The novel WEE1 inhibitor adavosertib, given after induction chemotherapy, yielded a 65% reduction in the risk of disease progression or death compared with active monitoring in patients with metastatic colorectal cancer and TP53/RAS mutations, according to the randomized phase II FOCUS4-C trial. These results were presented during the European Society for Medical Oncology (ESMO) Congress 20211 and simultaneously published in the Journal of Clinical Oncology.2
Treatment with adavosertib nearly doubled the median progression-free survival: 4 months vs 2 months with active monitoring (hazard ratio [HR] = 0.35; P = .0022), meeting the study’s primary endpoint, reported Jenny F. Seligmann, MBChB, MRCP, PhD, who is a consultant medical oncologist at the University of Leeds in the United Kingdom.
“We believe that future clinical development of adavosertib in metastatic colorectal cancer is warranted.”— Jenny F. Seligmann, MBChB, MRCP, PhD
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“We have demonstrated efficacy for adavosertib vs active monitoring, but it’s too early to promote adavosertib in this setting,” Dr. Seligmann acknowledged. “The RAS/TP53-mutant biomarker group is a sizable population [about one-third of patients with metastatic colorectal cancer] with a moderately poor prognosis and limited treatment options. For these reasons, we believe that future clinical development of adavosertib in metastatic colorectal cancer is warranted.”
Adavosertib is an oral and highly selective small-molecule inhibitor of the tyrosine kinase WEE1, which has a central role in cell-cycle progression, genomic stability, and other malignant processes. Inhibition of WEE1 can lead to a shortage of deoxyribonucleotide metabolites (dNTP), DNA replication stress, cumulative DNA damage, and unscheduled and inappropriate mitotic entry. The effects of inhibiting WEE1 appear to be greatest for tumors harboring TP53 and RAS mutations. These mutations can create vulnerability in the tumor’s dNTP pathway in ways that can be targeted by adavosertib—ultimately leading to cell death.
FOCUS4 is a molecularly stratified trial program with biomarker-driven cohorts of patients with metastatic colorectal cancer who are treated with molecularly targeted novel therapies. Patients are enrolled before or during first-line chemotherapy and before tumor tissue was molecularly profiled. They become eligible for randomization if they achieve response or stable disease after 16 weeks of first-line chemotherapy. Randomization choice is guided by the patient’s molecular profile.
The trial encompasses cohorts of BRAF-mutant (cohort A), PIK3CA-mutant (cohort B), and RAS- plus TP53-mutant (cohort C) cancers; all wild-type tumors (cohort D); and nonstratified tumors (cohort N). The current report focused on cohort C, of whom more than 50% responded to front-line chemotherapy with one of four standard regimens (more than half received FOLFOX [fluorouracil, leucovorin, oxaliplatin] or CAPOX [capecitabine, oxaliplatin]).
The primary endpoint of the trial was progression-free survival after randomization to the experimental or control arm. Stratification factors included primary tumor location, performance status, baseline disease assessment, number of metastatic sites, and type of front-line therapy.
Findings in Patients With RAS/TP53 Mutations
In cohort C, 69 patients with both RAS and TP53 mutations and a good performance status were randomly assigned 2:1 to receive oral adavosertib (n = 44) at a dose of 250 mg or 300 mg on days 1 to 5 and 8 to 12 every 21 days or undergo active monitoring (n = 25). Patients in both arms restarted front-line chemotherapy upon disease progression or unacceptable toxicity from the experimental regimen.
Treatment with adavosertib from the point of randomization led to a median progression-free survival of 4 vs 2 months with active monitoring (HR = 0.35; P = .0022). Benefit with adavosertib was observed across prespecified subgroups, with the most statistically significant difference observed according to the site of the primary tumor. “We can see a marked adavosertib effect in left-sided tumors (HR = 0.24; interaction P = .043), but no difference between the arms for patients with right-sided tumors (HR = 1.02). In the patients with left-sided tumors, we are also observing a statistically significant difference in overall survival,” she said. “Although these results are provocative, we consider them exploratory. Ongoing investigational work is exploring possible mechanistic explanations.”
Median overall survival was 13.1 months with adavosertib and 11.3 months with active monitoring, which was not statistically significant (HR = 0.86; P = .65); these data are immature, and cohort C was not powered to detect a difference. There was one partial response to adavosertib and no responses in the monitoring arm.
From biomarker and outcome data in the main FOCUS1 trial, the investigators also found the double-mutated group to be prognostically distinct from either mutation in isolation: the hazard ratio for death for the RAS/TP53-mutated group vs the RAS/TP53 wild-type reference population was 2.06 (P = .028); vs the RAS-mutant population, the double-mutated group had a “moderately poor prognosis,” she reported.
Adavosertib was reported to be well tolerated, with mainly grade 1 or 2 toxicities. The most common grade 3 event was fatigue, seen in 14% of patients at the higher dose and in 9% at the lower dose. Also, at the 300-mg dose, grade 2 diarrhea was observed in 14% and nausea was seen in 5%.
DISCLOSURE: Dr. Seligmann disclosed financial relationships with Roche Diagnostics, Pierre Fabre Medicament, Merck Serono, Servier, Bristol Myers Squibb, and GI Connect.
1. Seligmann JF, Fisher DJ, Brown LC, et al: Inhibition of WEE1 is effective in TP53 and RAS mutant metastatic colorectal cancer: A randomised phase II trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring. ESMO Congress 2021. Abstract 382O. Presented September 18, 2021.
2. Seligmann JF, Fisher DJ, Brown LC, et al: Inhibition of WEE1 is effective in TP53- and RAS-mutant metastatic colorectal cancer: A randomized trial (FOCUS4-C) comparing adavosertib (AZD1775) with active monitoring. J Clin Oncol. September 18, 2021 (early release online).
Pierre Laurent-Puig, MD
The invited discussant of the FOCUS4-C trial was Pierre Laurent-Puig, MD, Professor of Medicine, Université de Paris, Institut du Cancer Paris CARPEM. According to Dr. Laurent-Puig, the “promising results” for the WEE1 inhibitor adavosertib in colorectal cancer in the...