Adavosertib for RAS-/TP53-Mutant Metastatic Colorectal Cancer Reduced Risk of Progression, Death

Adavosertib demonstrated a 65% risk reduction in disease progression and death for patients with TP53-/RAS-mutant metastatic colorectal cancer following first-line chemotherapy.

For patients with TP53-/RAS-mutant metastatic colorectal cancer (mCRC) following first-line chemotherapy, adavosertib resulted in a 65% reduction in the risk of disease progression or death when compared with active monitoring, according to results of the phase 2 FOCUS4-C trial (EUDRACT 2012-005111-12) presented at the 2021 ESMO Congress.1

Findings, which were also published in the Journal of Clinical Oncology,2 showed that the median progression-free survival (PFS) was nearly doubled with adavosertib, at 3.61 months compared with 1.87 months for active monitoring (HR, 0.35; 95% CI, 0.18-0.68; P = .0022), which was statistically significant and met the study’s primary end point. The agent was also found to be well tolerated, lead study author Jenny F. Seligmann, MBChB, MRCP, PhD, explained in a virtual presentation during the meeting.

“FOCUS 4 [cohort C] met its primary end point reporting improved PFS with adavosertib vs active monitoring in RAS-/TP53-mutant mCRC, following induction chemotherapy,” said Seligmann, who is a consultant medical oncologist at the University of Leeds in Leeds, United Kingdom. The RAS-/TP53-mutant biomarker group is a sizeable population with a moderately poor prognosis, and limited treatment options. For these reasons, we believe that future clinical development of adavosertib in metastatic CRC is warranted.”

Agents that target the DNA damage-repair (DDR) pathway have shown success when used as single agents in tumors that harbor alterations in this pathway causing synthetic lethality; this is most notably seen with PARP inhibitors in BRCA-mutant cancers, Seligmann added.

Wee1 has a central role in cell cycle progression and genomic stability; it is also a key regulator of G2/M and intra-S checkpoint. By inhibiting Wee2, dNTP shortage and DNA replication stress occurs, as well as cumulative DNA damage and unscheduled and inappropriate mitotic entry. Additionally, RAS- and TP53-mutant tumors have G1/S checkpoint failure plus reliance on intra-S and G2/M checkpoint; they also have replication stress during the S-phase.

For the phase 2 trial, investigators hypothesized that the oral and highly selective small molecular Wee1 inhibitor adavosertib could lead to synthetic lethality with failure of checkpoint control and dNTP shortage, which would further add to DNA replication stress and, ultimately, cell death.

FOCUS4 is a molecularly stratified trial program with biomarker-driven cohorts enrolling patients with mCRC to receive novel therapies based on their molecular abnormalities. Patients were registered either before or during first-line chemotherapy before tumor tissue was analyzed via next-generation sequencing for molecular profiling.

Patients were eligible for randomization if they had stable disease or responses after 16 weeks of chemotherapy. Randomization choice was guided by patients’ molecular profile.

The trial encompasses cohorts of BRAF-mutant (cohort A), PIK3CA-mutant (cohort B), RAS- plus TP53-mutant (cohort C), all wild-type (cohort D), and non-stratified tumors (cohort N).

In cohort C, patients with mCRC who had both a RAS and TP53 mutation with an ECOG performance status of 0 or 1 were randomized 2:1 to undergo active monitoring (n = 25) or receive oral adavosertib (n = 44) at 250 mg in the first 21 patients or 300 mg in the subsequent 23 patients on days 1 to 5 and 8 to 12 every 21 days. Patients in both arms restarted frontline chemotherapy if disease progression or toxicity occurred.

Recruitment took place from April 2017 to March 2020; however, this was suspended due to COVID-19. Seligmann noted that an Independent Data Monitoring Committee later reviewed the data that were available and concluded that no additional recruitment was needed, and therefore, closed accrual in October 2020.

The primary end point of the trial is PFS; secondary end points include overall survival (OS), toxicity, and tumor response. Stratification factors included primary tumor location, performance status, baseline disease assessment, number of metastatic sites, and type of frontline therapy.

Overall, the median age of participants was 61 years and 65% were male; 67.5% of patients had left-sided tumors as their primary tumor location, and most patients (70%) had at least 2 metastatic sites. Following frontline chemotherapy, 56.2% of patients had achieved a complete or partial response to treatment, which included FOLFOX/CAPOX (55.5%), FOLFIRI (32%), FOLFOXIRI (9.5%), or other (3%).

Additional data showed that the median OS was 13.1 months with adavosertib and 11.3 months with active monitoring, which was not found to be statistically significant (HR, 0.86;95% CI, 0.46-1.62; P = .65). However, Seligmann noted that these data are immature, and that cohort C was not powered to detect a difference in OS.

The PFS benefit with adavosertib was observed across prespecified subgroups, except for patients with right-sided tumors (n = 22; HR, 1.02; 95% CI, 0.41-2.56). In left-sided tumors (n = 47), the PFS difference was statistically significant with adavosertib (HR, 0.24; 95% CI, 0.51), with an interaction P value between the 2 groups of .043.

“Although these results are provocative, we would consider them exploratory and ongoing translational work shall investigate possible mechanistic explanations for these interesting results,” Seligmann said.

Regarding safety, most adverse effects (AEs) reported with adavosertib were grade 1 or 2; a grade 3 or higher AE that occurred in more than 5% of patients on the 200-mg dose was fatigue (9%). On the 300-mg dose, grade 3 or higher AEs (≥5%) included diarrhea (14%), fatigue (14%), and nausea (5%).

References

  1. 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: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 382O.
  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. Published online September 18, 2021. doi:10.1200/JCO.21.01435