FOCUS4-C: WEE1 inhibition in patients with TP53 and RAS dual mutant first line metastatic colorectal cancer: A randomized phase II trial comparing adavosertib (AZD1775) with active monitoring


Year:

Session type:

Jenny Seligmann1, David Fisher2, Louise Brown2, Janet Graham3, Richard Adams4, Richard Kaplan2, Emma Yates2, Susan Richman1, Philip Quirke1, Rachel Butler5, Michael Braun6, Robert Jones4, Ewan Brown7, Fiona Collinson1, Enric Domingo8, Andrew Blake8, Richard Wilson9, Matt Seymour1, Tim Maughan8
1University of Leeds, 2Medical Research Council (MRC) – Clinical Trials Unit, 3Beatson West of Scotland Cancer Centre, 4Cardiff University, 5North Bristol NHS Trust, 6Other, 7NHS Lothian, 8University of Oxford, 9University of Glasgow

Abstract

Background

Outcomes in RAS mutant mCRC remain poor and patients have limited therapeutic options. Adavosertib is the first small molecule inhibitor of WEE1 kinase and there is interest in its use as monotherapy in tumours with cell cycle checkpoint or DNA replication/repair defects. We hypothesised that the frequent RAS and TP53 mutations seen in CRC would together sensitise tumours to WEE1 inhibition.

Method

Across 88 UK sites, pts with newly diagnosed mCRC were registered into the FOCUS4 Trial programme and tested for TP53 and RAS status. Pts with both mutations who were stable or responding after 16 weeks of chemotherapy, suspended their first line treatment and were randomised 2:1 between Adavosertib or active monitoring (AM). The primary outcome measure was progression-free-survival (PFS). Adjusted Cox regression was used to assess efficacy by intention-to-treat (ITT) analysis.

Results

Between 07/2017 and 03/2020, 718 pts were registered into FOCUS 4; 247 (34.3%) had both TP53 and RAS-mutations. 69 pts were randomised (44 Adavosertib; 25 AM). Starting doses of 250mg or 300mg QD were used in 23 and 21 pts. Adavosertib was associated with a PFS improvement compared with AM (HR = 0.40, p < 0.005). The overall survival analysis was underpowered and showed no statistical differences. Adavosertib was well tolerated; grade 3 toxicities at 300mg were diarrhoea (14%), nausea (5%) and neutropenia (5%). There were no differences in efficacy or toxicity between the doses.
In a pre-specified subgroup analysis, there was evidence of an interaction between primary tumour location (PTL) and treatment on PFS ; HR = 0.24 (95% CI 0.11 – 0.51) in 47 patients with left/rectal PTL versus HR = 1.02 (95% CI 0.41 – 2.56) in 22 patients with right PTL, interaction p = 0.043.


Conclusion

In this phase II randomised trial, Adavosertib demonstrates potential as a well-tolerated therapy for RAS +TP53 mutant mCRC. This activity seems to be greater in patients with left colon/rectal PTL. Further testing is required in this sizable population of unmet need, a broader range of patients and in other lines of therapy.

Impact statement

Wee1 inhibition is a potential therapy for TP53 and RAS mutant metastatic colorectal cancer and warrants further investigation.