Anderson, Daniel M.

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.

Key Points Ibrutinib has modest activity in FL with low response rates in rituximab-refractory patients. CARD11 mutations predict for lack of response to ibrutinib.

Erythropoiesis‐stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients with cancer chemotherapy‐associated anemia (CAA). Extended‐interval ESA dosing (administration less than once weekly) is common with DA, but previous studies suggested that EA might also be administered less often than weekly. In this multicenter prospective trial, 239 CAA patients with Hb <10.5 g/dL were randomized to receive EA 40,000 U subcutaneously once weekly (“40K” arm), EA 80,000 U every 3 weeks (“80K”), EA 120,000 U every 3 weeks (“120K” arm), or DA 500 mcg every 3 weeks (“DA”), for 15 weeks. The primary endpoint was the proportion of patients achieving Hb ≥ 11.5 g/dL or increment of Hb > 2.0 g/dL from baseline without transfusion. Secondary endpoints included transfusion requirements, adverse events (AEs), and patient‐reported outcomes (PROs). There were no significant differences between treatment arms in the proportion of patients achieving Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; P > 0.41 for all comparisons) or requiring RBC transfusion, but the median Hb increment from baseline was higher in the 40K and DA arms compared to the two extended dosing EA arms, and Hb response was achieved soonest in the weekly EA arm. There were no differences in PROs or AEs. The FDA‐approved schedules tested—weekly EA 40,000 U, and every 3 week DA 500 mcg—are reasonable standards for CAA therapy. Am. J. Hematol. 90:877–881, 2015. © 2015 Wiley Periodicals, Inc.