Adavosertib, taken as a daily pill, may delay tumour regrowth among patients with an aggressive sub-type of inoperable metastatic colorectal cancer, found a UK clinical trial, reports MedicalBrief.
The subset of patients who took part in the trial had tumours with two common mutations, RAS and TP53. About a third of colorectal cancer patients have tumours with these two mutations.
The Focus4-C trial looked at whether a drug called adavosertib, taken as a daily pill, could delay tumour regrowth among patients with an aggressive sub-type of inoperable bowel cancer who have limited treatment options.
Researchers compared 44 patients who took adavosertib with 25 patients who did not, and found the drug delayed tumour growth by about two months on average and had relatively few side effects. It had more effect in the 31 patients with left-sided/rectal tumours, increasing overall survival.
Lead author Dr Jenny Seligmann of the University of Leeds said: “These results show promising signs that adavosertib may be effective in delaying regrowth of bowel cancer in some patients and is well tolerated.
In the UK more than 42,000 people are diagnosed with bowel cancer annually. It is the fourth-most common cancer in the UK and the second-biggest cancer killer.
“The findings are particularly encouraging as the subset of patients involved represent a third of all bowel cancer patients and, while other patients have treatments developed specifically for their tumour types, this group currently has very limited treatment options.”
The research suggested adavosertib could benefit patients with other types of bowel cancer or alongside standard treatments in other lines of therapy. However, larger trials were needed to establish whether the drug improved survival compared with standard treatment.
Co-author Prof Louise Brown, from the Clinical Trials Unit at University College London, and statistical lead for the Focus4 trial, said: “The results for the adavosertib arm of the trial are potentially important and represent a glimmer of hope for patients in this group.”
Adavosertib kills cancer cells by inhibiting a protein that helps to regulate the process of cell division in the tumour. Side-effects included fatigue, diarrhoea, neutropenia (involving low levels of white blood cells called neutrophils) and nausea, but none occurred in more than 11% of patients.
A second study from a separate part of the Focus4 trial called Focus4-N, also published in the Journal of Clinical Oncology, looked at outcomes among patients who had a complete break from treatment after chemotherapy. They were compared with outcomes among those who continued chemotherapy using a simpler tablet called capecitabine.
Researchers found that, among those who had a complete break, the cancer started to grow sooner than in those on continued maintenance therapy. But that maintenance therapy did not lead to an increase in how long people lived, the study suggested.
The Focus4 trial is funded by the EME Programme – an MRC/NIHR partnership – and Cancer Research UK and is run from the MRC Clinical Trials Unit at UCL in collaboration with Oxford University, Leeds University and Cardiff University.
Study details
Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomised Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring
Jenny Seligmann, David Fisher, Louise Brown, Richard Adams, Philip Quirke, Timothy Humphrey, Mahesh Parmar, Richard Kaplan, Richard Wilson, Matthew Seymour, Timothy Maughan
Published in Journal of Clinical Oncology on 18 September 2021
Context
Key Objective
To test if adavosertib, which is a small-molecule inhibitor of the WEE1 kinase, is effective as monotherapy in patients with RAS/TP53-mutant metastatic colorectal cancer (mCRC) as maintenance therapy following induction chemotherapy.
Knowledge generated
In this phase II randomised trial, adavosertib was well-tolerated and improved progression-free survival in RAS/TP53-mutant mCRC compared with active monitoring. Treatment effect may be affected by primary tumor location and KRAS subtype, with greater benefit seen in left-sided cancers and those with KRAS codon 12/13 mutations. RAS/TP53 subgroup is a distinct moderately poor prognostic population.
Relevance
Adavosertib is a promising therapeutic agent in patients with RAS/P53-mutant mCRC, a poor prognostic population of unmet need, and was well-tolerated. This study demonstrates the potential of targeting the DNA damage response pathway in mCRC, which should be a research priority. Future studies of adavosertib should stratify patient outcomes according to primary tumor location and RAS subtype.
Abstract
Purpose
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 randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level.
Results
FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumours (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). 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. Further testing is required in this sizeable population of unmet need.
Results from the randomised FOCUS4-N Trial
Study details
Oral maintenance capecitabine versus active monitoring for patients with metastatic colorectal cancer (mCRC) who are stable or responding after 16 weeks of first-line treatment:
Richard Adams, David Fisher, Janet Graham, Jenny F. Seligmann, Matthew Seymour, Richard S. Kaplan, Emma Yates, Susan D Richman, Philip Quirke, Rachel Butler, Ewan Brown, Stephen Falk, Fiona Jane Collinson, Richard H. Wilson, Louise C. Brown, Tim Maughan.
Published in Journal of Clinical Oncology Volume 39 Issue 15
Background
There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy.
Methods
FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. While undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype.
Results
Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms.
Conclusions
Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy.
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