4126 Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30 th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were < 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]
4117 Background: Patients (pts) with advanced CCA who progressed on or after first line chemotherapy have no approved treatment options. Fibroblast growth factor receptor (FGFR) gene alterations are observed in many tumor types including 14-17% in CCA. Erdafitinib, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown clinical activity against solid tumors with FGFR alterations. Methods: LUC2001 is an open-label, multicenter, Ph2a study in advanced CCA pts with FGFR alterations (FoundationOne), who progressed after ≥ 1 prior treatment. The primary endpoint is objective response rate (ORR; RECIST 1.1). The secondary endpoints are disease control rate (DCR), progression free survival (PFS), duration of response (DOR), safety and pharmacokinetics (PK). Disease is evaluated every 8 weeks until disease progression (PD). Results: As of 3 Dec 2018, 222 CCA pts were molecularly screened; 34 had FGFR alterations, of whom 14 (8 FGFR2 fusion, 3 FGFR2 mutation, 1 FGFR3 fusion, 2 FGFR3 mutation) were dosed 8 mg once daily with up titration option. Median age was 51.5 years. 13/14 and 12/14 pts had prior platinum or gemcitabine based therapy respectively, 7/14 pts got re-treated with platinum or gemcitabine based therapy, and 9/14 pts had ≥2 prior lines of therapy. Median number of treatment cycles was 5.0 (range: 1; 22) and treatment duration was 4.83 (range: 0.5; 20.3) months. In 12 evaluable pts, there were 6 confirmed partial response (PR), 4 stable disease (SD) and 2 PD; ORR (CR+PR) was 6/12 (50.0%), DCR (CR+PR+uCR+uPR+SD) was 10/12 (83.3%); median DOR was 6.83 months (95% CI: 3.65; 12.16); median PFS was 5.59 months (95% CI: 1.87, 13.67). In 10 evaluable FGFR2+ pts, ORR was 6/10 (60.0%); DCR was 10/10(100%); median PFS was 12.35 months (95% CI: 3.15, 19.38). The most common TEAEs ( > 30%) were hyperphosphatemia, dry mouth, stomatitis, and dry skin. 9 pts had ≥ Grade 3 AEs (8 Grade 3,1 Grade 5), of which 7 drug related. TEAE led to treatment 1 discontinuation, 6 dose reductions and 1 death (not drug related). The results of PK and PK/PD relationship were consistent with other erdafitinib studies in different ethnic background pts. Conclusions: Asian advanced CCA pts with FGFR alterations treated with erdafitinib had encouraging efficacy and acceptable safety profile similar to experience in other tumor types and populations. Clinical trial information: NCT02699606.
Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC.This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients.Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018).Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.
Abstract The clinical evidence of applying programmed cell death-ligand 1 (PD-L1) inhibitors in the first-line setting to treat esophageal squamous cell carcinoma (ESCC) remains scarce. In this multicenter, randomized, double-blinded phase 3 trial, a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive sugemalimab (an anti-PD-L1 antibody; 1200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg/m 2 on day 1 plus 5-fluorouracil 800 mg/m 2 /day on days 1-4) every 3 weeks for up to 6 cycles. At the prespecified interim analysis, this study has met its dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival (PFS) was statistically significant with sugemalimab-chemotherapy compared with placebo-chemotherapy (median 6.2 v 5.4 months, hazard ratio [HR] 0.67 [95% confidence interval [CI] 0.54 to 0.82], P =0.0002) as assessed by blinded independent central review (BICR). Overall survival (OS) was also superior with sugemalimab-chemotherapy (median 15.3 v 11.5 months, HR 0.70 [95% CI 0.55 to 0.90], P =0.0076. A significantly higher objective response rate (60.1% v 45.2%) assessed by BICR was observed with sugemalimab-chemotherapy. The incidence of Grade 3 or above treatment-related adverse events (51.3% v 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged PFS and OS in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. This study is registered on ClinicalTrials.gov (NCT04187352).
4045 Background: At the protocol-specified interim analysis of the KEYNOTE-859 study (NCT03675737), first-line pembro + chemo significantly improved OS (HR, 0.78; 95% CI, 0.70-0.87; P<0.0001), PFS (HR, 0.76; 95% CI, 0.67-0.85; P<0.0001), and ORR (51.3% vs 42.0%; P=0.00009) vs placebo (pbo) + chemo in patients (pts) with HER2-negative G/GEJ cancer. We report results after an additional 11 months of follow-up. Methods: Pts with previously untreated locally advanced or metastatic HER2-negative G/GEJ cancer, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and known PD-L1 combined positive score (CPS) were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + investigator’s choice of chemo (5-FU + cisplatin [FP] vs capecitabine + oxaliplatin [CAPOX]). The primary end point was OS. Secondary end points included PFS, ORR, and DOR, all per RECIST v1.1 by BICR, and safety. The data cutoff was August 22, 2023. Results: The intention-to-treat (ITT) population comprised 1579 pts (pembro + chemo, n=790; pbo + chemo, n=789). Median follow-up from randomization to data cutoff was 41.6 mo (range, 33.6-48.9). In the ITT population, median OS was 12.9 mo (95% CI, 11.9-14.0) for pembro + chemo vs 11.5 mo (95% CI, 10.6-12.1) for pbo + chemo (HR, 0.79; 95% CI, 0.71-0.88), median PFS was 6.9 mo (95% CI, 6.3-7.2) vs 5.6 mo (95% CI, 5.5-5.7; HR, 0.76 [95% CI, 0.68-0.85]), ORR was 51.0% vs 42.0%, and median DOR was 8.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥1 (pembro + chemo, n=618; pbo + chemo, n=617), median OS was 13.0 mo (95% CI, 11.6-14.2) vs 11.4 mo (95% CI, 10.5-12.0; HR, 0.75 [95% CI, 0.66-0.85]), median PFS was 6.9 mo (95% CI, 6.0-7.2) vs 5.6 mo (95% CI, 5.4-5.7; HR, 0.73 [95% CI, 0.64-0.83]), ORR was 51.8% vs 42.6%, and median DOR was 8.3 mo (range, 1.2+ to 52.6+) vs 5.6 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥10 (pembro + chemo, n=280; pbo + chemo, n=273), median OS was 15.8 mo (95% CI, 14.0-19.3) vs 11.8 mo (95% CI, 10.3-12.7; HR, 0.64 [95% CI, 0.53-0.78]), median PFS was 7.8 mo (95% CI, 6.8-8.5) vs 5.6 mo (95% CI, 5.4-6.7; HR, 0.63 [95% CI, 0.51-0.77]), ORR was 60.0% vs 43.2%, and median DOR was 10.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.4+ to 41.0+). Among all treated pts, treatment-related AEs were reported in 751 (95.7%; grade 3-5, 466 [59.4%]) for pembro + chemo and 736 (93.5%; grade 3-5, 404 [51.3%]) for pbo + chemo. Conclusions: With a median follow-up of 41.6 months, use of pembro + chemo continued to show improved OS, PFS, and ORR vs pbo + chemo, regardless of PD-L1 expression. These results continue to support pembro + chemo as a first-line treatment option for pts with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. Clinical trial information: NCT03675737 .
95 Background: The treatment option for ESCC patients (pts) progressing after chemotherapy is still uncertain. Anlotinib is a multi-target tyrosine kinase inhibitor involved in tumor angiogenesis and growth, such as vascular endothelia growth factor receptor (VEGFR) 2/3, etc. Methods: Eligible pts were advanced ESCC who had progressed after platinum or taxane containing chemotherapy. Between January 6, 2016 and May 22, 2018, a total of 165 pts from 13 centers in China were randomly assigned (in a 2:1 ratio) to anlotinib arm (n=110), and placebo arm (n=55). Pts were given anlotinib (12 mg/day) or placebo orally from day 1 to day 14 in a 21-day cycle until disease progression or had unacceptable toxic effects. The primary end point was progression-free survival (PFS). Results: Median PFS was 3.0 months with anlotinib and 1.4 months with placebo (HR 0.5, 95% CI, 0.3-0.7; P<0.0001). Complete response occured in 2 pts with anlotinib and 0 pt with placebo. The objective response rates were 7% in the anlotinib group and 4% in the placebo group (P=0.498), and the disease control rates (DCR) were 64% and 18%, respectively (P<0.0001). In anlotinib arm, median duration of response was 5.8 months (range, 3.1-19.7+). Grade 3/4 treatment-related adverse events (TRAE) were reported in 36.7% and 11.0% of the two group pts, and grade 5 TRAE were 2.8% and 0%, respectively. The most common grade 3/4 TRAE (>5%) in anlotinib arm were hypertension (15.6%) and loss of appetite (5.5%). Median overall survival were similar between the groups (6.1 months vs 7.2 months; HR 1.2, 95%CI 0.8-1.8, P=0.4261). The ratio of pts received post study treatments was 41.2% (40/97) in anlotinib arm and 72.7% (40/55) in placebo arm (P=0.0002), including chemotherapy (23.7% vs 54.6%), PD-1 inhibitors (4.1% vs 11.0%), and Apatinib, a VEGFR inhibitor, (10.3% vs 20.0%), etc. Conclusions: In pretreated advanced ESCC pts, anlotinib significantly improved PFS and DCR compared with placebo, with a manageable safety profile. Clinical trial information: NCT02649361.
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