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.

Masitinib plus gemcitabine as first-line treatment of pancreatic cancer with pain: Results from phase 3 study AB12005.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4018-4018
Author(s):  
Joel Ezenfis ◽  
Olivier Hermine ◽  
Keyword(s):  
Pancreatic Cancer ◽  
Statistical Significance ◽  
Locally Advanced ◽  
Disease Stage ◽  
Study Cohort ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
Risk Of Death ◽  
First Line Treatment

4018 Background: Masitinib (MAS) is a small molecule drug targeting mast cell and macrophage activity, innate immune cells that are critical components of the tumor microenvironment. Proof of concept that MAS in combination with gemcitabine (GEM) improved overall survival (OS) in pancreatic cancer (PC) patients (pts) with pain, was previously shown [doi 10.1093/annonc/mdv133]. The presence of pain in PC is thought to identify pts whose disease is driven in part by a pro-tumoral immune response. Methods: AB12005 was a prospective, placebo (PBO) controlled, double blind, randomized (2:1 MAS:PBO, stratified by disease stage, ECOG and geographic region) phase 3 trial, evaluating oral MAS (6.0 mg/kg/d) in combination with GEM (1000 mg/m²) against PBO plus GEM for the treatment of unresectable locally advanced PC (LAPC) and/or metastatic PC (mPC) pts with pain criteria; i.e. baseline visual analog scale of pain intensity (VAS) > 20 and/or pt treated with an opioid analgesics dose ≥1 mg/kg/d at baseline. Eligible pts were chemo-naïve with histologically or cytologically confirmed inoperable LAPC or mPC and an ECOG status ≤2. The estimated sample size was ̃330 pts to detect an OS hazard ratio (HR) of 0.68 (80% power, 2-sided α = 0.025) after 310 deaths. The study was successful if improvement in median OS (primary endpoint) relative to control reached a 2.5% level of statistical significance for either a targeted subgroup of LAPC with pain criteria, or the overall study cohort. Results: A total of 384 pts were enrolled (safety population n = 383; mITT n = 379; target subgroup n = 92). In the predefined subgroup of unresectable LAPC with pain, MAS-GEM (n = 62) showed significant benefit over PBO-GEM (n = 30) with median OS of 13.0 months (97.5% CI [11.0;18.0]) vs 11.2 months (97.5% CI [7.4;13.0]); p = 0.007. The HR was 0.46 (97.5% CI [0.2;0.9], p = 0.0047), corresponding to a significant 54% reduction in risk of death for MAS-GEM pts relative to control. Secondary analyses in the same subgroup were convergent with this primary outcome. Median PFS showed a 1.8 month between group difference in favor of MAS-GEM (p = 0.039), with a HR of 0.47 (97.5% CI [0.3;0.9], p = 0.014). The 12-month and 18-month OS rates showed a 1.3 fold and 3.4 fold improvement, respectively, in favor of MAS-GEM (53.2% and 33.9% for MAS-GEM vs 40.0% and 10% for PBO-GEM, respectively). In the overall population, comprising LAPC and mPC pts with pain, no survival benefit was observed; median OS for MAS-GEM (n = 244) was 6.9 months vs 8.0 months for PBO-GEM (n = 135); p = 0.461. The MAS-GEM combination was well tolerated with no sign of add-on toxicity. The proportion of patients presenting at least one adverse event (AE) or serious AE was respectively, 96.3% and 19.1% for MAS-GEM (n = 246) vs 99.3% and 21.3% for PBO-GEM (n = 136). Conclusions: The combination MAS (6.0 mg/kg/d) plus GEM may provide a new first line treatment option for unresectable LAPC pts with associated pain. Clinical trial information: NCT03766295.

Genomic biomarker discovery of first-line gemcitabine/nabpaclitaxel treatment in Chinese advanced pancreatic carcinoma patients.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 436-436
Author(s):  
Juan Du ◽  
Qiuyue Pan ◽  
Huizi Sha ◽  
Zhengyun Zou ◽  
Weiwei Kong ◽  
...  
Keyword(s):  
Overall Survival ◽  
Amino Acid ◽  
Pancreatic Carcinoma ◽  
Locally Advanced ◽  
Single Amino Acid ◽  
Current Evidence ◽  
Amino Acid Substitutions ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

436 Background: Pancreatic carcinoma is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Gemcitabine plus Nab-paclitaxel (GNp) has been recommended by international guidelines for first-line treatment of locally advanced or metastatic pancreatic carcinoma. However, exploration into molecular biomarkers of GNp treatment is still limited. This study aims to observe and evaluate the efficacy and safety of first-line GNp treatment of pancreatic carcinoma, and to explore potential predictive and prognostic biomarkers to screen advantageous population. Methods: From December 20, 2018 to July 6, 2020, patients with metastatic pancreatic carcinoma, who received first-line GNp treatment, were enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AE). Patients were collected formalin fixed paraffin embedded (FFPE) samples and sequenced by a next-generation sequencing (NGS)-based 450 gene panel carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In this study, tissue samples from 101 patients were assessed by NGS, including 58 (57.4%) primary tissues and 43 (42.6%) metastasis tissues. So far, 72 patients were available for efficacy analysis, the ORR and DCR were 38.2% and 77.9%, respectively, and were similar between patients sampled from primary lesions and metastasis lesions. The PFS and OS were 176 days and 308 days, respectively. The most frequently mutated genes were KRAS (91.9%), TP53 (76.8%), CDKN2A (32.3%) and SMAD4 (26.3%). Germline pathogenic BRCA2 mutations were detected in 3 (3.0%) patients, while somatic mutations of BRCA2 were found in 2 (2.0%) patients. For KRAS, missense mutations resulted in single amino acid substitutions primarily at G12 (88.1%), and lower frequencies at Q61 (4.0%) and V14 (1.0%). At G12, five different amino acid substitutions have been identified, with G12D (37.6%) the predominant mutation, G12V (32.7%), G12R (11.9%), G12C (3.0%) and G12A (1.0%). The ORR to AG treatment was significantly higher in TP53-alteration (-alt, 47.1%) than in TP53-wild-type (-WT, 11.1%) subgroups (p=0.01). Median OS times in CDKN2B-alt and CDKN2B-WT patients were 180 days and 323 days (p=0.029), respectively. Conclusions: Current evidence indicates that GNp is a valuable option for the first-line treatment of metastatic pancreatic cancer. TP53 may serve as a novel response-predictive gene for GNp treatment in pancreatic carcinoma. Overall survival was significantly prolonged in CDKN2B-WT patients compared with CDKN2B-alt patients. This study provided insights in identifying patients who might potentially benefit from GNp therapy. Clinical trial information: NCT03768687.

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