There remains a critical need for prognostic biomarkers of treatment response in epithelial ovarian cancer (EOC). The KELIM score, derived from the rate of CA-125 elimination during the first 100 days of treatment, is a clinically available biomarker of treatment response to platinum-based chemotherapy, its utility is limited by the need for post-treatment data. Tumor–stroma proportion (TSP) has emerged as a prognostic biomarker across several malignancies. Studies from our group have shown that high TSP (≥50% stroma content assessed by pathologist evaluation, TSPmanual) is associated with platinum resistance and poor survival in EOC at diagnosis and before treatment. We compared the prognostic value of TSP and KELIM by analyzing manual pathologist (TSPmanual) and artificial intelligence–derived assessments (TSPauto) on digitized images from a cohort of EOC specimens. In this cohort, we showed the prognostic significance of TSPmanual, confirming prior findings. Furthermore, TSPauto and TSPmanual assessments were highly concordant (94% agreement, Cohen’s Kappa 0.89, p<0.001), providing a highly reproducible, automated approach. Unlike KELIM, which was only associated with platinum resistance, high TSPauto was significantly associated with poor survival (HR 1.99, p = 0.02). These findings support AI-derived TSP as a pre-treatment prognostic biomarker for EOC that complements KELIM.

BACKGROUND:Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. METHODS:We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age 18 years or older, performance status of 0-1, measurable disease, platinum-resistant disease and histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR) and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. RESULTS:We show that the combination is moderately well tolerated and most common grade 3-4 adverse events are gastrointestinal side effects and anemia. ORR is 2.9% and DCR is 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses reveal an upregulation of inflammatory and cytolytic genes and co-inhibitory checkpoints 6 weeks on-therapy. Upregulation of interferon signaling, antigen presentation and immune cell adhesion and migration gene sets are prominent on-therapy, together with an increase in density of CD8 + T-cells. Patients with a CA-125 and/or clinical response show an enrichment of adaptive and conserved immune response gene sets on-therapy. CONCLUSIONS:Our findings highlight the potential of epigenetic modulators to re-shape the tumor microenvironment of PROC toward a more inflammed phenotype and may point to approaches to augment immunotherapy response.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

Abstract Introduction: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. Methods: We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age ≥ 18 years, ECOG performance status of 0-1, measurable disease and platinum-resistant, histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR), and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic modulation and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. Target gene expression analyses were used to identify differentially expressed genes and pathways, and bulk RNA sequencing was used for gene set enrichment analyses (GSEA) and to infer T cell receptor (TCR) assemblies. Results: The combination of azacitidine and pembrolizumab was moderately well tolerated, and the most common grade 3-4 adverse events were gastrointestinal side effects and anemia. ORR was 2.9% and DCR was 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes (FDR-adjusted p=0.005) and co-inhibitory checkpoints (p=0.005) 6 weeks on-therapy. Upregulation of interferon signaling (p=0.006), antigen presentation (p=0.003), costimulatory signaling (p=0.002), and immune cell adhesion and migration (p=0.005) pathways were prominent on-therapy, together with an increase in CD8+ T-cell density (p=0.05). GSEA analyses were concordant with these findings, showing enrichment of immune and inflammatory gene sets on-therapy and upregulation of gene sets linked to IFN-γ response, natural killer cell-mediated cytotoxicity, and immunoregulatory interactions (p < 10e-13). Findings were not confounded by histological subtype. TCR abundance analyses evaluating significant TCR clonotypic expansions and regressions showed that intra-tumoral TCR repertoires were reshaped on-therapy. Furthermore, patients with a CA-125 and/or clinical response showed enrichment of hallmark inflammatory gene sets at baseline (p < 10e-10) and of adaptive and conserved immune response gene sets on therapy (p < 10e-09). Conclusions: Our findings highlight the potential of epigenetic modulators to reshape the tumor microenvironment of PROC toward a more inflammatory phenotype and may point to approaches to augment immunotherapy response. Citation Format: Blair V. Landon, Julia L. Boland, Andrea E. Wahner Hendrickson, Deborah K. Armstrong, Boris Winterhoff, Jaime Wehr, Akshaya V. Annapragada, Christopher Cherry, Archana Balan, Guneet Kaleka, Victor E. Velculescu, Stephen B. Baylin, Cynthia A. Zahnow, Dennis J. Slamon, Gottfried E. Konecny, John A. Glaspy, Valsamo (Elsa) Anagnostou. Pembrolizumab and epigenetic modification with azacitidine reprogram the tumor microenvironment of platinum-resistant epithelial ovarian cancer: clinical and translational findings from a phase II study [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 CT260.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Background: Paraneoplastic syndromes are associated with 10% of ovarian cancers. Neuromyelitis optica spectrum disorders (NMOSD), which can present with vision changes, paraplegia, vomiting, and/or intractable hiccups, are rarely associated with ovarian cancers. We present the first recorded case of NMOSD in the setting of malignant immature ovarian teratoma, with concurrent leptomeningeal carcinomatosis contributing to clinical presentation. Case: We describe a 27-year-old patient with Stage IVB Immature Ovarian Teratoma complicated by leptomeningeal carcinomatosis, who initially presented with intractable hiccups, nausea, and vomiting, and eventually developed attenuated vision. Neurological workup revealed AQP4-IgG antibodies, suggesting neuromyelitis optica (NMO) as a paraneoplastic syndrome (PNS). The patient’s cancer was treated with tumor resection, BEP (bleomycin, etoposide, cisplatin) therapy, maintenance bevacizumab, and brain radiation. While symptoms suspicious for NMO presented early on, it was not until after tumor resection and the development of double vision that NMO was diagnosed. NMO was promptly treated with plasma exchange and high dose steroids. While therapies did lead to disease stabilization, she was left with residual neurologic deficits requiring gait assistance. Conclusion: Early symptoms such as intractable hiccups, nausea, or vomiting may precede optic neuritis or myelitis and serve as initial warning signs of NMOSD. Clinicians should maintain a high index of suspicion and low threshold for neurology consultation and AQP4-IgG antibody titers, especially when neurologic symptoms are not fully explained by metastatic disease.

Women diagnosed with high grade serous ovarian cancer (HGSOC) often respond to initial rounds of neoadjuvant chemotherapy, but then undergo multiple rounds of relapse and regression before acquiring resistance. This pattern of response and relapse suggests that transient, non-genetic resistance mechanisms are engaged by a subpopulation of tumor cells allowing them to survive and re-form a tumor. To elucidate the mechanisms underlying this transient resistance, we performed scRNASeq and cyclic immunofluorescence (CyCIF) on matched pre- and post-treatment tissues from seven patients. Our transcriptomics data revealed that the interferon (IFN) pathways, IFNα and IFNγ, and the tumor necrosis factor alpha (TNFα) pathway were enriched following therapy in six out of the seven patients. The enrichment of the IFN and TNFα pathways following chemotherapy exposure suggested that tumor cells expressing these programs may survive treatment and thus contribute to relapse, prompting us to study this population further. Spatial analysis of three interferon-stimulated genes (ISGs) revealed that a large proportion of ISG+ tumor cells appear to occupy specific niches containing ISG+ immune cells, while other ISG+ tumor cells were not adjacent to ISG+ immune cells, suggesting both intrinsic and extrinsic mechanisms of IFN pathway activation. It has been reported that IFN is activated in the early lesions of HGSOC known as serous tubule intraepithelial carcinomas (STICs). To investigate whether the IFN pathway activity early in tumorigenesis may be associated with reactivation of retroviral DNA, we performed CyCIF on samples containing STICs and found correlated expression of ISGs and the LINE1 protein product, ORF1P. These STIC areas were typically not associated with immune cells. Similarly, we detected correlated expression of ORF1P with ISGs in invasive tumor cells. Together, our findings suggest that endogenous retroviral reactivation may activate the cGAS/STING pathway, turning on IFN and establishing an IFN+ tumor cell population. To further investigate the cellular heterogeneity of HGSOC and identify pathways that are co-expressed with the inflammatory pathways, we sub-clustered individual patients’ tumors. This analysis revealed two distinct tumor cell states: one associated with high expression of the inflammatory pathways with additional stress-related programs and EMT, and the other with MYC pathway, cellular proliferation, and metabolic pathways. We were able to confirm this coordinated expression in an additional 40 pre-treatment samples. Using an independent cohort from the TRIO14 ovarian cancer trial, we found the same pattern in HGSOC tumors from 46 patients. Future studies of this population aim to understand the functional importance of the IFN/inflammatory/stress state and to identify targetable vulnerabilities. Nomeda Girnius, Muyi Liu, Laura M. Selfors, Jaeyoung Kang, Linna Lahmadi, Mayura Thomas, Aylin Z. Henstridge, Morgan Gruner, Jordan Mattson, Dennis J. Slamon, Gottfried E. Koneckny, Andrew C. Nelson, Timothy K. Starr, Ronny Drapkin, Boris J. Winterhoff, Joan S. Brugge. Chemotherapy enriches one of two pre-existing coordinated cellular programs characterized by inflammatory and stress pathways in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1249.

DNA methyltransferase (DNMT) and PARP inhibitors induce a stimulator of IFN gene-dependent pathogen mimicry response (PMR) in ovarian and other cancers. In this study, we showed that combining DNMT and PARP inhibitors upregulates expression of the nucleic acid sensor NFX1-type zinc finger-containing 1 (ZNFX1) protein. ZNFX1 mediated the induction of PMR in mitochondria, serving as a gateway for stimulator of IFN gene-dependent IFN/inflammasome signaling. Loss of ZNFX1 in ovarian cancer cells promoted proliferation and spheroid formation in vitro and tumor growth in vivo. In patient ovarian cancer databases, expression of ZNFX1 was elevated in advanced stage disease, and ZNFX1 expression alone significantly correlated with an increase in overall survival in a phase III trial for patients with therapy-resistant ovarian cancer receiving bevacizumab in combination with chemotherapy. RNA sequencing revealed an association between inflammasome signaling through ZNFX1 and abnormal vasculogenesis. Together, this study identified that ZNFX1 is a tumor suppressor that controls PMR signaling through mitochondria and may serve as a biomarker to facilitate personalized therapy in patients with ovarian cancer.Significance: DNMT and PARP inhibitors induce a nucleic acid sensor, ZNFX1, that serves as a mitochondrial gateway to STING-dependent inflammasome signaling with tumor suppressor properties in ovarian cancer.

Within ovarian cancer research, patient-derived xenograft (PDX) models recapitulate histologic features and genomic aberrations found in original tumors. However, conflicting data from published studies have demonstrated significant transcriptional differences between PDXs and original tumors, challenging the fidelity of these models. We employed a quantitative mass spectrometry-based proteomic approach coupled with generation of patient-specific databases using RNA-seq data to investigate the proteogenomic landscape of serially-passaged PDX models established from two patients with distinct subtypes of ovarian cancer. We demonstrate that the utilization of patient-specific databases guided by transcriptional profiles increases the depth of human protein identification in PDX models. Our data show that human proteomes of serially passaged PDXs differ significantly from their patient-derived tumor of origin. Analysis of differentially abundant proteins revealed enrichment of distinct biological pathways with major downregulated processes including extracellular matrix organization and the immune system. Finally, we investigated the relative abundances of ovarian cancer-related proteins identified from the Cancer Gene Census across serially passaged PDXs, and found their protein levels to be unstable across PDX models. Our findings highlight features of distinct and dynamic proteomes of serially-passaged PDX models of ovarian cancer.

Introduction/Background Antiangiogenic therapy using bevacizumab has proven effective for patients with advanced ovarian cancer. However, there is still an unmet need in ovarian cancer to identify patients who benefit from such treatment. The nine-protein signature score vascular endothelial growth factor inhibition response predictor (ViRP) has been shown predictive for response in patients with HER2-negative breast cancer. Methodology ICON7 was an international, phase 3, open-label, randomized trial assigning patients with either high-risk early-stage disease or more advanced disease to standard chemotherapy +/- bevacizumab, given concurrently and continued in maintenance therapy. DASL gene expression arrays have been performed on FFPE tissue from patients enrolled in the German contribution to the trial. The mRNA based ViRP score was calculated using quantile normalized and probe averaged mRNA expression values and its association with clinical outcome was studied. Results mRNA expression was available for 359 patients, of whom 189 patients were treated with bevacizumab. We used the earlier determined cut-off <0.3 as a positive ViRP score. Clinical characteristics were balanced across the groups with positive/negative ViRP score. Patients with a positive ViRP score have statistically significant longer progression-free survival with a median of 26.7 months compared to 19.1 months in patients with negative ViRP score (HR 0.58, 95%CI 0.41–0.84, p=0.003). Furthermore, overall survival was significantly longer in patients with a positive ViRP score with median OS not reached compared to 48.2 months in patients with negative ViRP score (HR 0.63, 95%CI 0.41–0.97, p=0.033). Among patients treated with chemotherapy alone ViRP was significantly associated with PFS (HR 0.67, 95%CI 0.46–0.97, p=0.034), but not OS (HR 0.80, 95%CI 0.52–1.23, p=0.31). Conclusion The ViRP score is predictive for survival benefit of treatment with chemotherapy with bevacizumab in patients with ovarian cancer. This indicates a tumor agnostic signal which identifies patients deriving the largest benefit from adding bevacizumab. Disclosures KL: Receipt of grants/research supports: GSK, research funding paid to Institution; Receipt of honoraria or consultation fees: Advisory board fees: Astra Zeneca, Nycode, GSK, Eisai FH: Receipt of honoraria or consultation fees: Novocure, PharmaMar, Astra Zeneca, Roche, Tesaro, GSK, Clovis, Amedes, NewOncology, Zailab RK: Receipt of honoraria or consultation fees: Astra Zeneca, MSD; GSK, Roche, Novocure JS: Research Funding: Institution: AZ, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, Roche. Consulting/Ad Bds: AZ, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, J&J, Roche, Ingress Health, Riemser, Sobi, GSK, Novartis; Honoraria: AZ, Eisai, Clovis Oncology, Olympus Medical Systems, J&J, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GSK, Bayer; Travel, Accommodations, Expenses: AZ, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, Olympus.

Objectives We sought to confirm utility of our institution's modified Proactive Molecular Risk Classifier for Endometrial Cancer protocol in our daily practice, which includes mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) immunohistochemistry with in-house next-generation sequencing for POLE, TP53, and CTNNB1.Methods We conducted a retrospective review of all patients in our institution who underwent primary endometrial carcinoma resection from the year prior to protocol implementation (PRE; October 1, 2020, to September 30, 2021) through first year of implementation (POST; October 1, 2021, to September 30, 2022) to compare the distribution of molecular and traditional staging factors using GOG-249 criteria to assign clinical risk.Results In total, 136 of 260 PRE patients were classified as clinically low risk (LR), of whom 31 were MMR deficient. Of the 157 LR POST patients with endometrioid-type carcinoma, 45 were MMR deficient, 5 were POLE mutant, 5 were TP53 mutant, 56 were of no specific molecular profile (NSMP), and 46 did not receive full protocol testing. Of all 79 POST NSMP endometrioid-type cases, 18 were CTNNB1 mutated and 8 showed L1CAM expression.Conclusions Our protocol identified 22 (14%) of 157 LR tumors that harbored incipient intermediate- to high-risk molecular aberrations in TP53, CTNNB1, or L1CAM. Moving forward, results of ongoing trials assessing adjuvant therapy decisions based on molecular classification are necessary to confirm protocol utility and identify appropriate modifications.

Abstract Introduction: Immunotherapy has demonstrated modest effectiveness for patients with platinum-resistant ovarian cancer, which is in part related to the immunosuppressive tumor microenvironment (TME) of ovarian cancers. Epigenetic modulators in combination with immune checkpoint inhibitors (ICIs) may represent a potential way to sensitize ovarian cancer to immunotherapy by TME reprogramming. Methods: We evaluated the effect of epigenetic modulation in combination with ICI by comprehensive transcriptomic analyses of serially biopsied platinum-resistant/refractory ovarian cancer. Leveraging serial tumor samples from 30 patients that received oral azacitidine and pembrolizumab in the TRIO026 phase II clinical trial (NCT02900560), we performed bulk RNA sequencing and direct digital counting of 770 target genes using molecular barcodes (nCounter, NanoString) for 72 serial tumor samples, prior to treatment initiation and 6 weeks on-therapy. RNA sequencing of ~200 million reads for each sample was used for differential gene expression and gene set enrichment analysis (GSEA) and cell type deconvolution. Target gene expression data was normalized and analyzed for differential gene and pathway expression. Results: Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes (IFNG, GZMA and GZMH; FDR-adjusted p=0.0184) as well as the co-inhibitory molecule CTLA-4 (FDR-adjusted p=0.0184). GSEA revealed an enrichment of IFNG response, natural killer cell mediated cytotoxicity, neutrophil degranulation, inflammatory response, and antigen processing/presentation related gene sets on-therapy (FDR-adjusted p < 0.001). Target gene expression analyses orthogonally confirmed these findings, which were also concordant with pathway scoring analyses showing an increased score for immune inflammatory pathways such as INFG signaling (Wilcoxon rank sum test p=0.01). Immune cell subset deconvolution suggested TME reshaping driven by a greater density of intra-tumoral T cells on-therapy (Wilcoxon rank sum test p=0.012). Higher IFNG, CXCL13, CXCR5 expression, CD8 T cell and NK cell density were associated with longer time on treatment, both at baseline and at the on-therapy timepoint. GSEA revealed an upregulation of interferon gamma, adaptive immunity, antigen presentation as well as conserved immune response gene sets on-therapy, for the patients attaining longer time on-treatment. Conclusion: Combination epigenetic and immunotherapy induces an inflammatory response and reshaping of the tumor microenvironment that may enhance their clinical efficacy, highlighting the therapeutic potential of utilizing epigenetic modulators as a way to sensitize platinum-resistant ovarian cancer to immune checkpoint inhibition. Citation Format: Blair V. Landon, Guneet Kaleka, Archana Balan, Julia L. Boland, Christopher Cherry, Gavin Pereira, Cynthia Zahnow, Boris Winterhoff, Stephen Baylin, Victor E. Velculescu, Gottfried E. Konecny, John A. Glaspy, Valsamo Anagnostou. Combined epigenetic therapy and immune checkpoint blockade drive reshaping of the tumor microenvironment of platinum resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7551.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT , in HGSOC ( p = 3.9 × 10 −8 ). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

3082 Background: CLDN6, a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies and has little to no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of new therapeutics. TORL-1-23 is first-in-class ADC targeting the tumor-specific antigen CLDN6. Methods: TORL123-001 (NCT05103683) is an ongoing, 2-part, first in human study to characterize the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TORL-1-23 monotherapy in participants with advanced solid tumors. Serum pharmacokinetics (PK), immunogenicity and clinical efficacy are also assessed. TORL-1-23 is administered as a 30-minute IV infusion once every 3 weeks in 21-day cycles. During Part 1 (Dose Escalation), cohorts of 1 to 6 participants are evaluated at each dose level according to an accelerated titration design. In Part 2 (Dose Expansion), several cohorts of patients with CLDN6-expressing cancers will be evaluated to confirm the RP2D in ovarian cancer, NSCLC, and other CLDN6-expressing cancers using a CLDN6 IHC companion diagnostic. Results: As of 01FEB2023, 22 patients with ovarian (n=18), testicular (n=3), and endometrial (n=1) cancers were enrolled and treated across 8 dose levels ranging from 0.2 to 2.4 mg/kg IV every 3 weeks. 95% of pts had received ≥ 3 prior lines of treatment in the metastatic setting. The most common treatment-related adverse events were Gr1/2 fatigue (n=5), Gr1 peripheral neuropathy (n=4), and Gr1 nausea (n=3). No DLTs have been reported and no dose reductions have been required. Preliminary PK data demonstrate sustained exposure of TORL-1-23 ADC over the 21 day dosing interval and low levels of serum MMAE indicating low off-target MMAE exposure outside of tumor. Partial responses (PR) were observed in 4/17 efficacy evaluable participants with CLDN6+ disease (3 ovarian, 1 testicular). Dose escalation is ongoing and updated results will be presented. Conclusions: TORL-1-23 has a favorable safety/tolerability profile and PK characteristics with preliminary antitumor activity in pts with heavily-pretreated CLDN6-expressing ovarian and testicular cancers. Doses above the historic MTD for MMAE containing ADCs may be explored given the safety/tolerability and PK data observed up to 2.4 mg/kg. Dose finding is ongoing to identify the MTD and optimal doses for subsequent development. Clinical trial information: NCT05103683 .

CLDN6 is expressed at high levels in multiple cancers with little to no expression in normal tissues and has been implicated in the initiation, progression, and metastasis of some cancers. CLDN6 is an ideal target for development of new therapeutics. TORL-1-23 is first-in-class ADC targeting the tumor-specific antigen CLDN6. This ongoing first in human study (TORL123-001, NCT05103683) characterizes the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TORL-1-23 in participants with advanced solid tumors. Pharmacokinetics (PK), immunogenicity and clinical efficacy are also assessed. TORL-1-23 is administered IV every 3 weeks. In Dose Escalation, cohorts up to 6 participants are evaluated at each dose level according to an accelerated titration design. In Dose Expansion, patients with CLDN6-expressing cancers will be evaluated to confirm the RP2D in ovarian cancer, NSCLC, and other CLDN6+ cancers using an IHC companion diagnostic. Doses above the historic MTD for MMAE containing ADCs are being evaluated given the favorable safety/tolerability at doses <2.4 mg/kg. 30 patients with ovarian (n=22), testicular (n=5), and endometrial (n=3) cancers were enrolled across 9 dose levels ranging from 0.2 to 3 mg/kg IV every 3 weeks (as of 01MAY2023). 93% of pts had received ≥ 3 prior lines of treatment in the metastatic setting. The most common treatment-related adverse events were Gr1/2 fatigue (n=6), anemia (n=5), and peripheral neuropathy (n=4). No DLTs were observed at doses ≤2.4 mg/kg. Sustained PK exposure of TORL-1-23 over the dosing interval and low levels of circulating MMAE are noted. Partial responses (PR) were observed in 7/22 (32%) efficacy evaluable participants with CLDN6+ disease (6 ovarian, 1 testicular) across dose levels. 3/3 (100%) participants with CLDN6+ ovarian cancer responded at the 2.4 mg/kg dose level. Data from 3 mg/kg are pending. In participants with heavily-pretreated CLDN6-expressing ovarian cancer, the novel TORL-1-23 ADC has a favorable safety/tolerability profile and encouraging antitumor activity in a phase 1 dose finding study. Further evaluation in ovarian cancer and other CLDN6+ cancers is warranted.

e13655 Background: Over the past decades, US congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. It remains unclear whether multiple designations per indication are redundant. This study analyzes cancer drugs with multiple special designations regarding their FDA approval timelines, evidence, benefit, epidemiology and price. Methods: All anti-cancer drugs and their supplemental indication approvals were identified in the Drugs@FDA database from 2000 to 2022. For each indication, clinical trial characteristics, epidemiologic, and price data were collected from FDA labels, the Global Burden of Disease Study, and Medicare & Medicaid Part B and D, respectively. The association between overall survival (OS) and progression-free survival (PFS) hazard ratios (HR) and drug indications’ number of special designations were compared in meta-analyses and meta-regressions. Results: We identified 170 anti-cancer drugs with FDA approval in 455 indications. The median time to first FDA approval was 13.8 years for drugs with zero, 7.3 years with one, 7.1 years with two, 7.8 with three, 5.8 with four, and 5.3 with five special designations (HR per additional designation: 1.27, 95%CI: 1.09-1.48, p=.002). Drug indications with more special designations were more frequently granted to rare diseases with fewer treatment options supported by smaller and shorter open-label phase 1/2 trials. OS HRs were 0.79 for indications with zero, 0.74 with one, 0.73 with two, 0.69 with three, 0.59 with four, and 0.52 with five special designations (p=.024). On average, each additional special designation was associated with lower HRs for OS (ß=-0.03, p=.002) and PFS (ß=-0.07, p<.001). Each additional special designation was associated with a 19.05% (95%CI: 4.56-35.55, p=.013) higher drug price. Conclusions: The FDA’s special designations are non-redundant. Multiple special designations are associated with faster approval times and a greater efficacy for patients with high unmet needs, while multiple special designations are associated with less robust trial evidence and higher drug prices. This study supports the strategy of special FDA designations for unmet clinical needs.

Appendix 1: Additional Methods for Subtype Assignment Figure S1. Consistency check between published supervised classification vs. novel unsupervised clustering in TCGA Figure S2. Subclasses were computed by applying a consensus NMF clustering method which confirmed the presence of four stable clusters. Consensus matrices and sample correlation matrices are shown for k=2 to k=8 using the 1500 probe sets based on genes described by TCGA. Figure S3. Kaplan Meier analysis of progression free and overall survival for bevacizumab vs. standard treatment. Panel A: total study population. Panel B: patients at high risk for progression (suboptimally cytoreduced stage III and all stage IV patients) Supplemental Table 1. Results of progression-free survival restricted mean