Adavosertib Elicits Efficacy in RAS/TP53+ mCRC With Potential Additive Benefit in Left-Sided Tumors

Pipeline Report | <b>Pipeline Report: December 2021</b>

The WEE1 inhibitor adavosertib improved progression-free survival with a tolerable safety profile compared with active monitoring in patients with RAS/TP53-mutated metastatic colorectal cancer.

The WEE1 inhibitor adavosertib improved progression-free survival (PFS) with a tolerable safety profile compared with active monitoring in patients with RAS/TP53-mutated metastatic colorectal cancer (mCRC), according to findings from the phase 2 FOCUS4-C trial that were published in the Journal of Clinical Oncology.

The median PFS in the per-protocol analysis (PPA) population (n = 64) was 3.61 months with adavosertib (n = 40) vs 1.87 months with active monitoring (n = 24; HR, 0.35; 95% CI, 0.18-0.68; P = .0022). In the intention-to-treat (ITT) population (n = 69), the PFS benefit with adavosertib (n = 44) vs active monitoring (n = 25) was reflected in unadjusted (HR, 0.55; 95% CI, 0.32-0.94; P = .032) and adjusted (HR, 0.40; 95% CI, 0.21-0.75; P = .0051) analyses.

Moreover, findings from prespecified subgroup analyses showed that the activity of adavosertib was greater in patients with left-sided tumors (HR, 0.24; 95% CI, 0.11-0.51) vs right-sided tumors (HR, 1.02; 95% CI, 0.41-2.56; P = .043).

WEE1 is a nuclear tyrosine kinase that plays a critical role in cell cycle regulation. It is also the key regulator of the G2/M checkpoint through actions on CDK1.

“Inhibition of WEE1 causes unscheduled entry into mitosis, aberrant firing of replication origins leading to dithiobis 5-nitropyridine shortage and replication stress, and accumulation of DNA damage during S phase, leading to increased reliance on the G1/S checkpoint,” wrote the study authors.

Adavosertib is the first developed small molecule WEE1 inhibitor. The agent has been tested in combination with chemotherapy and radiation therapy. Additionally, data have shown that single-agent adavosertib generates synthetic lethality in tumors harboring DNA damage repair defects.

As such, inhibiting WEE1 with adavosertib was hypothesized to yield efficacy in patients with RAS- and TP53-mutant mCRC, which, mechanistically, could be highly sensitive to the agent.

The FOCUS4-C program utilized an adaptative, molecularly stratified, umbrella platform trial to evaluate the safety and efficacy of novel treatments, including adavosertib, in targeted biomarker-based subgroups of patients.

Patients over the age of 18 years with newly diagnosed mCRC were eligible for enrollment on the FOCUS4-C trial while undergoing induction chemotherapy. Patients were enrolled from 88 United Kingdom–based hospitals. All patients underwent tumor testing with next-generation sequencing to inform stratification into molecular subtypes, including BRAF-, PIK3CA-, TP53-, and RAS-positive disease.

From April 11, 2017, to March 18, 2021, 817 patients were accrued to the study. Of these patients, 34% (n = 247) harbored confirmed RAS and TP53 mutations.

In the ITT population, the mean age was 59.2 years (standard deviation [SD], 12.8) in patients who received adavosertib and 61.9 years (SD, 12.2) in patients who received active monitoring. Across arms, most patients were male and had a WHO performance status of 0.

Primary tumors were mostly located in the rectum. In the adavosertib arm, the state of primary tumors included the resected primary (n = 23; 52%), unresected primary (n = 19; 43%), and unresected local recurrence (n = 2; 5%). In the active monitoring arm, the state of tumors was 36% (n = 9), 64% (n = 16), and 0% (n = 0), respectively.

Additionally, across arms, most patients had synchronous timing of metastases, 2 or more metastatic sites, and a partial response at the end of their first-line treatment. Frontline regimens included FOLFOX, FOLFIRI, CAPOX, FOLFOXIRI, and others.

Nearly all patients in both arms had PIK3CA wild-type status.

Further results of the study did not show a statistically significant overall survival (OS) benefit with adavosertib compared with active monitoring (HR, 0.92; 95% CI, 0.44-1.94; P = .93).

Adavosertib was associated with an improved disease-control rate of 47% compared with 28% with active monitoring at any time during the trial. Moreover, one patient obtained a partial response with adavosertib.

Regarding the subgroup analyses, the median OS was 14.1 months with adavosertib vs 11.3 months with active monitoring in patients with left-sided tumors (HR, 0.37; 95% CI, 0.15-0.87). The median OS was 6.5 months vs 15.5 months, respectively, in patients with right-sided tumors (HR, 6.5; 95% CI, 0.72-6.43; interaction P = .0032).

Disease stability was reported in 38% of adavosertinib-treated right-sided tumors compared with 42% of actively monitored right-side tumors. For left-sided tumors, disease stability was reported in 53% vs 19% of patients, respectively.

Additionally, patients who derived a response vs stable disease with induction chemotherapy (interaction P = .14) and who had 2 or more metastatic sites (P = .12) appeared to derive additional benefit from adavosertib vs active monitoring.

Another subset analysis demonstrated that patients who harbored RAS and TP53 mutations had worse OS compared with patients who harbored either mutation alone (HR, 2.06; 95% CI, 1.08-3.93; P = .028).

“This suggests that the RAS/TP53-mutant population is a poor-prognosis subgroup but not as marked as for patients with a BRAF mutation or microsatellite instability-high tumor,” the study authors wrote.

Moreover, these findings are consistent with those observed during the registration period of the study where 33% of patients with RAS/TP53-mutant mCRC progressed during the first 16 weeks of induction chemotherapy. This is similar to the rate observed in patients with BRAF-mutant disease (34%) but higher than that observed in RAS-mutant (24%) and all wild-type (22%) subgroups.

Additionally, further findings showed that patients with KRAS codon 12/13 mutations derived significant benefit from adavosertib (interaction P = .014). However, no detectable benefit was observed with the agent in patients with KRAS mutations at other codons or NRAS mutations. A potentially additive benefit between KRAS subtype and primary tumor location on PFS was observed within the subgroup of patients with left-sided, KRAS codon 12/13 disease (HR, 0.16; 95% CI, 0.05-0.50) vs right-sided, non-codon 12/13 subtypes (HR, 1.56; 95% CI, 0.49-4.97).

“The subtype of TP53 mutation or the co-occurrence of PIK3CA mutation did not affect the outcome,” wrote the study authors.

Regarding safety, adavosertib was generally well tolerated among patients allocated to the treatment. Adavosertib compared with active monitoring was associated with increased all-grade toxicities, including diarrhea (61% vs 28%, respectively), fatigue (75% vs 56%, respectively), nausea (68% vs 32%, respectively), and vomiting (41% vs 4%, respectively).

Grade 3 or higher diarrhea, fatigue, nausea, and vomiting were observed in 9%, 11%, 5%, and 2% of patients who received adavosertib, respectively; no grade 3 or higher events were observed with active monitoring.

Increasing the dose of adavosertib from 250 mg to 300 mg caused an increased frequency of grade 3 diarrhea from 4% to 14%, but the safety profile was similar with the increased dose otherwise. Similar rates of dose modifications and delays were observed with the increased dose.

Furthermore, regarding dosing, the median PFS was 2.2 months with the 250-mg dose of adavosertib vs 3.7 months with the 300-mg dose; however, the difference was not deemed statistically significant (P = .48)

“Given this clear demonstration of efficacy in a [randomized controlled trial] and acceptable toxicity profile, future clinical development of adavosertib is warranted particularly as it may represent a future treatment opportunity in this sizable population of unmet need,” the study authors concluded.

Reference

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. 2021;39(33):3705-3715. doi:10.1200/JCO.21.01435