Alterations in fibroblast growth factor receptor 2 (
) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, ...covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with
-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors.
In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic
fusion-positive or
rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.
Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring
mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment.
In previously treated patients with
fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).
Summary Background Combination chemotherapy with gemcitabine and a platinum-based agent is regarded as a standard treatment for patients with advanced biliary-tract cancer. Results of phase 2 trials ...of single-agent erlotinib in biliary-tract cancer and of gemcitabine plus erlotinib in pancreatic cancer have shown modest benefits. Therefore, we aimed to investigate the efficacy of gemcitabine and oxaliplatin plus erlotinib versus chemotherapy alone for advanced biliary-tract cancer. Methods In this open label, randomised, phase 3 trial, we randomly assigned patients (in a 1:1 ratio) with metastatic biliary-tract cancer (cholangiocarcinoma, gallbladder cancer, or ampulla of Vater cancer) to receive either first-line treatment with chemotherapy alone (gemcitabine 1000 mg/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2) or chemotherapy plus erlotinib (100 mg daily). Treatment was repeated every 2 weeks until disease progression or unacceptable toxic effects. Randomisation was done centrally (stratified by participating centre and presence of measurable lesion). The primary endpoint was progression-free survival. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov , number NCT01149122. Findings 133 patients were randomly assigned to the chemotherapy alone group and 135 to the chemotherapy plus erlotinib group. The groups were balanced except for a higher proportion of patients with cholangiocarcinoma in the group given erlotinib than in the chemotherapy alone group (96 71% patients vs 84 63%). Median progression-free survival was 4·2 months (95% CI 2·7–5·7) in the chemotherapy alone group and 5·8 months (95% CI 4·6–7·0) in the chemotherapy plus erlotinib group (hazard ratio HR 0·80, 95% CI 0·61–1·03; p=0·087). Significantly more patients had an objective response in the chemotherapy plus erlotinib group than in the chemotherapy alone group (40 patients vs 21 patients; p=0·005), but median overall survival was the same in both groups (9·5 months 95% CI 7·5–11·5 in the chemotherapy alone group and 9·5 months 7·6–11·4 in the chemotherapy plus erlotinib group; HR 0·93, 0·69–1·25; p=0·611). All-cause deaths within 30 days of random assignment occurred in one (1%) of the patients in the chemotherapy alone group and in four (3%) of those in the chemotherapy plus erlotinib group. The most common grade 3–4 adverse event was febrile neutropenia (eight 6% patients in the chemotherapy alone group and six 4% in the chemotherapy plus erlotinib group). No patient died of treatment-related causes during the study. Subgroup analyses by primary site of disease showed that for patients with cholangiocarcinoma, the addition of erlotinib to chemotherapy significantly prolonged median progression-free survival (5·9 months 95% CI 4·7–7·1 for chemotherapy plus erlotinib vs 3·0 months 1·1–4·9 for chemotherapy alone; HR 0·73, 95% CI 0·53–1·00; p=0·049). Interpretation Although no significant difference in progression-free survival was noted between groups, the addition of erlotinib to gemcitabine and oxaliplatin showed antitumour activity and might be a treatment option for patients with cholangiocarcinoma. Funding None.
Stereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC.
We ...retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed.
A total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients.
LAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT.
Summary
Purpose nab
-paclitaxel plus gemcitabine (AG) and FOLFIRINOX have been established as standard first-line treatment in metastatic pancreatic cancer (mPC). We performed retrospective analysis ...comparing the efficacies of AG and FOLFIRINOX in daily practice setting.
Materials and Methods
We analyzed 308 patients who presented initially as mPC and received AG (
n
= 149) or FOLFIRINOX (
n
= 159) as first-line treatment between 2013 and 2016. Primary endpoints were progression-free survival (PFS) and overall survival (OS).
Result
There were no significant differences between the two groups in terms of baseline characteristics, except older age and higher Charlson Comorbidity Index (CCI) score in AG group. The response rates (34% vs 34%) and median PFS (6.8 vs 5.1 months) were comparable between two groups (
p
= 0.88 and
p
= 0.19, respectively), while median OS was significantly better with AG than FOLFIRINOX (11.4 vs 9.6 months;
p
= 0.002). Elevated baseline CA19–9 level and liver metastasis were independent adverse prognostic factors for PFS and OS. In subgroup analyses, PFS with AG was better in patients with age ≥ 65 years, peritoneal metastasis, and higher CCI than that with FOLFIRINOX.
Conclusion
Both AG and FOLFIRINOX showed comparable efficacy outcomes in daily practice setting. AG might be preferentially considered in patients with peritoneal metastasis, comorbid medical conditions or old age.
Purpose More than half of patients with bile duct cancer (BDC) develop recurrence even after curative resection. Recurrent BDC has a poor prognosis, and no optimal treatment modality has been ...established. We therefore analyzed our experience on the survival outcomes of radiation therapy (RT) for recurrent extrahepatic bile duct cancer (EHBDC). Patients and methods We retrospectively analyzed the records of patients with recurrent EHBDC who underwent concurrent chemoradiation therapy (CCRT) or RT alone at our institution between January 2001 and June 2015. Freedom from locoregional progression (FFLP), progression-free survival (PFS), and overall survival (OS) were assessed, and univariate and multivariate analyses were performed to identify the prognostic factors. Results A total of 76 patients were included in the analysis. The median OS was 16 months and the rates of 2-year FFLP, PFS, and OS were 61%, 25%, and 33%, respectively. Among the evaluable patients, the first site of failure was the locoregional area in 16 patients, distant metastasis in 27, and both sites in 8. On univariate analysis, disease-free interval (p = 0.012) and concurrent chemotherapy (p = 0.040) were found as significant prognostic factors for OS. One patient with CCRT developed a grade 3 hematologic toxicity, and two patients experienced late grade 3 toxicities including duodenal ulcer bleeding and obstruction. Conclusions RT for recurrent EHBDC showed favorable survival and local control with limited treatment-related toxicities. Considering that the most common pattern of failure was distant metastasis, further studies on the optimal scheme of chemotherapy and RT are warranted.
Background
Recent advances in molecular targeted therapy have identified HER2 as an important target for anti-cancer therapy in gastric cancer (GC). Although the clinical relevance and prognostic ...significance of HER2 in breast cancer has been well acknowledged, it remains controversial in GC.
Methods
HER2 expression was investigated in two independent series of GC by immunohistochemical staining. One series corresponded to 1,414 cases of whole-tissue sections and the other corresponded to 595 cases of tissue microarrays (TMAs). Results were compared and correlated with clinicopathologic parameters.
Results
HER2-positivity was detected in 12.3% of whole-tissue sections and 17% of TMAs. Among samples scored 3+, 90.1% stained ≥50% of the tumor area, but only 40.9% in score 2+ cases stained ≥50% of the tumor area. In whole-tissue sections, HER2-positivity was correlated with age (
P
= 0.002), histological type (differentiated or intestinal,
P
< 0.001), lymphovascular invasion (
P
= 0.005), and lymph node metastasis (
P
= 0.009). In TMAs, HER2-positivity was correlated only with age (
P
= 0.003) and histological type (
P
< 0.001). Multivariate analyses of the differentiated GC subgroup revealed that HER2-positivity was an independent poor prognostic factor (
P
= 0.042). The cases with HER2-positive in ≥50% of the tumor area showed worse prognosis than those of <50% (
P
= 0.021).
Conclusions
Despite discrepancies in the results from whole-tissue sections and TMAs, HER2 overexpression was positively correlated with aggressive biological behavior and was an independent poor prognostic factor for recurrence in differentiated GCs. Therefore, HER2-positive GCs should be considered for adjuvant trastuzumab therapy.
Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). ...Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcgammaR) play an important role in initiating ADCC. Studies have shown that two IgG FcgammaR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab.
Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) -based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples.
FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test).
Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.
We aimed to assess the efficacy of second-line fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer (BTC) after failure of gemcitabine plus cisplatin (GEMCIS).
We ...retrospectively examined patients with histologically documented advanced BTC who received first-line GEMCIS between December 2010 and June 2015. Among 748 patients treated with first-line GEMCIS, 321 (43%) subsequently received fluoropyrimidine-based second-line systemic chemotherapy.
Fluoropyrimidine monotherapy and fluoropyrimidine-platinum combination were used in 255 and 66 patients, respectively. In patients with measurable disease, the overall response rate (ORR) was 3% and disease control rate was 47%. After a median follow-up of 27.6 months (range, 0.9-70.4 months), the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval (CI), 1.6-2.2) and 6.5 months (95% CI, 5.9-7.0), respectively. The ORR was significantly higher in patients who received fluoropyrimidine-platinum combination compared with those who received fluoropyrimidine alone (8 vs 1%, P=0.009), although the PFS (P=0.43) and OS (P=0.88) did not significantly differ between these groups.
Fluoropyrimidine-based chemotherapy was modestly effective as a second-line chemotherapy for advanced BTC patients after failure of GEMCIS. Fluoropyrimidine-platinum combination therapy was not associated with improved survival outcomes, as compared with fluoropyrimidine monotherapy.
In biliary tract cancer (BTC), standard chemotherapy has limited benefit and no molecular targeted agents have been approved. This study investigated the genetic profile of BTC to identify potential ...new therapeutic targets and predictive biomarkers.
Targeted exome sequencing was performed for 124 patients with BTC gallbladder cancer (GBC), 25; intrahepatic cholangiocarcinoma (ICC), 55; extrahepatic cholangiocarcinoma (ECC), 44. Survival analysis was performed in 112 patients who received palliative chemotherapy for locally unresectable or metastatic disease.
Genetic alterations were observed in 104 patients (83.8%); the most commonly mutated genes were TP53 (44.4%), KRAS (29.0%), ARID1A (12.1%) and IDH1 (9.7%). IDH1/2 mutations appeared more frequently in ICC (23.6%, P = 0.0002) than in GBC (4.0%) or ECC (2.3%), while ERBB2/3 mutations were found only in GBC (20.0%) and ECC (11.4%). Patients harbouring TP53 mutations had shorter overall survival (OS; median 15.2 vs. 37.8 months, P = 0.018), while IDH1 mutations showed a tendency for longer progression-free survival (PFS; 10.6 vs. 6.1 months, P = 0.124). Potentially actionable genetic alterations were found in 54.8%, and 7.1% received appropriate molecular targeted therapy in the clinical trial setting. Germline or somatic mutations in DNA damage repair (DDR) genes were found in 63.5% of patients and were significantly associated with longer PFS (6.9 vs. 5.7 months, P = 0.013) and OS (21.0 vs. 13.3 months, P = 0.009) in patients who received first-line platinum-containing chemotherapies (n = 88).
A subgroup of patients with BTC may benefit from targeted therapy by the aid of genetic information. In particular, DDR alterations may be a predictive biomarker for response to platinum-containing chemotherapy in patients with BTC.
•We examined genetic landscape of biliary tract cancer with targeted sequencing.•Certain genetic mutations were associated with clinical outcomes.•More than half of patients harboured at least one potentially actionable alteration.•DNA damage repair gene alterations were associated with a better response to platinum-based treatment.
HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour ...activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer.
HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment.
Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 56% were female and 35 44% were male; 52 65% were Asian; median age was 64 years IQR 58–70) and seven in cohort 2 (five 71% were male and two 29% were female; five 71% were Asian; median age was 62 years IQR 58–77). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 74% patients). The median duration of follow-up was 12·4 months (IQR 9·4–17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% 95% CI 30·4–52·8). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four 5% patients) and decreased ejection fraction (three 3% patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths.
Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer.
Zymeworks, Jazz, and BeiGene.
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