4 pts, and IRI to 3 pts. 2 pts did not receive chemotherapy (1 had surgery only post-adjuvant OX, and 1 immunotherapy). Overall response rate (ORR) was 71%, with all pts achieving a partial response or stable disease. The median progression-free survival was 7.5 months (range: 1.8- 31.7 months) and median overall survival 68.5 months (range: 10.5- 68.5 months) respectively. Conclusions: BRCA 1/2 mutations are present in a small subset of mCRC pts. Pts with these mutations tend to be younger at diagnosis. BRCA 1/2 mutations are associated with favourable response to first line chemotherapy. Targeting BRCA 1/2 mutations may broaden treatment options for these patients.

KEYlargo: A phase II study of first-line pembrolizumab (P), capecitabine (C), and oxaliplatin (O) in HER2-negative gastroesophageal (GE) adenocarcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 228-228
Author(s):  
Hope Elizabeth Uronis ◽  
Christel Rushing ◽  
Gerard C. Blobe ◽  
Shiaowen David Hsu ◽  
Niharika B. Mettu ◽  
...  
Keyword(s):  
Phase Ii ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Clinical Activity ◽  
First Line ◽  
Tumor Biopsy ◽  
Gastroesophageal Junction Adenocarcinoma

228 Background: Gastric and esophageal adenocarcinomas are a leading cause of cancer death worldwide. Many of these patients (pts) present with locally advanced unresectable or metastatic disease and are treated with combination cytotoxic chemotherapy. Single agent P is FDA approved for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ) whose tumors have a combined positive score (CPS) ≥ 1 after disease progression on or after two lines of therapy including fluoropyrimidine and platinum and her2/neu-targeted therapy (if indicated). More effective therapy is needed earlier in the disease trajectory. We conducted a single-arm phase II trial to establish the safety and efficacy of first-line C and O + P. Methods: Pts with previously untreated metastatic GE adenocarcinoma regardless of PDL-1 status received intravenous (IV) P 200mg with IV O 130mg/m2 every three weeks and oral C 850mg/m2 twice daily for 14 days on/7 days off. After the 6 patient safety cohort, pts first completed a biomarker cycle that included fresh tumor biopsy before P and one week after P before chemotherapy started. Archived FFPE tumor samples were also obtained from all pts with available tissue. The primary endpoint was progression free survival (PFS); secondary endpoints included response rate (RR) and overall survival (OS). Results: 36 pts were enrolled and 34 pts were evaluable for efficacy (1 pt withdrew for personal reasons before end of cycle 1 and 1 pt had immune-related toxicity during cycle 1 and was taken off study before any efficacy assessment). 9 pts (26%) had an esophageal primary, 18 pts (53%) had a GEJ primary and 7 pts (21%) had a gastric primary. Median PFS was 7.6 months [95% CI: 5.8 to 12.2], RR was 72.7% [95% CI: 57% to 88%], and median OS was 15.8 months [95% CI: 11.6 to NE]. 27 patients (81.8%) had decrease in disease burden (ranging from -19% to -100%). After > 18 months of follow-up, 5 patients remained in durable complete response (CR). Immune-mediated treatment related adverse events (TRAEs) included thyroid disorders (n=5; 14%), colitis (n=4; 11%), adrenal insufficiency (n=2; 5%), and type 1 diabetes (n=1). Sixteen patients (44%) experienced grade 3 or 4 TRAEs. There were no grade 5 TRAEs. Conclusions: The combination of C and O + P had acceptable safety and significant clinical activity. These promising results indicate that C and O + P merits further study as a first line option for patients with unresectable locally advanced or metastatic GE adenocarcinoma. Updated survival and correlative data will be presented. Clinical trial information: NCT03342937.

Genomics-driven precision medicine for advanced pancreatic ductal carcinoma (PDAC): Early results from the COMPASS trial (NCT02750657).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 211-211 ◽  
Author(s):  
Kyaw Lwin Aung ◽  
Sandra Fischer ◽  
Rob Denroche ◽  
Gun Ho Jang ◽  
Anna Dodd ◽  
...  
Keyword(s):  
Ductal Carcinoma ◽  
Brca2 Mutation ◽  
Locally Advanced ◽  
Genetic Alterations ◽  
Disease Assessment ◽  
Pancreatic Ductal Carcinoma ◽  
Chemotherapy Response ◽  
Tumor Biopsy ◽  
Early Results ◽  
A Prospective Study

211 Background: COMPASS is a prospective study with the primary aim to identify predictive mutational and transcriptional features in advanced PDAC for improved patient stratification and treatment selection. Methods: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy for whole genome sequencing (WGS) and RNA sequencing (RNASeq). Fresh tumor tissue was acquired by image guided percutaneous core needle biopsy of locally advanced primary or metastatic tumors. Laser capture microdissection was performed for all cases to ensure high-resolution genomic analyses. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results: Of 63 patients who underwent a tumor biopsy between December 2015 and June 2017, WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Three patients with an ‘unstable’ genomic subtype, including two with a novel ‘duplicator’ phenotype, responded well to m-FOLFIRINOX. Of two cases with the same germline BRCA2 mutation, only the chemotherapy responder had loss of heterozygosity and genomic hallmarks of double stranded break repair deficiency. Approximately 25% of tumors displayed the basal-like RNA expression signature and these were chemotherapy resistant, with tumor shrinkage mainly observed in those with the classical RNA subtype (P = 0.003). Thirty percent of patients had potentially actionable genetic alterations. Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes providing the impetus for further studies. Clinical trial information: NCT02750657.

Treatment of metastatic recurrence of urothelial carcinoma after previous cisplatin-based chemotherapy: A retrospective comparison of different chemotherapy regimens.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17005-e17005
Author(s):  
Olivia A Do ◽  
Lorin Ferris ◽  
Sarah K Holt ◽  
Jorge Ramos ◽  
Lauren C Harshman ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Advanced Disease ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
First Line ◽  
Metastatic Recurrence ◽  
Locally Advanced Disease ◽  
Response To Chemotherapy ◽  
Metastatic Setting ◽  
Line Chemotherapy

e17005 Background: The optimal choice of first-line chemotherapy for urothelial carcinoma (UC) patients who recur after previous cisplatin-based chemotherapy for locally-advanced disease is unclear. Our objective is to compare the efficacy of platinum (PBC) versus non-platinum (NPBC) based first-line chemotherapy regimens for such patients after metastatic recurrence. Methods: Data was collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database consisting of patients with muscle-invasive or advanced UC from 28 centers between 2005 and 2012. Patient inclusion criteria included: 1) UC with no initial metastases (cT2-4, cN0-N3, and cM0), 3) receipt of cisplatin in the locally advanced setting, and 4) receipt of chemotherapy in the first-line metastatic setting. Overall survival (OS) was the primary endpoint. Secondary endpoints included progression-free survival (PFS) and response to chemotherapy. Kaplan-Meier and Cox regression models estimated OS, PFS, and response, adjusting for age, gender, Eastern Cooperative Oncology Group (ECOG-PS), Charlson comorbidity index (CCI), surgery, T and N stage, albumin, creatinine clearance, number of initial cisplatin cycles, and time from last chemotherapy. Results: 152 patients with metastatic UC (88 PBC and 64 NPBC) were analyzed. Twelve (7.9%) patients received local definitive radiation and 7 of these 12 also underwent cystectomy. The most common NPBC regimens included taxanes, gemcitabine, or pemetrexed. The median OS was 8.70 (95% CI: 7.53 to 11.16) and 10.27 months (95% CI: 7.37 to 13.10) for PBC and NPBC (HR: 1.04, 95% CI: .67 – 1.61, p = 0.86), respectively. Multivariable analysis showed an independent prognostic effect on OS for number of previous chemotherapy cycles (3-4 vs. 1-2) (HR: 0.44, 95% CI 0.20 – 0.96, P = 0.03) and whether surgery was performed (HR: 0.44, 95% CI 0.26 – 0.75, P = 0.003). Time from last chemotherapy was not prognostic for OS (HR: 0.99, 95% CI: 0.99 – 1.00, p = 0.19). There were no significant differences for both investigator-designated PFS (HR: 0.84, 95% CI: 0.57 – 1.24, p = .39) and response to chemotherapy between PBC and NPBC (p = 0.57). Conclusions: There is no significant outcome difference between PBC vs. NPBC in patients with metastatic-recurrent urothelial carcinoma who previously received cisplatin-based chemotherapy for locally advanced disease. Those who previously underwent radical surgery or who received 3-4 cycles of cisplatin had better OS with PBC.

scholarly journals CCNE1 Amplification as a Predictive Biomarker of Chemotherapy Resistance in Epithelial Ovarian Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 279
Author(s):  
Justin W. Gorski ◽  
Frederick R. Ueland ◽  
Jill M. Kolesar
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Predictive Marker ◽  
Predictive Biomarker ◽  
The United States ◽  
Genetic Alterations ◽  
Cyclin E1 ◽  
One Year ◽  
Line Setting

Ovarian cancer is the most-deadly gynecologic malignancy, with greater than 14,000 women expected to succumb to the disease this year in the United States alone. In the front-line setting, patients are treated with a platinum and taxane doublet. Although 40–60% of patients achieve complete clinical response to first-line chemotherapy, 25% are inherently platinum-resistant or refractory with a median overall survival of about one year. More than 80% of women afflicted with ovarian cancer will recur. Many attempts have been made to understand the mechanism of platinum and taxane based chemotherapy resistance. However, despite decades of research, few predictive markers of chemotherapy resistance have been identified. Here, we review the current understanding of one of the most common genetic alterations in epithelial ovarian cancer, CCNE1 (cyclin E1) amplification, and its role as a potential predictive marker of cytotoxic chemotherapy resistance. CCNE1 amplification has been identified as a primary oncogenic driver in a subset of high grade serous ovarian cancer that have an unmet clinical need. Understanding the interplay between cyclin E1 amplification and other common ovarian cancer genetic alterations provides the basis for chemotherapeutic resistance in CCNE1 amplified disease. Exploration of the effect of cyclin E1 amplification on the cellular machinery that causes dysregulated proliferation in cancer cells has allowed investigators to explore promising targeted therapies that provide the basis for emerging clinical trials.

Trial design for a phase 3 study evaluating pemigatinib (INCB054828) versus gemcitabine plus cisplatin chemotherapy in first-line treatment of patients with cholangiocarcinoma with FGFR2 rearrangement.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS462-TPS462 ◽  
Author(s):  
Tanios S. Bekaii-Saab ◽  
Juan W. Valle ◽  
Mitesh J. Borad ◽  
Davide Melisi ◽  
Arndt Vogel ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Genetic Alterations ◽  
Current Evidence ◽  
Survival Duration ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
History Of ◽  
First Line Treatment

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.

The natural history of fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16686-e16686
Author(s):  
Lipika Goyal ◽  
Angela Lamarca ◽  
John H. Strickler ◽  
Michael Cecchini ◽  
Daniel H. Ahn ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Median Time ◽  
Genetic Alterations ◽  
Initial Diagnosis ◽  
High Rate ◽  
Molecular Characteristics ◽  
Fusion Partner ◽  
First Line ◽  
Molecular Features ◽  
Systemic Therapies

e16686 Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.

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