Sarah Cannon Research Institute

Abstract Background: Treatment approaches for early-stage breast cancer (EBC) have advanced significantly in recent decades, with the addition of HER2-targeted therapies, immunotherapy, and personalized chemotherapy. However, despite these advances, many questions related to treatment cannot be practically or ethically addressed in prospective, randomized clinical trials. The required extended follow-up in EBC treatment trials may delay the dissemination of practice-changing results. Additionally, many EBC trials have poor representation of less common tumor subtypes (such as invasive lobular carcinoma, ILC) and limited enrollment of patients of diverse racial/ethnic backgrounds. In this context, observational registry Real-World Data clinical trials, such as FLEX, which analyze clinical and pathologic data, treatment history, outcomes, and other metadata such as whole transcriptomics can provide actionable evidence that can inform clinical practice. The ongoing, multi-center, FLEX study (NCT03053193) seeks to enroll 30,000 EBC patients to create a large-scale, diverse, population-based registry of whole transcriptome data matched with clinical data with 10 years of follow-up to investigate new gene expression signatures of prognostic and/or predictive value in a real-world setting. Efforts are focused on enriching enrollment of diverse racial/ethnic minorities, historically underrepresented groups, and uncommon EBC tumor histologies. An additional objective is supporting investigator-initiated sub-studies to address clinically relevant questions in EBC with up to 10 years of follow-up. Methods: FLEX is a large prospective, observational trial that enrolls patients (male or female) who are ≥ 18 years old with stage I-III breast cancer. Patients who receive standard of care MammaPrint® (70-gene signature risk of recurrence), with or without BluePrint® (80-gene signature molecular subtype) on their primary breast tumor and consent to clinically annotated whole transcriptome data collection are eligible for enrollment. Within 7 years of trial initiation, FLEX has enrolled over 20,000 patients across 102 sites in the US, 3 sites in Canada, and 1 site each in Greece and Israel. Of the total FLEX population, 9495 (47%) have reached 3 years of follow-up, and 4047 (20%) have reached 5 years of follow-up. To address racial/ethnic disparities in clinical trials, a concerted effort has led to the inclusion of 1892 Black/African American, 1722 Latin American/Hispanic, and 490 Asian American/Pacific Islander EBC patients of self-reported racial/genetic ancestry, making FLEX a highly diverse study of EBC patients. Similarly, FLEX represents one of the largest cohorts of ILCs, composed of 2196 ILC and 649 mixed ILC/ductal histology tumors. Studies from FLEX have led to 3 peer-reviewed publications, with 3 submitted in 2025 currently under review. Fourteen FLEX investigator-initiated sub-study abstracts have been presented in 2025. Additionally, over 53 FLEX abstracts have been accepted at congresses internationally (2018-2025), including 11 presentations focused on therapy selection, 12 on differences in tumor biology and clinical outcomes by race/ethnicity, and 2 on ILC, among others. Data generated from FLEX include important new findings in EBC management. Among these findings are the prediction of absolute chemotherapy benefit in genomically high-risk patients, prediction of survival benefit from adjuvant anthracyclines, associations of genomic signatures that predict resistance to CDK4/6 inhibition, and overrepresentation of aggressive ER+ basal-type tumors in Black/African American patients. Citation Format: L. P. Gold, L. Samiian, K. Hoskins, S. Diab, L. Lee, V. K. Gadi, E. A. Brown, J. R. Ramadurai, J. A. Elayoubi, R. E. Kaczynski, R. E. Fine, T. Bah, L. Matt-Amaral, B. J. Lieblong, W. Audeh, J. O'Shaughnessy. Flex: from genomic profiling to real-world insights in 30,000 patients with early-stage breast cancer [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 PS5-09-19.

SummaryBackgroundSurvivin, an inhibitor of apoptosis protein (IAP), is highly expressed in various cancers but has weak immunogenicity as a self-derived tumour-associated antigen (TAA). OVM-200, a survivin recombinant overlapping peptide (ROP) vaccine, consists of overlapping peptides linked by the target sequence (LRMK) for cathepsin S, preserving T-cell and most antibody epitopes. OVM-200 elicits both cellular and humoral immune responses against survivin-expressing cancer cells. This phase 1a, multicentre, open-label trial (OVM-200-100) evaluates OVM-200 as a therapeutic vaccine in patients with non-small cell lung, ovarian, and prostate cancer. This Phase 1 trial is also the first time the ROP technology platform has been used in human trials.MethodsTwelve eligible patients received three subcutaneous OVM-200 doses at 2-week intervals using a 3 + 3 dose-escalation design. Four dose levels (250, 500, 1000, and 2000 μg) were tested to determine the optimal dose for phase 1b. The primary endpoint was safety and tolerability, while secondary endpoints included immunogenicity (antibody and T-cell response) and tumour response (RECIST criteria). This trial was registered with ClinicalTrials.gov (NCT05104515) and EudraCT (2021-001545-12) and took place from 28/09/2021 to 04/05/2023.FindingsOVM-200 was well tolerated, with no serious adverse drug reactions (ADRs) or dose-limiting toxicities (DLTs). All adverse events were Grade 1 injection site reactions (ISRs). The 2000 μg dose group achieved the highest median anti-survivin IgG titre (1:327,680) at the end of the study (EOS) and a median ELISpot T cell response of 1282 SFU per million cells on day 22. Disease stabilisation (SD) was observed in 6 of 12 patients (50%), including all 3 patients (100%) in the 2000 μg group, some of which were stabilisations of limited duration. Based on these findings, the 2000 μg dose was selected for further evaluation in phase 1b.InterpretationOVM-200 is well tolerated and induces a robust humoral response, with a considerable cellular response and preliminary evidence of disease stabilisation. Phase 1b is ongoing to further evaluate its safety and efficacy at the selected dose.FundingOxford Vacmedix UK Ltd.

Clinical studies have shown that outcomes of patients with prostate cancer could vary depending on race. In this study, the authors sought to determine if the treatment effect of apalutamide, an androgen receptor pathway inhibitor (ARPI), on overall survival (OS) varies depending on the race of the patient. This pooled analysis includes individual patient data from two phase 3 trials, TITAN and SPARTAN, which randomized patients to androgen deprivation therapy (ADT)±apalutamide in metastatic hormone-sensitive and nonmetastatic castration-resistant prostate cancer, respectively. Race was self-identified and categorized as Asian, Black, White, and Others categories. The authors applied a stratified (stratification for the trial) multivariable Cox proportional hazards regression model to determine heterogeneity of treatment effect on OS after adjustment for age, performance status, body mass index, T- and N-stage, Gleason score, comorbidities, and exposure to statins and metformin. Overall, 2190 patients were included: 16.9% patients were Asian, 3.7% were Black, 67.4% were White, and 12.0% were from the Others category. The authors did not find any significant heterogeneity of treatment effect from apalutamide on OS across racial groups (interaction-p=.46). Among ADT plus apalutamide-treated patients, there was no association of race with OS (hazard ratio for Asian, 0.77 [95% CI, 0.56-1.06]; Black, 0.82 [95% CI, 0.49-1.37]; and Others, 1.00 [95% CI, 0.75-1.34], all compared to White). In this study, the authors did not find any evidence of difference in the treatment effect of apalutamide on OS across patients of different races, although interpretation remains limited by poor representation of racial minorities. Among apalutamide-treated patients, there was no association of race with OS.

AC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100-600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% of patients, most commonly nausea (19%), fatigue (16%), and neutropenia (16%). All treatment-related adverse events were Grade 1/2, with no dose reductions/discontinuations; the maximum tolerated dose was not reached. Of 26 efficacy-evaluable patients, 4 (15%) achieved partial responses and CBR was 23%. In exploratory analysis of patients with ESR1 mutations, ORR and CBR were 40% and 45%, respectively. Median DOR and PFS were 6.5 and 3.6 months overall, and 6.5 and 7.4 months in ESR1-mutant patients. AC699 steady-state exposure increased approximately dose-proportionally between 100-400 mg, plateauing at 600 mg. AC699 demonstrated favorable safety, predictable PK, and encouraging antitumor activity, particularly in ESR1-mutant disease.

Adavosertib is a highly selective, small molecule Wee1 inhibitor that sensitizes tumor cells to cytotoxic agents. We report results from the lead-in cohorts of two phase II studies: carboplatin/pemetrexed plus adavosertib versus carboplatin/pemetrexed in first-line metastatic non-squamous non-small-cell lung cancer (NSCLC) (NCT02087241); and docetaxel plus adavosertib versus docetaxel in recurrent NSCLC (NCT02087176). Both lead-in cohorts assessed early safety and efficacy (objective response rate [ORR]). First-line metastatic treatment was carboplatin (area under the curve to 6 h [AUC6]) plus pemetrexed 500mg/m2 intravenously on day 1, every 21 days; recurrent treatment was docetaxel 75mg/m2 intravenously on day 1 plus prophylactic granulocyte-colony stimulating factor 6mg subcutaneously on day 4 every 21 days. All patients received adavosertib 225mg twice daily orally on days 1-3 (five doses). After a planned safety analysis of the first-line trial, dose and schedule were modified to reduce toxicity. First-line: 14 patients were enrolled in four treatment cohorts. Median time on trial was 17.3 weeks, with an ORR of 29%. The most common adverse events were diarrhea (50%), nausea (50%), vomiting (50%), anemia (43%), neutropenia (43%), decreased appetite (43%), and dehydration (43%). Recurrent: 32 patients were enrolled. The ORR was 9%. The most common adverse events were diarrhea (66%), anemia (50%), nausea (47%), fatigue (47%), vomiting (44%),and thrombocytopenia (41%). Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care. ClinicalTrials.gov, NCT02087241 and NCT02087176.