NORDIC9: A randomized phase II trial comparing first-line palliative full-dose monotherapy (S-1) with reduced dose-combination therapy (SOx) in older and frail patients with metastatic colorectal cancer (mCRC)

Abstract

Background: Most patients (pts) with mCRC are older than 70 years, but they are underrepresented in clinical trials. NORDIC9 evaluated efficacy of palliative treatment strategies based on S‐1, which has previously demonstrated less toxicity but similar efficacy as 5FU, and here we present initial results. Methods: Older mCRC pts (≤70 years) who were not candidates for full‐dose combination therapy, were randomized to full‐dose monotherapy (Arm A: S‐1 30 mg/m2 po bid d 1‐14 q3w, followed by irinotecan upon progression) or reduced (80%) combination therapy (Arm B: S‐1 20 mg/m2 po bid d 1‐14+ oxaliplatin 100 mg/m2 iv d 1 q3w, followed by S‐1+ irinotecan q3w). Addition of bevacizumab (7.5 mg/kg iv d 1) before randomization was optional. Geriatric screening tools (G‐8, VES‐13, handgrip strength, Timed‐Up‐and‐Go), Charlson Comorbidity Index and quality of life were evaluated at baseline. Blood samples and tumor tissue were prospectively collected. Primary endpoint was PFS. Secondary endpoints were response rate, survival and correlations between screening tools, efficacy and safety. Results: From March 2015 to October 2017, 156 eligible/160 planned pts were randomized. Median age was 78 years (range 70‐88), 51% were male, 34%/47%/19% had performance status 0/1/2. 28% received bevacizumab. Baseline characteristics were well balanced. At cut‐off date (March 1st 2018) 15% continued first‐line treatment and 40% were alive. There was no significant difference in RR (34% vs 40%), but PFS (5.3 vs 6.7 months, p=0.05) and OS (11.5 vs 18.3 months, p=0.08) were longer in arm B. Patients selected for bevacizumab had longer PFS (5.2 vs 8.5 months, p=0.02) and OS (13.4 vs 21.4 months, p=0.13). Treatment was tolerable, but grade 3‐4 diarrhea (11% vs 3%, p=0.04) and fatigue (10% vs 5%, p=0.29) were more frequent in arm A and grade 3‐4 neuropathy (7%) was only seen in arm B. One pt in arm B stopped therapy due to cardiac ischemia. Febrile neutropenia grade 3 was observed in 1 pt in arm B. No hand‐foot‐syndrome was seen. Conclusions: Dose‐reduced combination therapy with S‐1 and oxaliplatin is well‐tolerated in older and frail pts and may be more effective than full‐dose monotherapy.