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

Abstract

PURPOSE

Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors.

PATIENTS AND METHODS

Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR).

RESULTS

Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue.

CONCLUSION

Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.

INTRODUCTION

Cell cycle progression is orchestrated by the orderly expression of cyclins (regulatory subunits), which sequentially activate the cyclin-dependent kinases (CDKs) that govern the cell division machinery.^1,2 Cyclin E (E1 and E2) is most abundant between G1 phase and S phase. Cyclin E binds to Cdk2 to form a unique configuration that is required for the transition from G1 to S phase of the cell cycle and determines the initiation of DNA duplication.^3,4 Overexpression of cyclin E has been shown to promote genomic instability by causing DNA replication stress and deregulating the G1 to S transition.^4-10

CONTEXT

• Key Objective

• CCNE1 amplification is frequently identified in many types of malignancies, associated with resistance to chemotherapy and short survivals duration. In this phase II trial, we investigated the clinical activity of the WEE1 kinase inhibitor adavosertib in advanced malignancies harboring CCNE1 amplification.

• Knowledge Generated

• Adavosertib demonstrated promising preliminary antitumor activity, with a response rate of 27% in 30 patients with metastatic malignancies harboring CCNE1 amplification. A response rate of 36% was observed in 14 patients with metastatic epithelial ovarian cancer, associated with a median duration of response of 6.3 months.

• Relevance (G.F. Fleming)

• No WEE1 kinase inhibitors are currently US Food and Drug Administration approved, but WEE1 inhibition holds promise as a therapy for patients whose tumors exhibit CCNE1 amplification, particularly women with ovarian cancer.*

  *Relevance section written by JCO Associate Editor Gini F. Fleming, MD.

WEE1 kinase, which arrests cells in G2/M through inhibition of CDK1/2 to block premature mitotic entry, is essential to prevent massive DNA damage and cell death in cyclin E-overexpressed cells,^11-13 which can be reversed by WEE1 kinase inhibition with adavosertib, resulting in mitotic catastrophe and apoptosis induced by unrepaired DNA damage.^13-16 Laboratory studies showed that cyclin E overexpression was predictive of antitumor response to adavosertib,¹⁷ which provided preclinical proof-of-mechanistic evidence to support the use of cyclin E as a potential biomarker of response to adavosertib.¹⁸

CCNE1 is frequently amplified in many human tumors, such as in uterine, ovarian, stomach, esophageal, lung, and pancreatic cancer and sarcoma, with a frequency of 2%-40%.^19,20 We hypothesized that CCNE1 amplification in cancer cells leads to an overexpression of cyclin E1 protein, which sensitizes cancer cells to adavosertib. Therefore, we conducted a multicenter open-label, phase II clinical trial (ClinicalTrials.gov identifier: NCT03253679, NCI 10136) to evaluate the antitumor activity of adavosertib in patients with metastatic solid tumors harboring CCNE1 amplification.

PATIENTS AND METHODS

Patient Selection

This was a single-arm phase II study (NCI 10136) conducted at six different cancer centers in the United States through the National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network. We identified all patients, aged 18 years or older, who had histologically confirmed metastatic solid tumors harboring CCNE1 amplification, for which there was no effective standard-of-care therapy available. CCNE1 amplification was preidentified by a Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory, such as Foundation One, UW-OncoPlex—Cancer Gene Panel, MSK-IMPACT, or Solid Tumor Genomic Assay by Life Technologies. There was no limitation on the number of prior treatment lines, but WEE1 kinase inhibitors were not allowed. Other eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease by RECIST 1.1,²¹ and adequate organ function (absolute neutrophil count of ≥ 1,500/µL, hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/µL, serum creatinine < 1.5 × upper limit of normal [ULN] or creatinine clearance ≥ 45 mL/min, total bilirubin concentration ≤ ULN or ≤ 1.5 × ULN in patients with known hepatic metastases, ALT and AST concentrations ≤ 3 × ULN or ≤ 5 × ULN in patients with known hepatic metastases), recovery to ≤ grade 1 toxicity or baseline from prior cancer therapy, the ability to swallow and absorb oral medications, and willingness and ability to comply with study treatment and follow-up procedures.

This study was reviewed and approved by the NCI Central Institutional Review Board, the six individual site Institutional Review Boards, and the US Food and Drug Administration; it was conducted in accordance with ethical principles per the Declaration of Helsinki. The trial was registered on ClinicalTrials.gov (identifier: NCT03253679).

Treatment Plan

After patients had provided written informed consent, they received oral adavosertib at a starting dose of 300 mg once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. All patients received a 5-hydroxytryptamine-3 antagonist and dexamethasone (unless contraindicated or not well-tolerated) before each dose of adavosertib. Treatment continued until disease progression, unacceptable toxicity, intercurrent illness that prevented further treatment, or patient withdrawal from this study. Dose delay and reduction by 50 mg were allowed, depending on the grade of the adverse event.

Efficacy and Safety Assessments

All patients underwent periodic safety assessments through in-person office visits or telemedicine. Laboratory tests, including CBC and comprehensive metabolic panel, were assessed weekly during cycle one and then once every subsequent cycle, or more frequently, as clinically indicated. Safety and adverse events were assessed and graded according to the NCI Common Terminology Criteria for Adverse Events version 5.0.

Tumor response and progression were evaluated using the revised RECIST guidelines (version 1.1).²¹ The same imaging technique used during the screening, or more sophisticated studies, was performed once every 9 weeks or sooner as clinically indicated. Tumor markers, if applicable, were tested once with each imaging study or more frequently as indicated.

Correlative Biomarker Assays

In all patients, CCNE1 amplification (ie, CCNE1 amplification > 7 on the basis of the targeted custom AmpliSeq panel on the Ion Torrent Personal Genome Machine or CCNE1 amplification on alternate CLIA platforms such as Foundation One, Solid Tumor Genomic Assay by Life Technologies) had been detected by a CLIA-certified Molecular Diagnostic Laboratory, with genomic testing performed as part of their routine care. After informed consent had been obtained, the results of these genomic tests were obtained before therapy began.

Statistical Analyses

The primary objective of this phase II study was to evaluate the objective response rate (ORR) to adavosertib in patients with advanced refractory cancers harboring CCNE1 amplification. Subgroup analysis was not designed in this study. The response was defined as a complete response (CR) or partial response (PR) within 6 months of the start of therapy, per RECIST version 1.1. The duration of response was measured from the date of the initial CR or PR to the first date that recurrent or progressive disease was objectively documented. The trial used a two-stage Bayesian optimal phase II (BOP2) design²² with the null hypothesis of ORR = 5% and the alternative hypothesis of ORR = 20%. In the first stage, 10 patients were enrolled. If one or more responses were observed, this study continued to the second stage of enrolling additional 19 patients. If four or more responses were observed among the total of 29 patients, the null hypothesis would be rejected, concluding that adavosertib was promising. For this trial, the BOP2 design was identical to Simon's two-stage design.²³ The design yielded 80% power, while controlling one-sided type 1 error rate at the level of 5%. There was a 49% chance of stopping after the first stage under the null hypothesis.

Descriptive summary statistics were used to characterize demographics, safety, and antitumor activity. Categorical data were summarized using frequencies, percentages, and 95% exact CIs. Differences in categorical variables were assessed by Fisher's exact tests. Continuous data were summarized by medians with 95% CIs and ranges. Progression-free survival (PFS) and overall survival (OS) durations were estimated using the Kaplan-Meier method in all patients who received at least one dose of the study agent. PFS duration was defined as the time from enrollment to death or disease progression (whichever was first). Patients without evidence of progression or death were censored at the date of the last radiographic assessment of disease progression. OS duration was defined as the time from enrollment to death or September 28, 2021, at which time the patients' data were censored. Log-rank tests were used to compare PFS and OS duration distributions between patients with epithelial ovarian cancer and those with other cancers. Statistical inferences were based on two-sided tests at a significance level of P < .05. Statistical analyses were carried out using SPSS Statistics version 24 (IBM, Armonk, NY).

RESULTS

Patient Characteristics

Between January 10, 2019, and May 5, 2020, 31 patients had signed informed consent for study enrollment at six individual NCI Experimental Therapeutics Clinical Trials Network cancer centers. One patient (No. 25) did not receive any study agent. Thus, 30 patients were considered evaluable; the baseline characteristics are presented in Table 1. Most (87%) were female, and 14 had epithelial ovarian cancer. The patients' median age was 65 years, and the median number of prior systemic therapies was three (range, 1-7).

TABLE 1.

Patient Characteristics

Antitumor Activity

Antitumor activity was assessed in all patients. At the data cutoff date on September 28, 2021, the median follow-up period was 9.9 months. One patient was undergoing active therapy (updated on May 24, 2022), while the remaining 29 were removed from the study for the following reasons: disease progression (n = 22), treatment intolerance (n = 2), death on study due to tumor progression (n = 3), alternative therapy (n = 1), and patient withdrawal 1 week after beginning protocol therapy (n = 1). Twenty-seven patients had sufficient tumor measurement data for tumor response evaluation (Fig 1). Three patients could not be evaluated since they had experienced rapid clinical deterioration before a restaging imaging study could be performed. Figure 2 shows changes in tumor measurements over time. We observed no CR, eight PRs, and three stable diseases (SDs) of ≥ 6 months, leading to an ORR of 27% (n = 8; 95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (n = 11; 95% CI, 20 to 56), a median PFS duration of 4.1 months (95% CI, 1.8 to 6.4), and a median OS duration of 9.9 months (95% CI, 4.8 to 15), as shown in Figure 3. Therefore, the null hypothesis of ORR = 5% was rejected because the number of responses ≥ 4, and the treatment was regarded as promising. Among patients who experienced a PR, the median duration of response was 2.1 months (95% CI, 0.2 to 4), ranging from 1.9 months to 10.3 months.

FIG 1.

A waterfall plot shows best tumor responses in all 30 patients. ^aPatients had overall progressive disease with < 20% increase on target lesions but had new nontarget lesions. ^bPatients had rapid clinical deterioration before a restaging imaging study could be performed, who are documented a 21% tumor increase. ^cOne patient was still on treatment at the last updated date on May 24, 2022.

FIG 2.

A spider plot of tumor measurement changes over time in all 30 patients. ^aPatients had overall PD with < 20% increase on target lesions but had new nontarget lesions. ^bPatients had rapid clinical deterioration before a restaging imaging study could be performed, who are documented a 21% tumor increase. ^cOne patient was still on treatment at the last updated date on May 24, 2022. PD, progressive disease; PR, partial response; SD, stable disease.

FIG 3.

Kaplan-Meier plots show the probabilities of (A) PFS and (B) OS in all 30 patients (blue curve), in 14 patients with epithelial ovarian cancer (red curve), and 16 patients with metastatic malignancies other than epithelial ovarian cancer (teal curve). 95% CI are indicated in parentheses. OS, overall survival; PFS, progression-free survival.

Among 14 patients with epithelial ovarian cancer, five experienced PRs and three had SD ≥ 6 months, leading to an ORR of 36% (n = 5; 95% CI, 13 to 65), a SD ≥ 6 months/PR rate of 57% (n = 8; 95%, 29 to 82), a median PFS duration of 6.3 months (95% CI, 2.4 to 10.2), a median OS duration of 14.9 months (95% CI, 8.9 to 20.9), and a median duration of response of 6.3 months (95% CI, 1.6 to 11). Patients who did not have epithelial ovarian cancer had a median PFS duration, OS duration, and duration of response of 2.6 months (95% CI, 2.3 to 2.9), 5.9 months (95% CI, 4.6 to 7.2), and 2 months (95% CI, 1.9 to 2.1), respectively.

Safety

All 30 patients who had received at least one dose of adavosertib were evaluable for toxicity. Treatment-emergent (TEAE) and treatment-related adverse events are presented in Appendix Figure A1 (online only) and Appendix Tables A1 and A2 (online only). Three patients died during the study due to disease progression. There was no treatment-related death. Table 2 presents common TEAEs. Twenty-four patients experienced ≥ grade 3 TEAEs (80%). Eighteen patients experienced ≥ grade 3 treatment-related adverse events (60%), including anemia (20%), decreased neutrophil count (17%), diarrhea (17%), decreased platelet count (13%), nausea (13%), fatigue (10%), decreased WBC (10%), sepsis (7%), decreased lymphocyte count (3%), vomiting (3%), Urinary tract infection (3%), hypokalemia (3%), acute kidney failure (3%), dehydration (3%), and thromboembolic events (3%). Two patients were removed from the study for treatment intolerance. Dose reduction of adavosertib to 250 mg occurred in 17 patients (57%) and then further to 200 mg in nine patients (30%). Six patients had a dose reduction after cycle 1, five after cycle 2, two after cycle 3, one after cycle 4, and three after cycle 6 and beyond. One patient had a second dose reduction after cycle 1, three after cycle 2, four after cycle 3, and one after cycle 6 and beyond.

TABLE 2.

TEAEs Occurring ≥ 20% of Patients by Maximum Grade

Potential Biomarker Exploration

Molecular profiles, per FoundationOne CDx (n = 14), MDACC Solid Tumor Genomic Assay 2018 (n = 10), Guardant360 CDx (n = 2), Columbia Combined Cancer Panel (n = 1), GEM ExTra (n = 1), Invitae Breast and Gyn Cancer Panel (n = 1), and TEMPUS x T597 Gene Panel (n = 1), were obtained before trial therapy, as presented in Appendix Figure A2 (online only). Baseline molecular profiles of the 30 patients with CCNE1 amplification showed concurrent TP53 gene aberration (90%), AKT2 amplification (23%), MYC amplification (17%), CCND2 amplification (10%), and NOTCH1 mutations (10%). Selected genes are arranged according to their tumor responses, as shown in Figure 4. One patient was found to have a BRCA1 variant of unknown significance. No deleterious BRCA1 and BRCA2 mutation was identified in this cohort of patients. Among 17 patients tested, no microsatellite instability-high was detected. One patient with melanoma had a high tumor mutation burden of 28.4 mutations per megabase, per the Columbia Combined Cancer Panel, and experienced a PR. Another patient with epithelial ovarian cancer was identified to have homologous recombination deficiency that was associated with a loss of heterozygosity score of ≥ 16%, per FoundationOne CDx, and died of tumor progression 54 days after starting the study. Besides concurrent TP53 aberrations in responders, we identified one patient with concurrent RAD51 deletion, PIM1 amplification, and HRAS mutation; one with deletion of NF1 and mutations of BRIP1, DICER1, FAT1, and MAX; and one with amplification of KRAS, RAD51C, and RNF43.

FIG 4.

Baseline molecular profiling was performed per next-generation sequencing in a Clinical Laboratory Improvement Amendments–certified molecular diagnostic laboratory; selected genes are arranged according to their tumor responses, as shown in a heatmap. PD, progressive disease; PR, partial response; SD, stable disease.

DISCUSSION

The results of this multicenter, open-label, single-arm phase II trial showed that adavosertib displayed promising preliminary antitumor activity in advanced malignancies harboring CCNE1 amplification, especially in 14 patients with CCNE1-amplified epithelial ovarian cancer: ORR = 36%; SD ≥ 6 months/PR = 57%, a median PFS duration of 6.3 months, and a median OS duration of 14.9 months. All patients who experienced a PR or SD for at least 6 months had a concurrent TP53 mutation.

More than 50 clinical trials of the WEE1 kinase inhibitor adavosertib, alone or in combination, have been conducted to determine its roles in sensitization to chemotherapy and radiation therapy.^24-31 Antitumor activities were observed with adavosertib, as well as other WEE1 kinase inhibitors such as ZN-c3,^32-36 supporting the use of a WEE1 kinase inhibitor for cancer therapy.

To the best of our knowledge, our reported findings represent the results of the first biomarker-driven study to demonstrate that adavosertib has substantial antitumor activity as a single agent in CCNE1-amplified malignancies, especially in epithelial ovarian carcinoma 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 cancer²⁷; 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 patients³¹; 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

In view of our observations, one important question is whether adavosertib treatment would be an effective mechanism-driven therapeutic strategy in a biomarker-driven patient selection trial. In a biomarker-driven study in recurrent small-cell lung cancer patients with MYC amplification or CDKN2A and TP53 coalterations, no response to adavosertib was observed.³⁸ TP53 biomarker-driven clinical studies showed modest clinical benefit with adavosertib alone or in combination in patients with TP53-mutant platinum-resistant or platinum-refractory ovarian cancer,^39,40 TP53-mutant platinum sensitive ovarian cancer,²⁸ and TP53- and RAS-mutant metastatic colorectal cancer who were stable or responding after 16 weeks of chemotherapy.⁴¹

In this report, we did not identify concurrent deleterious BRCA1/2 mutations or microsatellite instability-high in this cohort of patients. Approximately 90% of patients with CCNE1 amplification had concurrent TP53 mutations. Objective responses were observed in eight of 27 patients with concurrent TP53 mutations but not in the three patients without. These data support the hypothesis that WEE1 kinase inhibition might be most active against cells that lose G1/S cell-cycle checkpoint control.

Proportionally high numbers of new lesions or rapid clinical deterioration were observed in eight patients treated with adavosertib, which might be due to mechanism-driven heterogeneity in response to WEE1 kinase inhibition. When several cell checkpoints simultaneously lose control as a result of genetic defects, such as CCNE1 amplification and TP53 aberration, and pharmacologic intervention through WEE1 kinase inhibition, cells are forced to go through cell cycling. Cells with low levels of accumulated DNA damage will continue to undergo cell cycling, resulting in tumor growth that may present clinically as new lesions, until those tumor cells accumulate high levels of DNA damage, leading to lethal genomic instability, mitotic catastrophe, and cell death and resulting in tumor shrinkage that may present clinically as a tumor response. If this theory is true, this may pose a clinical challenge for the further development of WEE1 kinase inhibition in the treatment of advanced malignancies using this synthetic lethality strategy.

When considering the clinical findings of this study, several caveats should be borne in mind. First, patient selection bias that is associated with the eligibility criteria may limit the generalizability of our findings, as it does in many clinical trials. Second, the small sample sizes in the subgroup analyses may limit the validity of the statistical assessments of individual pathological diagnoses. Third, this study might not test an optimal phase II dose for cancer therapy, in part because patients required excessive antiemetic support with steroid (10 days every 21 days), which might limit its potential systemic antitumor activity for its immunosuppressive effect.^42,43 Fourth, this study allowed several different CLIA-certified molecular diagnostic assays to preidentify eligible patients, which might result in enrolling patients with different copy numbers of CCNE1 gene since the cutoffs for these assays may not be same. The ongoing correlative biomarker exploration including cyclin E1 expression levels by immunohistochemistry and RNA-seq, as well as copy numbers of CCNE1 gene by targeted genomic next-generation sequencing on tumor specimens obtained from this study, may facilitate learning and thinking of the definition of CCNE1 amplification in different assays.

In conclusion, 300 mg once daily of adavosertib, given by mouth for 5 days a week for 2 weeks, with 1 week off, was tolerated by patients with refractory solid tumors that harbored CCNE1 amplification, although a dose reduction may be eventually needed over time for better tolerance. The traditional strategy of including unselected patients with cancer may not meet the challenges of the current landscape of early drug development. Further evaluation of adavosertib or other WEE1-directed therapy, alone or in combination with other therapeutic agents targeting concurrent gene aberrations,⁴⁴ is warranted in patients with advanced malignancies harboring CCNE1 amplification and TP53 aberration.

APPENDIX

FIG A1.

Toxicity assessment board for frequencies and grades of (right) TEAEs and (left) TRAEs. ALP, alkaline phosphatase; GERD, gastroesophageal reflux disease; NOS, not otherwise specified; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; UTI, urinary tract infection.

FIG A2.

Baseline molecular profiling was performed per next-generation sequencing in a Clinical Laboratory Improvement Amendments–certified molecular diagnostic laboratory; the results are arranged according to their best tumor responses, as shown in the waterfall plot. ^aPatients had overall PD with < 20% increase on target lesions but had new nontarget lesions, or patients had rapid clinical deterioration. PD, progressive disease; PR, partial response; SD, stable disease.

TABLE A1.

TEAE (grade ≥ 2)

TABLE A2.

TRAE (grade ≥ 2)

DATA SHARING STATEMENT

Adavosertib is an investigational agent; hence, the data collected for this study will not be made available to others.

AUTHOR CONTRIBUTIONS

Conception and design: Siqing Fu, Ying Yuan, Naoko Takebe, Khandan Keyomarsi, Funda Meric-Bernstam

Financial support: Siqing Fu, Funda Meric-Bernstam

Administrative support: Siqing Fu, Naoko Takebe, Funda Meric-Bernstam

Provision of study materials or patients: Siqing Fu, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard D. Carvajal, Thomas J. George, Ying Yuan, Shannon N. Westin, Yan Xing, Ecaterina E. Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Naoko Takebe, Karen Lu, Funda Meric-Bernstam

Collection and assembly of data: Yuan Yuan, Anthony D. Elias, Richard D. Carvajal, Ying Yuan, Lihou Yu, Yan Xing, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Karen Lu, Funda Meric-Bernstam

Data analysis and interpretation: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Thomas J. George, Richard D. Carvajal, Ying Yuan, Lihou Yu, Shannon N. Westin, Yan Xing, Ecaterina E. Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Naoko Takebe, Karen Lu, Khandan Keyomarsi, Funda Meric-Bernstam

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

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Siqing Fu

Research Funding: Novartis (Inst), NeuPharma, Inc (Inst), BeiGene (Inst), MacroGenics (Inst), BioAtla (Inst), Parexel International, LLC (Inst), Boehringer Ingelheim (Inst), Abbisko (Inst), Lilly (Inst), Hookipa Pharma (Inst), IMV (Inst), Innovent Biologics (Inst), Lyvgen Biopharma (Inst), Millennium (Inst), Nerviano Medical Sciences (Inst), NIH/NCI (Inst), Sellas Life Sciences (Inst), Soricimed (Inst), NovoCure (Inst), Turnstone Bio (Inst), Taiho Oncology (Inst), NCCN (Inst), Exelis (Inst), K-Group Beta (Inst), NextCure (Inst), Ningbo NewBay Medical Technology (Inst), PureTech (Inst), SQZ Biotech (Inst), Sumitomo Dainippon Pharma Oncology (Inst), Treadwell Therapeutics (Inst), Tyligand Bioscience (Inst), Vaccibody (Inst), Greenfire Bio (Inst)