Arriaga, Yull

4540 Background: Patients w/ locally advanced or metastatic urothelial carcinoma (UCC) have a poor prognosis. Prior to atezolizumab’s approval, there were no approved treatments (txs) for pts who progressed after chemotherapy. Even w/ immune checkpoint inhibitors, most pts require additional txs. FGFR3 is frequently overexpressed in UCC and 15-20% of pts w/ advanced disease have tumors w/ FGFR3 gene mutations or fusions. B-701 (formerly R3Mab) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. NCT02401542 is a phase (ph) 1b/2 study designed to evaluate the safety and efficacy of B-701 plus docetaxel (D) in advanced UCC pts. Methods: The study has a lead-in (n=20 pts) and a randomized ph (n=201). Eligible pts: Stage IV UCC, relapsed/refractory to 1 or 2 prior chemotherapy regimens not including taxanes with ECOG 0-1. Txs: B-701 at 25 mg/kg q3w (+ loading dose on C1D8) and D at 75 mg/m2 q3w. Efficacy assessed by RECIST 1.1. Primary obj: PFS and safety. Secondary obj: overall response rate (ORR); duration of response (DOR); disease control rate (DCR); overall survival (OS). Exploratory obj: association of FGFR3 status w/ efficacy and AEs. Results: As of 20 Jan 2017, 19 pts enrolled to lead-in ph w/median age 66 yrs, ECOG 1 58%, Hgb <10 gm/dL 5%, liver mets 26% and ≥ 2 prior regimens 63%. 17 evaluable for PFS/ORR. 5 pts w/ FGFR3 mut or TACC3-fus. Gr ≥3 AEs occurring in ≥2 pts: decreased neutrophils (26.3%), neutropenia (10.5%), decreased WBCs (10.5%). 2 pts had D dose reductions and 1 pt discontinued tx due to AE (disseminated intravascular coagulation). Conclusions: Preliminary results show that B-701 combines safely and effectively with D in UCC, with the combination being well tolerated and showing promising ORR and PFS in pts w/ FGFR3 mut/fus. The protocol has been amended to add Cohorts 2 (B-701+D) and 3 (B-701) (n=20 pts/cohort) for pts w/ FGFR3 mut/fus+ tumors only. Clinical trial information: NCT02401542. [Table: see text]

Abstract Background In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization. Methods This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation. Results In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in &lt;1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand–foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3–4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6–2.7). Conclusion In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. Implications for Practice Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.

735 Background: In the phase III CORRECT study, regorafenib significantly improved overall survival and progression-free survival (PFS) vs placebo in patients with treatment-refractory mCRC. CONSIGN (NCT01538680) was a large phase IIIb study that included 2872 patients from 25 countries; it was designed to provide continued access to regorafenib for patients with mCRC who failed standard therapy and to further characterize the safety of regorafenib. In CONSIGN, adverse events (AEs) and PFS were consistent with those reported in phase III studies. We present a retrospective subgroup analysis of patients enrolled in CONSIGN in the USA. Methods: Patients with mCRC who progressed on standard therapies and had an ECOG PS 0─1 received regorafenib 160 mg QD for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity. The primary endpoint was safety. PFS (per investigator) was the only efficacy variable assessed. Results: A total of 364 patients in the USA were assigned to treatment (all evaluable for safety). The median age was 60 years; 38% and 62% had ECOG PS 0 and 1, respectively. KRAS mutation was present in 59%, KRAS wt in 38%; 74% had ≥ 3 prior regimens for metastatic disease. Median duration of treatment was 2.3 months (range: 0–30). Median PFS (95% CI) was 2.3 (2.0–2.6) months (2.1 months KRAS wt; 2.3 months KRAS mutant). NCI-CTCAE v4.0 grade ≥ 3 AEs occurred in 81% of patients and were considered drug-related in 53% (Table). Grade ≥ 3 hepatobiliary disorders occurred in 2%. Grade ≥ 3 treatment-emergent laboratory toxicities included bilirubin (9%), AST (6%), and ALT (3%). Conclusions: In patients from the USA enrolled in CONSIGN, the safety profile of regorafenib was consistent with that of the overall population and the known safety profile of regorafenib in mCRC. Median PFS was in the range of that reported in phase III trials. Clinical trial information: NCT01538680. [Table: see text]