AstraZeneca (Singapore)

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-HER2 antibody and a cytotoxic topoisomerase I inhibitor, is approved for the treatment of HER2-positive and HER2-low breast cancer as well as HER2-high gastric and HER2-mutant lung cancer tumours. The AKT inhibitor capivasertib is approved for the treatment of HER2- ER+ breast cancer with alterations in PIK3CA, PTEN and AKT-1. The potential for the combination of T-DXd with AKT inhibition to enhance anti-tumour activity was explored in HER2+ or HER2-low preclinical models. In vitro, combination activity was observed in both HER2-high and HER2-low expressing breast cancer as well as in gastric, endometrial and ovarian models, irrespective of HER2 expression level or PI3K-AKT status pathway alterations. The T-DXd-capivasertib combination effect translated in vivo with increased anti-tumour benefit in HER2 expressing, PI3K-AKT pathway altered tumour xenografts when compared to the combination of trastuzumab and capivasertib. In cell lines sensitive to the combination, combining T-DXd with capivasertib targeted complimentary pathways which resulted in disruption of the cell cycle and increased cell death. These results suggest that T-DXd combined with capivasertib has the potential to be active in HER2-positive as well as HER2-low tumours independent of PI3K pathway alteration status.

Abstract Human Leukocyte Antigen (HLA)-G is selectively expressed by fetal trophoblast cells that invade maternal tissue and encounter maternal natural killer (NK) cells early in pregnancy. In NK cells, the endosomal receptor KIR2DL4 responds to soluble HLA-G by inducing a broad transcriptional program to support placental development. Structural features of KIR2DL4 that control ligand binding and endocytosis are unknown. Random mutagenesis revealed that three cysteines in the first immunoglobulin domain of KIR2DL4 regulated endocytosis and uptake of HLA-G. We found that the Cys10-Cys28 bond visible in the KIR2DL4 crystal structure is an allosteric disulfide with potential to switch to a Cys28-Cys74 bond. Mass spectrometry analysis showed that KIR2DL4 in human cells exists in both disulfide-bonded states. The Cys10-Cys28 bond in purified KIR2DL4 was reduced by protein disulfide isomerase (PDI) in vitro. Inhibition of PDI caused retention of KIR2DL4 at the plasma membrane and prevented HLA-G uptake. Mutants in the Cys10-Cys28 configuration endocytosed spontaneously but did not bind HLA-G. Conversely, KIR2DL4 with a Cys28-Cys74 bond was at the plasma membrane and endocytosed HLA-G. A structural change predicted by AlphaFold upon disulfide switching to the Cys28-Cys74 form reorients the D0 domain into a conformation that binds HLA-G. Thus, conversion of KIR2DL4 from an inactive state to an HLA-G binding form can regulate NK cell function to promote fetal development.

Abstract Background: T-DXd is approved for the treatment of adult pts with HER2+ mBC who have received a prior anti-HER2-based regimen. Recent results from the planned interim analysis of the Phase 3 DESTINY-Breast09 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review for T-DXd + pertuzumab versus standard of care (taxane + trastuzumab + pertuzumab) in first-line (1L) HER2+ mBC (median 40.7 vs 26.9 months; hazard ratio 0.56 [95% CI 0.44, 0.71]). The T-DXd monotherapy module remains blinded until final PFS analysis. DESTINY-Breast07 (NCT04538742; initiated prior to DESTINY-Breast09) was a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. Results presented are from the final analysis of the dose-expansion phase assessing T-DXd ± pertuzumab as 1L treatment in HER2+ mBC. Methods: Eligible pts had locally assessed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+ / in situ hybridization-positive) mBC. No prior therapy for mBC was allowed and a disease-free interval of ≥12 months from (neo)adjuvant therapy was required. Pts were stratified by hormone receptor status (positive [estrogen or progesterone receptor ≥1%] vs negative), disease status (recurrent vs de novo), and PD-L1 expression (positive [IHC ≥1%] vs negative). Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with pertuzumab 420 mg IV Q3W, with an 840-mg loading dose. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response, and PFS, per RECIST 1.1 by investigator, as well as time to progression on subsequent therapy (PFS2) by investigator, and overall survival (OS). Results: At final data cutoff (January 31, 2025), 75 pts in the T-DXd module and 50 pts in the T-DXd + pertuzumab module had received study treatment; demographics and disease characteristics were well balanced. Median follow up was 37.1 months with T-DXd and 38.6 months with T-DXd + pertuzumab. Median total treatment duration was 26.8 months in the T-DXd module, and 27.6 months for T-DXd and 26.0 months for pertuzumab in the T-DXd + pertuzumab module. Confirmed ORR (80% CI) was 78.7% (71.4, 84.7) with T-DXd and 84.0% (75.3, 90.5) with T-DXd + pertuzumab. At 36 months, 65.5% and 69.4% of pts remained in response in the T-DXd and T-DXd + pertuzumab modules, respectively. At study completion, median PFS and median OS were not reached for either module. The 80% CI lower limit for median PFS was 40.2 months for T-DXd + pertuzumab; all other CI limits were not evaluable. PFS rate (80% CI) at 24 months was 71.4% (63.5, 77.8) with T-DXd and 67.8% (58.2, 75.7) with T-DXd + pertuzumab. Grade ≥3 adverse events (AEs) occurred in 57.3% (n=43/75) and 62.0% (n=31/50), and serious AEs in 21.3% (n=16/75) and 28.0% (n=14/50), of pts in the T-DXd and T-DXd + pertuzumab modules, respectively. Adjudicated drug-related interstitial lung disease / pneumonitis events occurred in 11 (14.7%; Grade 1, n=3; Grade 2, n=8) pts who received T-DXd and 7 (14.0%; Grade 2, n=6; Grade 3, n=1) who received T-DXd + pertuzumab. Additional data by subgroup, including biomarker analyses, will be presented. Conclusion: In this Phase 1b/2 DESTINY-Breast07 study, safety profiles for T-DXd and pertuzumab were generally consistent with the known profiles of each agent. Encouraging clinical activity was demonstrated in pts who received either T-DXd monotherapy or T-DXd + pertuzumab as a 1L treatment for HER2+ mBC; results from the T-DXd + pertuzumab module are consistent with the interim findings from the Phase 3 DESTINY-Breast09 study. Citation Format: F. André, E. Hamilton, S. Loi, C. Anders, P. Schmid, E. Artamonova, R. Villanueva-Vázquez, J. Pedrini, D. Doval, S. C. Chen, S. Boston, A. Konpa, M. Markowska, G. Fabbri, K. Jhaveri. Trastuzumab deruxtecan (T-DXd) monotherapy and T-DXd + pertuzumab in patients (pts) with previously untreated HER2+ unresectable/metastatic breast cancer (mBC): final results from DESTINY-Breast07 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-14.

Abstract Introduction: Neoadjuvant chemotherapy (CT) with pembrolizumab (P) is standard for most patients (pts) with high-risk early TNBC. Biomarkers for the addition of P to CT are lacking. The prognostic and predictive value of TILs in pts who receive neoadjuvant CT+P vs CT alone and the significance of change in TILs from pre- to post-treatment samples remains unclear. Methods: From the prospective DFCI Multicenter TNBC Registry, pts with stage I-III TNBC who received neoadjuvant CT or CT+P were identified. Stromal TILs were scored in tumor samples at baseline (BL) and surgery (if residual disease, RD). TILs were evaluated as a continuous and binary variable using a threshold selected based on BL distribution. Fisher’s exact test was used to compare TILs between CT and CT+P, and between RCB groups. Association with pathologic complete response (pCR) and with recurrence-free (RFS), distant recurrence-free (DRFS) and overall survival (OS) were evaluated using logistic regression and Cox proportional hazards models, respectively, adjusting for clinical stage and neoadjuvant treatment. All statistical tests were two-sided (significance p < 0.05). Results: Between 5/2019-1/2024, 121 TNBC pts were identified; 18 (14.9%) stage I, 49 (40.5%) stage II, 52 (43.0%) stage III, 2 (1.7%) unknown. 19 (15.7%) had germline BRCA1/2 mutations. 49 (40.5%) received CT and 72 (59.5%) CT+P, with anthracycline-based CT in 40 (81.6%) and 62 (86.1%) pts, respectively. The pCR rate was 51.0% (25/49; 95% CI 36.3-65.6%) with CT alone and 58.3% (42/72; 95% CI 46.1-69.8%) with CT+P. Median follow-up was 2.2 years (interquartile range [IQR] 1.4-3.9): CT, 4.2 years (IQR 3.4-5.1); CT+P, 1.7 years (IQR 1.2-2.2). 115 pts had TILs scored at BL and 41 at RD, of whom 35 had paired samples. BL TILs (range 0-90%) were categorized by quartiles (5%, 10%, 30%) with 10% used for primary analysis. Both BL and RD TILs did not differ between CT vs CT+P as a continuous variable (BL p=0.11; RD p=0.56) or ≥10% cutoff (BL p=0.62; RD p=0.56). High BL TILs (≥ 10%) were significantly associated with pCR and this did not differ by treatment (interaction p=0.36). No association was observed between TILs (at BL or RD) and RCB class (TILs as continuous variable: BL p=0.36, RD p=0.84; or 10% cutoff: BL p=0.31, RD p=0.86). High BL TILs (≥ 10%) were associated with longer RFS (aHR 0.15, p=0.01), DRFS (aHR 0.17, p=0.01) and OS (aHR 0.19, p=0.05; or as a continuous variable, aHR per 5-unit increase 0.46, p=0.05). Neither TILs in RD nor increase from BL to RD (in 14/35 pts, 40%) were associated with RFS, DRFS or OS. Conclusion: In this multicenter TNBC cohort, BL TILs were reinforced as a prognostic marker for pCR, regardless of the addition of P to CT. TILs at RD and changes during neoadjuvant therapy were not prognostic. Additional follow-up for survival outcomes is ongoing. Citation Format: R. S. Lee, Q. Jin, B. Binboga Kurt, B. Koca, J. Gomez Tejeda Zanudo, A. Patel, A. Barkell, J. Baginska, O. M. Cunningham, C. E. Stever, T. S. Parker, T. Rahman, M. Luo, I. G. Martino, B. M. Drummey, S. A. Virani, K. Santos, J. Bsat, C. Snow, N. Tung, S. Lo, M. G. Faggen, N. Sinclair, N. Ahmad, M. Constantinou, S. Sinclair, J. L. Meisel, S. A. Kirschner, T. A. King, R. Salgado, E. A. Mittendorf, N. U. Lin, N. Tayob, E. P. Winer, E. C. de Bruin, S. M. Tolaney, A. Moeini, A. C. Garrido-Castro. Association of tumor-infiltrating lymphocytes (TILs) with outcomes in patients with early TNBC treated with neoadjuvant chemotherapy with or without pembrolizumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-18.

Abstract Background: Saruparib (AZD5305) is a highly selective, potent inhibitor and trapper of PARP1. Camizestrant is an oral next generation SERD and complete ER antagonist. PETRA (NCT04644068) is a Phase 1/2a, modular, open label, multicenter study of saruparib as monotherapy or in combination with anticancer agents in pts with advanced solid malignancies. We present safety and preliminary efficacy of saruparib + camizestrant in pts with advanced/relapsed ER+/HER2- breast cancer. Methods: Pts were aged ≥18 years with histologically/cytologically confirmed breast adenocarcinoma, a locally-documented ER+ and HER2- tumor and an ECOG PS 0/1. Pts were required to have recurrence or progression on ≥1 line of endocrine therapy, and were allowed ≤2 prior lines of chemotherapy in the advanced setting and ≤1 prior PARP inhibitor. Pts could receive prior CDK4/6 inhibitors or fulvestrant, but not oral SERDs. Pts received 60 mg saruparib + 75 mg camizestrant daily orally. The primary objective was assessment of safety and tolerability; secondary objectives included pharmacokinetic (PK) assessments and preliminary antitumor activity. Results: At data cutoff (Mar 31, 2025), 38 pts had received ≥1 dose of the combination. Median age was 56 years; median prior lines of therapy was 3.5 (range, 1-13). BRCA1/BRCA2 mutation (m) and PALB2m were detected in 8 (21.1%) and 2 (5.3%) pts, respectively, based on local testing. Safety is summarized in the Table. Hematological toxicities included anemia and neutropenia; gastrointestinal toxicities included nausea and vomiting. PK data showed no evidence of drug interaction between saruparib and camizestrant. Saruparib exposure was comparable following single-dose saruparib versus saruparib at steady-state in combination with camizestrant, for AUC (42,219 vs 41,703 h*ng/mL) and Cmax (2,834 vs 3,250 ng/mL). Eight of 35 evaluable pts achieved confirmed partial responses (by RECIST v1.1) for an objective response rate (ORR) of 22.9%; median duration of response was 5.5 months. In addition, 12 pts (34.3%) achieved stable disease for a disease control rate of 57.1%. An ORR of 33.3% was reported in 9 pts with measurable disease and BRCA1/BRCA2m or PALB2m. The median progression-free survival was 4.4 months (80% CI, 2.0-5.6) overall and 6.1 months (80% CI, 4.4-7.3) in pts with mutations. Conclusion: Saruparib + camizestrant was well tolerated with no new safety signals versus prior monotherapy studies of each drug. PK of saruparib in combination with camizestrant was consistent with monotherapy data. Preliminary efficacy of the combination was promising and compared favorably with camizestrant monotherapy. This combination is being tested in a randomized Phase 3 trial in pts with ER+/HER2- and BRCA1m/BRCA2m or PALB2m (EvoPAR-Breast01; NCT06380751). Citation Format: T. A. Yap, K. Yonemori, W. Li, S. Kitano, F. Lynce, A. Sharp, A. Falcón, J. Garcia-Corbacho, R. D. Baird, J. Balmaña, S. Nanda, I. Song, K. Sugibayashi, L. Womersley, M. Squatrito, E. Gangl, T. Milenkova, S. J. Luen. Phase 1/2a trial of new generation PARP1-selective inhibitor saruparib + next generation selective ER degrader (SERD) camizestrant in patients (pts) with advanced/relapsed ER+/HER2-negative or low (HER2−) breast cancer (PETRA Module 6) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-28.

Accurate human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) scoring is crucial to identify patients for HER2-directed therapy; however, validated HER2 scoring guidelines are lacking for non-breast/gastric solid tumors. We investigated concordance in IHC scores from independent pathologists using three different scoring algorithms in non-gastric/breast solid tumors. Whole-slide scans of HER2-stained tumor samples from DESTINY-PanTumor02 (NCT04482309) and a commercial pan-tumor sample set were scored by three independent, board-certified pathologists using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) scoring algorithms for gastric (reference) and breast cancers, and a clinical trial-based algorithm for endometrial cancers (evaluated for endometrial tumors only). The pathologists evaluated 488 samples from multiple solid tumor types. Mean positive percentage agreement (PPA; across pathologists) between the breast and gastric algorithms was higher for samples scored as IHC 3 + or IHC 0 compared with IHC 2 + or IHC 1 + . Inter-pathologist PPA for each algorithm was greatest in samples scored as IHC 3 + and IHC 0. The majority of inter-pathologist pairwise comparisons had Cohen's κ coefficient values > 0.4 when using the gastric or breast algorithm to determine IHC scores, indicating at least moderate agreement between pathologists; Cohen's κ coefficient values were generally lower (range 0.17-0.43) for the endometrial algorithm. ASCO/CAP scoring algorithms for gastric and breast cancer were comparable for identifying HER2 IHC 3 + tumors; lower concordance was observed for IHC 2 + /1 + tumors. These findings highlight a real-world issue of inter-pathologist variability and emphasize a need for greater awareness of best scoring practices.

With current evidence of homologous recombination deficiency (HRD) emerging as a predictive and prognostic biomarker in high-grade serous/endometrioid ovarian cancers (HGSOC/HGEOC), the HALO study (NCT04991051) evaluated the prevalence of the HRD in patients with HGSOC/HGEOC, primary peritoneal cancer (PPC), and fallopian tube cancer (FTC) across Asia, Middle East and Africa (MEA), and Russia. The MEA subset of this cross-sectional, non-interventional study enrolled patients with newly diagnosed stage III/IV (International Federation of Gynaecology and Obstetrics [FIGO] classification) HGSOC/HGEOC, PPC, FTC during May 2021-Jan 2022 with formalin-fixed paraffin-embedded tumour block(s) collected within 120 days of enrolment. Primary endpoints included prevalence of HRD, genomic instability (GI) excluding tumour BRCA mutations (tBRCAm), and tBRCAm. Logistic regression model predicted the risk factors associated with HRD positivity and tBRCAm. Of 195 patients (median [range] age, 58.2 [24.0-89.0] years), 88.7% had primary ovarian tumour. The HRD status was analysed in 180 patients; 52.2% (94/180) were HRD positive – 23.9% (43/180) had high GI scores excluding tBRCA1/2m, and 28.3% (51/180) had tBRCAm. More than two-thirds (71.3%) of patients underwent debulking surgery, 45,1% received neoadjuvant and 50.8% received adjuvant therapy. No patients received PARPi therapy. In univariate analysis, nulliparity was associated with lower odds of HRD positivity (odds ratio [OR]: 0.27, p=0.003). Family history (OR: 0.39, p=0.02) and nulliparous women (OR: 0.19, p=0.03) were associated with lower odds of high GI score. Higher odds of tBRCAm were observed in ex-smokers (OR: 6.77, p=0.02), family history (OR: 3.11, p=0.0009), and surgically resected tissue (OR: 2.00, p=0.04); lower odds in patients with FIGO stage IV (OR: 0.26, p=0.004). In multivariate analysis, h/o genetic-related cancer (OR: 3.75, p=0.002), h/o contraceptive use (OR: 5.19, p=0.009) was associated with higher odds of tBRCA1m whereas FIGO stage IV disease (OR: 0.24, p=0.006) had lower odds of tBRCAm. In the Middle East subset of HALO study, a substantial proportion of patients were HRD positive and had tBRCA1/2m, supporting the clinical relevance of these biomarkers for guiding novel targeted therapies. The study provides real-world evidence of HRD and tBRCA prevalence, informing future research and policy development in precision oncology for the region. Number-NCT04991051 (Date of Approval-September 2020).