Inhibition of WEE1 is effective in TP53 and RAS mutant metastatic colorectal cancer (mCRC): A randomised phase II trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring

Abstract

Background Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small molecule inhibitor of WEE1 kinase. We hypothesised that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitise tumours to WEE1 inhibition. Methods Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomised 2:1 between Adavosertib or active monitoring (AM). The primary outcome was progression-free-survival (PFS). Results Between Jul 2017 and Mar 2020 718 patients were registered into FOCUS4; 247 (34%) were RAS/TP53-mutant. 69 patients were randomised from 25 UK hospitals (44 to Adavosertib; 25 to AM) and recruitment terminated early due to COVID-19 and following DMEC review of efficacy data. Adavosertib was associated with a PFS improvement over AM (median 3.61 vs 1.87 months; HR=0.35[95% CI 0.18-0.68], p=0.0022). In pre-specified subgroup analysis, Adavosertib activity was greater in left-sided tumours HR=0.24 [95% CI 0.11�0.51], versus right-sided HR=1.02 [95% CI 0.41�2.56] (interaction p=0.043). Adavosertib activity was limited to tumours with KRAS12/13 mutations, rather than mutations in extended KRAS or NRAS (interaction p=0.01). Overall survival (OS) was not improved with Adavosertib vs AM (median 14.0 vs 12.8 months; HR=0.92[95%CI 0.44-1.94], p=0.93); however in left-sided tumours, median OS was 14.1 vs 11.3 months (HR=0.37 [95%CI 0.15-0.87]) and 6.5 vs 15.5 months in right-sided (HR=2.15 [95%CI 0.72-6.43], interaction p=0.0047). Adavosertib was well tolerated; grade 3 toxicities were diarrhoea (9%), nausea (5%) and neutropenia (7%). Conclusions In this phase II randomised trial, Adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Activity was greater in patients with left-sided tumours, with potential impact on OS. Further testing is required in this sizable population of unmet need.