Lheureux, Stéphanie

Abstract Background: Zedoresertib (zedo) and lunresertib (lunre) are oral, highly selective WEE1 and PKMYT1 inhibitors, respectively. Inhibition of these targets leads to premature mitotic entry, and in the presence of high replication stress causes mitotic catastrophe. In preclinical models, the combination of the zedo and lunre is synthetically lethal, supporting this first-in-class trial combination (NCT04855656). Methods: In this Phase 1 trial, patients (pts) with advanced solid tumors with CCNE1 amplification (amp), or FBXW7 or PPP2R1A deleterious mutations (mut) were treated with zedo (daily dosing) plus lunre (3 days on/4 days off), guided by preclinical modelling of the pharmacological contributions of WEE1 and PKMYT1 inhibition in achieving tumor regression. Objectives included safety, tolerability, recommended doses (RD), pharmacokinetics (PK), pharmacodynamics (PDy), antitumor activity and molecular response rate (MRR; ≥50% decline in circulating tumor DNA). Results: As of 18 Nov 2025, 54 pts (55.6% female ; prior lines of therapy 1 - 9, main cancer types: ovarian (OC) (35.2%), colorectal (31.5%), pancreatic (7.4%) and breast (5.6%)) were treated at 5 dose levels (DL) from 150 mg to 260 mg of zedo plus 60 mg or 80 mg of lunre. The most common ≥G3 treatment related adverse events (TRAEs) were anemia (9.3%), neutropenia (7.4%) and Palmar Plantar Erythrodysesthesia (PPE) (7.4%). There were no G5 TRAEs. 4 (9.3%) of 54 pts had a dose-limiting toxicity (G3 pain in extremity and G1 rash in same pt (zedo 150 mg / lunre 60 mg), G3 rash (200 mg / 80 mg), G3 PPE (260 mg / 60 mg), G3 vomiting (260 mg / 60 mg)). PK/PDy analyses showed dose-dependent exposures for both zedo and lunre and target engagement in most pts, with reductions in pCDK1 Thr14 and Tyr15 and yH2AX induction. 24 (55.5%) of 44 RECIST v1.1 evaluable pts showed tumor shrinkage (3 cCR, 5 uPR, 15 SD and 1 PD). Of 16 evaluable pts with advanced OC (12 platinum resistant , 2 unknown and 2 platinum sensitive) with CCNE1 amp (13 pts) or FBXW7 mut (3 pts), 13 (81.3%) showed tumor shrinkage (3 cCR, 3 uPR and 7 SD); clinical benefit rate (pts with CR, PR or SD) was 93.8%; 7 (43.8%) OC pts were on treatment for at least 16 weeks; 4 (25%) OC pts achieved GCIG CA-125 responses. Of 23 pts with a post baseline ctDNA analysis, a MRR of 39% was seen across all DLs. Conclusion: We report the first disclosure of clinical data of the first-in-field synthetic lethal combination of WEE1 and PKMYT1 inhibitors in a molecularly defined pt population. The safety profile of zedo and lunre was expected and manageable. Promising antitumor activity was observed in pts with CCNE1 amp or FBXW7 mut solid tumors, especially pts with OC. Further dose optimization of this combination is ongoing. Citation Format: Timothy A. Yap, Rahul Aggarwal, Elisa Fontana, Martin Hojgaard, Benedito A. Carneiro, Linda Duska, Patricia LoRusso, Siddhartha Yadav, Stephanie Lheureux, Cara Mathews, Ryan H. Moy, Nehal Lakhani, Mia Weiss, Joan Tymon-Rosario, Gerardo Colon-Otero, Ignacio Garrido-Laguna, Elisabeth K. Lee, Esteban Rodrigo Imedio, Jonathan Wessen, Luke Piggott, Vito Dozio, Noemie Luong, Christophe Mas, Alison M. Schram. First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT022.

e15024 Background: Anetumab ravtansine (AR) is an antibody-drug conjugate (ADC) containing the microtubule inhibitor DM4. ADC drugs have high interpatient variability in pharmacokinetics and pharmacodynamics (PK/PD), which raises concerns whether current dosing based on body weight (mg/kg) is optimal. Thus, we evaluated the effects of patient characteristics, including novel biomarkers of the innate immune system (IIS), on the PK/PD of AR. Methods: Studies were performed in patients in three clinical trials of different cancers with AR as part of treatment: 1) platinum-resistant or refractory high-grade ovarian cancer treated with AR at 2.2mg/kg IV weekly plus bevacizumab(N = 19); 2) pleural mesothelioma treated with AR at 6.5 mg/kg IV every 3 weeks plus pembrolizumab(N = 28); and 3) mesothelin-positive advanced pancreatic adenocarcinoma treated with AR at 5.5-6.5 mg/kg IV every 3 weeks plus nivolumab (and ipilimumab or gemcitabine, N = 27). Intensive plasma PK sampling was performed after the first dose to calculate clearance (CL), volume of distribution (Vd), and area-under-the-plasma-concentration-time curve (AUC 0-inf ). The relationship between biomarkers of FcɣRs (CD64, CD32, CD16) on IIS blood cells, total body weight (TBW), body surface area (BSA), lean body mass (LBM), and sex with PK parameters and clinical outcomes were evaluated by pearson correlation, t-test and multivariate regression analysis. Population PK (popPK) methods further evaluated patient covariates and variability in PK. Results: Patients with higher IIS FcγR CD64 and/or higher TBW or higher BSA had higher AR ADC CL (p < 0.05). AR ADC CL was lower in females (0.030 ± 0.007 L/h) versus males (0.042 ± 0.006 L/h) (p < 0.05). Patients with stable disease and partial response had higher AR ADC AUC 0-inf versus patients with progressive disease AR ADC disposition was described by linear CL with two pathways for the release of the payload DM4, hydrolysis and the IIS. A time-varying drug-to-antibody ratio predicted the release of the DM4 payload. In the PopPK model, LBM and albumin were associated with CL of the AR ADC, LBM and IIS FcγR CD64 were associated with the Vd of the AR ADC, and LBM and age were associated with the CL of the released DM4. Conclusions: These results suggest that TBW-based dosing of AR ADC is not optimal, whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex may be more appropriate to reduce PK variability and improve response.

ABSTRACTAnetumab ravtansine, like other ADC drugs, has high inter‐patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0‐inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

Abstract Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.

5579 Background: Adavosertib (AZD-1775) is a potent small molecule inhibitor of Wee-1, currently in clinical development. In a double-blind, placebo-controlled, phase 2 trial (NCT02151292), adavosertib and gemcitabine significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with recurrent platinum-resistant or platinum-refractory high grade serous ovarian cancer (HGSOV) compared to gemcitabine alone. We investigated whether plasma and intra-tumoral adavosertib concentrations correlated with survival in these patients. Methods: Adavosertib was administered orally on Days 1, 2, 8, 9, 15 and 16 at 175 mg per day, and gemcitabine was administered on Days 1, 8 and 15 at 1000 mg/m2 every 28 days. Serial blood samples were collected on Day 1 of cycle 1 after adavosertib administration. Tumor biopsies were taken 1-2 weeks after initiation of study treatments. Plasma and tumor adavosertib concentrations were determined using validated HPLC-MS/MS. Patients were divided into groups with plasma or tumor adavosertib concentrations above or below the biologically active concentration (BAC) of 125 ng/ml (Leijen et al, J Clin Onco 2016). Survival was described using the Kaplan-Meier method. Results: Among 61 HGSOV patients who received adavosertib, plasma samples were available in 47, and tumor samples were available in 31 patients. Among 25 non-HGSOV patients (exploratory cohort), plasma and tumor samples were available in 21 and 17 patients respectively. The mean maximum adavosertib concentration (Cmax) was 355.3 ± 120.9 ng/ml and 358.6 ± 117.9 ng/ml respectively. Cmax was above BAC in all patients. The mean tumor adavosertib concentration was 609.2 ± 1129.2 ng/ml (range: 0.47 – 5501 ng/ml) for HGSOV patients, and 964.2 ± 1611.2 ng/ml (range: 0.22 – 6116 ng/ml) for non-HGSOV patients. There was no correlation between Cmax and tumor adavosertib concentrations. In HGSOV, the median PFS was 5.8 months for patients with tumor concentrations above BAC, and 3.5 months for those with tumor concentrations below BAC (Hazard ratio (HR): 0.46, 95% confidence interval: 0.19 – 1.14, p = 0.06). No difference in PFS was seen in non-HGSOV patients according to tumor adavosertib concentration. Tumor adavosertib concentration did not correlate with OS. Conclusions: Although Cmax was above BAC in all patients, there was a high variability in tumor adavosertib concentrations. In HGSOV, higher tumor adavosertib concentration was associated with a trend towards improved PFS, but not OS. Our results indicate that the current adavosertib dosing regimen may not produce the desired concentrations in tumors for some patients, and further optimization may be needed.

Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

6010 Background: The efficacy of treatment for recurrent endometrial cancer (EC) remains limited. Vascular endothelial growth factor and inflammatory chemokines are proangiogenic factors and immune modulators involved in immune suppression. Reprogramming the tumor microenvironment by combining antiangiogenic and immunotherapy (IO) could enhance antitumor responses. Methods: A 2:1 randomized phase 2 trial compared the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in recurrent EC. Primary endpoint was progression free survival (PFS) assessed by RECIST 1.1 (NCT03367741). Women with recurrent measurable EC were eligible. There were no limits on prior therapy, but at least one prior platinum-based chemotherapy was required. Patients (pts) were stratified according to MSI status and assessed by CT every 8 weeks. Cabozantinib was given at 40 mg daily (Arm A) and nivolumab at 240 mg, on D1 and D15 of a 28-day cycle for 4 cycles, followed by 480 mg every 4 weeks (Arms A & B). Pts with carcinosarcoma or prior IO were enrolled in an exploratory cohort and received combination treatment (Arm C). A baseline biopsy was required for all pts. CyTOF analysis was performed on fresh biopsies. Results: 76 evaluable pts were enrolled (Arm A: 36, Arm B: 18, Arm C: 9 carcinosarcoma, and 20 post IO including 7 pts crossed over from Arm B). 55% of pts had received ≥3 prior lines of therapy. Two pts were MSI high in Arm A and none in Arm B. The Kaplan-Meier estimated median PFS was 5.3 (95% CI: 3.5-9.5) months in Arm A and 1.9 (95% CI: 1.6-3.8) months in Arm B, with a log-rank p = 0.07, which met the significance level of 0.1 used for sample size calculation. Objective response rate (ORR) was 25% for Arm A and 16.7% for Arm B; stable disease (SD) was seen in 44.4% vs 11.1%, respectively. Clinical benefit (ORR+SD) was significantly higher in arm A vs B (p < 0.001). In Arm C-carcinosarcoma, one patient had a partial response (11.9 months duration) and four SD. In Arm C-prior IO, six pts responded and eight had SD. The most common related AEs in Arm A were diarrhea (47.2%), elevated liver enzymes (44.4%), fatigue (38.9%), anorexia, hypertension, and nausea (30.6%), mainly grade 1/2. Preliminary CyTOF analysis across treatment arms identified multiple immune subsets for further interrogation including activated CD8+ and CD4+ T cells. Conclusions: Cabozantinib plus nivolumab demonstrates improved PFS compared to nivolumab in heavily pre-treated women with recurrent EC. In-depth CyTOF analysis of the tumor microenvironment to identify predictive immune biomarkers of response is ongoing. Clinical trial information: NCT03367741.

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.