160 Background: Bemarituzumab (bema), a first-in-class humanized IgG1 monoclonal antibody, selectively binds to FGFR2b, inhibits ligand binding and mediates antibody-dependent cell-mediated cytotoxicity. A phase 1 study of bema monotherapy in solid tumors had no dose-limiting toxicities and a confirmed objective response rate (ORR) of 18% in patients (pts) with refractory FGFR2b+ gastric cancer (GC). Methods: The FIGHT study (NCT03343301) is a global, randomized, double-blind, placebo-controlled phase 2 trial. Pts with unresectable locally advanced or metastatic GC that was not HER2+ were eligible if their tumor was positive for FGFR2b overexpression by centrally performed immunohistochemistry (IHC) or for FGFR2 amplification by circulating tumor DNA (ctDNA). Pts were treated with mFOLFOX6 and randomized 1:1 to bema 15mg/kg or placebo (pbo) every 2 weeks with 1 additional 7.5mg/kg bema/pbo dose on day 8. Treatment was continued until disease progression, intolerable toxicity, or death. The primary endpoint was investigator-assessed progression-free survival (PFS) and key secondary endpoints include overall survival (OS), overall response rate (ORR), and frequency of adverse events. Statistical significance (2-sided a of 0.2) was tested sequentially for PFS, OS and ORR. Results: Of 910 1L GC pts whose tumors were evaluated 275 (30%) were FGFR2b+. Of 155 pts randomized, 77 to bema+mFOLFOX6 and 78 to pbo+mFOLFOX6, 149 were FGFR2b+ by IHC and 26 by ctDNA. The primary endpoint was met with an improvement in median PFS of 9.5 mo (bema) vs 7.4 mo (pbo) (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.44-1.04; p=0.07). The secondary endpoint of OS was met; median not reached in the bema arm vs 12.9 mo for pbo (HR, 0.58, 95% CI, 0.35-0.95; p=0.03). Among patients with measurable disease, ORR improved from 40% (pbo) to 53% (bema). Improved efficacy was observed across all 3 endpoints (PFS, OS, ORR) with increasing levels of overexpression of FGFR2b on tumor cells. Grade ≥3 AEs were reported in 83% of pts in the bema arm vs 74% pts in the pbo arm with serious AEs in 32% and 36% respectively. Stomatitis was higher in the bema arm (31.6% vs 13.0%) and corneal AEs were more common in the bema arm (67% vs 10%). There were no reported AEs of retinal detachment or hyperphosphatemia in the bema arm. Conclusion: Approximately 30% of 1L pts with advanced GC not HER2+, were identified to be FGFR2b+, primarily by IHC. In this randomized, placebo controlled, double-blind phase 2 study, the addition of bema to mFOLFOX6 led to clinically meaningful and statistically significant improvements in PFS, OS and ORR. An increase in corneal AEs and stomatitis was associated with bema. These results support a prospective randomized phase 3 study in GC and the evaluation of bema in other FGFR2b+ tumor types. Clinical trial information: NCT03694522.

Lessons Learned. The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.Background.Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase‐like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.Methods.Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second‐line 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.Results.In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow‐up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.Conclusion.The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC.

No abstract

Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer.

4010 Background: Bema is a first-in-class humanized IgG1 monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b). Results from the FIGHT study showed an improvement in progression-free survival (PFS), overall survival (OS), and overall response rate with the addition of bema to mFOLFOX6 in FGFR2b+, non HER2+ GC. This report provides updated analyses of patient (pt) subgroups, additional data on ocular adverse events (AEs), and the median OS result for the bema+mFOLFOX6 combination. Methods: Pts were treated with mFOLFOX6 and randomized 1:1 to bema (15 mg/kg) or placebo (pbo) every 2 weeks (wks) with an additional 7.5 mg/kg bema/pbo dose on cycle 1 day 8. Eligible pts had unresectable locally advanced or metastatic GC not known to be HER2+, and had FGFR2b overexpression (any 2+/3+ staining) by centrally performed immunohistochemistry (IHC+) or FGFR2 amplification by circulating tumor DNA (ctDNA+). Results: Of the 155 pts who were randomized, 149 (96%) were FGFR2b+ by IHC, 26 (17%) by ctDNA, and 20 (13%) by both. 96 pts (62%) had tumors with FGFR2b IHC 2+/3+ in ≥10% of tumor cells. The proportion of pts with ctDNA+ or with ≥5% or ≥10% tumor cells FGFR2b+ by IHC was similar across geographic regions. Bema showed a benefit vs pbo across pre-specified subgroups including age, gender, geographic region, and prior adjuvant therapy. Patients with FGFR2b overexpression irrespective of ctDNA gene amplification benefited from bema: IHC+/ctDNA- PFS hazard ratio (HR) 0.63 (95% CI 0.4, 0.99), OS HR 0.66 (95% CI 0.39, 1.12); IHC+/ctDNA+ PFS HR 0.15 (95% CI 0.02, 1.18), OS HR 0.10 (95% CI 0.01, 0.83). Frequency and severity of ocular AEs were similar for the overall enrolled population and for pts with ≥5% or ≥10% FGFR2b+ by IHC. Corneal AEs in the bema arm increased in frequency and severity over time; 10.5% (0% G3) wk 1-8 vs 44.1% (15.3% G3) wk ≥25. Following discontinuation of study treatment, subsequent anti-cancer therapy was balanced in the 2 arms (bema 53%; pbo 49%). With a median follow-up of 12.5 months (mo), the bema arm had a median OS of 19.2 mo (95%CI: 13.6, not reached) vs 13.5 mo (95%CI: 9.3, 15.9) for placebo (HR:0.60 95%CI: 0.38, 0.94) for the intent-to-treat population; for the subset of pts with ≥10% FGFR2b+ by IHC, the median OS for bema was 25.4 mo (95%CI: 13.8, not reached) vs 11.1 mo (95% CI: 8.4, 13.8) for placebo (HR: 0.41 95%CI: 0.23, 0.74). Conclusions: The addition of bema to mFOLFOX6 improved the OS of 1L FGFR2b+ GC pts vs mFOLFOX6 alone. Outcomes favored bema across pre-specified subgroups. Pts with overexpression of FGFR2b even without ctDNA amplification demonstrated a benefit from the addition of bema to mFOLFOX6, supporting further evaluation of bema in tumors with FGFR2b overexpression without the requirement for gene amplification. Clinical trial information: NCT03694522.