Adavosertib is a first-in-class small molecule inhibitor of the WEE1 kinase. In the randomised, phase II FOCUS-4C study, this drug improved the progression-free survival compared to active monitoring in patients with RAS/TP53-mutant metastatic colorectal cancer (mCRC). The advantage of adavosertib was found to be most pronounced in patients with left-sided tumours.
Agents targeting the DNA damage repair (DDR) pathway have been successfully used as monotherapy in tumours with alterations in the DDR pathway, causing synthetic lethality. WEE1 is a nuclear kinase with a central role in cell cycle progression and genomic stability and is a key regulator of the G2/M and intra-S checkpoint. Inhibition of WEE1 causes dNTP shortage and DNA replication stress, with cumulative DNA damage and unscheduled and inappropriate mitotic entry. Adavosertib is an orally, highly selective small molecule inhibitor of the WEE1 kinase that is now being tested in RAS/TP53 mutant metastatic colorectal cancer (mCRC). As RAS/TP53-mutant tumours will have G1/S checkpoint failure and reliance on intra-S and G2/M checkpoints, as well as replication stress during the S-phase, WEE1 inhibition with adavosertib will lead to synthetic lethality with failure of checkpoint control and dNTP shortage adding further to DNA replication stress.
FOCUS4 is a molecularly stratified trial programme in metastatic colorectal cancer with the aim of testing novel agents in hypothesis-led biomarker groups. Patients were registered before or during first-line chemotherapy and their tumours were sent to the trial laboratories for molecular profiling using an NGS platform. Those mCRC patients with both TP53 and RAS mutations who were stable or responding after 16 weeks of chemotherapy were enrolled in FOCUS-4C and were randomised (2:1) between adavosertib (250 or 300 mg on days 1-5 and 8-12 of each 21-day cycle) or active monitoring (AM). Upon progression or toxicity, first-line chemotherapy was restarted. The primary endpoint of the study was progression-free survival (PFS).
Between July 2017 and March 2020, 247 mCRC patients with both RAS and TP53 mutations were registered. Of them, 69 patients were randomised in FOCUS-4C: 25 patients in the AM arm and 44 patients in the adavosertib arm. The vast majority of patients received chemotherapy doublets and just over half of patients had a response to treatment. Due to the small size of the trial, there are some minor imbalances between the trial arms, which are corrected for in the analysis as per the primary model.
Adavosertib was associated with a PFS advantage, with a median PFS of 3.61 months compared to 1.87 months with active monitoring, translating into a statistically significant hazard ratio of 0.35 (p= 0.0022). As such, FOCUS-4C met its primary endpoint. In a pre-specified subgroup analysis, adavosertib activity was found to be significantly greater (interaction p= 0.043) in patients with left-sided (HR[95%CI]: 0.24[0.11–0.51]) than in right-sided tumours (HR[95%CI]:1.02[0.41–2.56]). Overall survival (OS) was not improved with adavosertib vs. AM (median 13.1 vs. 11.3 months; HR[95%CI]: 0.86[0.46-1.62], p= 0.65). Adavosertib was well tolerated with mainly grade 1-2 toxicities. The most common grade 3 toxicities were diarrhoea (14%), nausea (5%) and fatigue (14%), which were more common in patients treated at the 300 mg dose.
FOCUS-4C met its primary endpoint and reported improved PFS with adavosertib vs. active monitoring in RAS/TP53-mutant mCRC, following induction therapy. Adavosertib was well tolerated and its activity was most marked in patients with left primary tumour location. The RAS/TP53-mutant biomarker group is a sizable population with a moderately poor prognosis. Future clinical development of adavosertib in mCRC is warranted.
Seligmann JF, Fisher D, Brown L, et al. 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. Presented at ESMO 2021; Abstract 382O.