IGNITE: A phase II signal-seeking trial of adavosertib targeting recurrent high-grade, serous ovarian cancer with cyclin E1 overexpression with and without gene amplification.

Abstract

5515 Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score>50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]

Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification

“…Our results support the hypothesis that WEE1 kinase inhibition might be most active against cells that lose G1/S cell-cycle checkpoint control; these results are supported by the results of a randomized phase II study comparing adavosertib and gemcitabine with placebo and gemcitabine in patients with recurrent platinum-resistant or platinum-refractory ovarian cancer 27 ; a phase I trial of adavosertib in advanced solid tumors that demonstrated baseline cyclin E1 overexpression in two responding patients and in none of the three nonresponding patients 31 ; and a recently reported phase II study of adavosertib that showed 6% CR (n = 2) and 44% PR (n = 14) in the initial 32 patients with cyclin E1 overexpression and nonamplified CCNE1 patients with platinum-resistant high-grade serous ovarian cancer overexpressing cyclin E1 protein detected by immunohistochemistry (H-score > 50) without ≥ eight copies of CCNE1 by fluorescent in situ hybridization. 37…”

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancer

“…In the current study, we were unable to examine whether protein overexpression of BLM or cyclin E1 in clinical samples, in addition to mRNA up-regulation, correlates with clinical benefit to CHK1i because of the paucity of fresh core biopsy samples. This should be further investigated in the BRCA -mutant HGSC setting because cyclin E1 protein overexpression by immunohistochemistry staining has been associated with a higher ORR in platinum-resistant HGSC to the WEE1 inhibitor adavosertib ( 57 ). We contend that patients with high mRNA expression of replication stress along with replication fork-related biomarkers should be considered for CHK1i-based therapy.…”

CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

“…Through phosphorylation of the CDK1/CCNB complex, Wee1 kinase is an inhibitor of the G2/M transition, which is more critical for HGSC with deficient G1/S transitions. Notably, in a recent phase 2 trial, adavosertib has also shown promising response rates in CCNE1 overexpressing recurrent HGSC regardless of amplification status 39 . Alternatively, using a CRISPR–Cas9‐screen, PKMYT1 , which encodes a protein kinase also involved in G2/M transition, was identified as a synthetic lethal target for CCNE1 high‐expressing cells, which were sensitive to inhibition by a selective PKMYT1 inhibitor 40 .…”

“…Notably, in a recent phase 2 trial, adavosertib has also shown promising response rates in CCNE1 overexpressing recurrent HGSC regardless of amplification status. 39 Alternatively, using a CRISPR–Cas9‐screen, PKMYT1 , which encodes a protein kinase also involved in G2/M transition, was identified as a synthetic lethal target for CCNE1 high‐expressing cells, which were sensitive to inhibition by a selective PKMYT1 inhibitor. 40 This suggests that perhaps both CCNE1 expression and amplification status should be assessed when testing CCNE1 as predictive marker for new molecular therapy.…”