Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring —Seligmann 2021
RAS-mutant metastatic colorectal cancer (mCRC ) has poor outcomes and limited therapy choices Adavosertib is an inhibitor of WEE1 kinase and it was expected that mCRC with RAS and TP53 mutations would be sensitive to WEE1 inhibition. Patients with mCRC were examined for TP53 and RAS mutations in FOCUS4. After 16 weeks of chemotherapy, patients with both mutations who were stable or responding were assigned randomly Adavosertib or active monitoring (AM). Adavosertib was administered orally on days 1-5 and 8-12 of a 3-week cycle. PFS was the primary endpoint, with a target HR of 0.5 and 80% power at a one-sided 0.025 significance level. The randomized trial FOCUS4-C enrolled 718 patients between April 2017 and March 2020; 247 (34%) were RAS/TP53-mutant. 69 patients from 25 UK hospitals (44 adavosertib, 25 AM) were randomly assigned. Adavosertib improved PFS over AM (median 3.61 versus 1.87 months; HR = 0.35; CI, 0.18 to 0.68; P =.0022). Adavosertib did not enhance overall survival (median 14.0 versus 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P =.93). Adavosertib activity was stronger in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51) than right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P =.043). Adavosertib was well-tolerated; diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION: Adavosertib enhanced PFS compared with AM and may be a well-tolerated treatment for RAS/TP53-mutant mCRC. This unmet demand group needs more testing.
Seligmann, J. F., Fisher, D. J., Brown, L. C., Adams, R. A., Graham, J., Quirke, P., Richman, S. D., Butler, R., Domingo, E., Blake, A., Yates, E., Braun, M., Collinson, F., Jones, R., Brown, E., de Winton, E., Humphrey, T. C., Parmar, M., Kaplan, R., … Maughan, T. S. (2021). Inhibition of Wee1 is effective in tp53- and ras-mutant metastatic colorectal cancer: A randomized trial (FOCUS4-C) comparing Adavosertib (AZD1775) with active monitoring. Journal of Clinical Oncology, 39(33), 3705–3715. https://doi.org/10.1200/jco.21.01435
