Importance Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation. Objective To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC. Design, Setting, and Participants The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor-naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024. Interventions Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years. Main Outcomes and Measures The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life. Results A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair-proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2). Conclusions and Relevance The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial.

Background: Ethnic and socioeconomic disparities in cancer outcomes are exacerbated by clinical trial underrepresentation. This study aims to identify inequalities in ethnicity and socioeconomic features among ovarian cancer clinical trial participants in two London cancer centres. Methods: All ovarian cancer patients treated between 2017 and 2022 were included. Patients participating in clinical trials were classified as the trial population (TP); the remainder were considered the non-trial population (NTP). Data on disease characteristics and sociodemographic features, including ethnicity and Indices of Multiple Deprivation (IMD) deciles, were accessed from electronic patient records. Results: Of the 892 patients, 212 (24%) were enrolled in trials: 87 in Phase II, 103 in Phase III, and 21 in prospective, non-investigational medicinal product trials. The TP were more likely to be of White ethnicity (72.6% vs. 57.5%; p < 0.001), younger (mean age 58 vs. 60; p = 0.003), living in less deprived areas (most deprived tercile: 21.2% vs. 34.0%; p = 0.004), and English-speaking (95.8% vs. 90.9%; p = 0.041). In the multivariate analysis, White ethnicity (p < 0.0001), age (p = 0.003), IMD decile (p = 0.007), and interpreter requirement (p = 0.037) were independent predictors of trial participation. Conclusions: Ethnic and socioeconomic inequalities affect trial participation, potentially worsening health disparities in ovarian cancer patients. Strategies to overcome trial recruitment barriers for underserved groups are needed to improve the equity of care.

Introduction/Background MOC is a rare form of epithelial ovarian cancer, most frequently presenting at an early stage. We investigated real-world outcomes in this rare pathology across two tertiary centres. Methodology Patients with a diagnosis of MOC treated at University College London and St Bartholomew's Hospitals between 2009–2021 were identified and data collected. Calculations were performed using Prism v9.5.1; p=<0.05 was considered significant. Results 90 patients were identified; FIGO I n=67 (75%), II n=12 (13%), III n=9 (10%), IV n=1 (1%); unknown n=1 (1%). Tumour grade(G)1 n=24 (27%), G2 n=43 (48%) and G3 n=11 (12%); unknown n=2 (2%). Median age 51 years (21–97); 88/90 (98%) had primary surgery; 2/90 (2%) inoperable. 51 patients had documented appendectomy; 1/51 (2%) with serosal involvement. 33 patients had systemic anti-cancer therapy (SACT); carboplatin/paclitaxel n=26 (79%); single agent carboplatin n=3 (10%) and FOLFOX/CAPOX n=4 (12%). Long term survival data available for 88 patients; 2 lost to follow-up. Relapse rate (RR); FIGO I 10/65 (15%), II 1/12 (8%), III 8/9 (89%) and IV 1/1 (100%). RR for FIGO I G3 was 3/6 (50%), significantly higher (p=0.0072) compared to G1 1/28 (4%) but not G2 disease 6/32 (19%). 9/61 (15%) FIGO I G1/G2 disease received SACT with no significant difference in RR p=0.06. For FIGO I/II disease, median progression free survival (mPFS) and overall survival (mOS) not reached; III mPFS 10 months and mOS 33 months; IV mPFS 6 months and OS 6months. Conclusion We found MOC most frequently presented with FIGO I/II disease which, alongside tumour grade, inferred a better prognosis. We found no benefit from SACT in reducing relapse in early-stage low grade tumours. Patients with advanced stage disease are likely to recur with a short mPFS and mOS reflecting the need for further research to SACT options in this population. Disclosures See attached COI forms.

Background Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK.Methods Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG.Results 132 pts were included. Median age was 56 years (28-91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5-6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts.Conclusion This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience.

Abstract Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating “TGFβ remodeling of the extracellular matrix” as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.

Understanding the genomic complexity of high-grade serous ovarian cancer is now essential in guiding patient management, particularly in the first-line setting. Our knowledge in this area has expanded rapidly in recent years, with biomarkers developing in parallel to agents designed to exploit cancer-associated genetic aberrations. In this review we will take stock of the current landscape of genetic testing and look towards the future with developments that aim to refine personalized treatment paradigms and track treatment resistance in real time.

In this study we explored the effects of chemotherapy on the extracellular matrix of high-grade serous ovarian cancer metastasis (HGSOC) at structural-textural protein level and transcriptionally, in order to identify the microenvironmental features that accompany a successful response. We studied two murine orthotopic, transplantable syngeneic models of HGSOC, one that displays excellent response to carboplatin/paclitaxel (60577) and one that is resistant to treatment (HGS2)1. Using immunohistochemistry, we stained omental tumors from both models for the ECM components fibronectin (FN1), collagen 1A1 (COL1A1) and versican (VCAN), also using Masson’s Trichrome to stain for collagen. We analyzed their abundance, textural features (Haralick features) and structure with the image analysis softwares, QuPath and TWOMBLI respectively. A compilation of 44 ECM metrics, which we named the “structure index”, correlated with response to chemotherapy, as measured by reduction in omental tumor weight. In parallel, we performed RNAseq on the omental tumors, identifying clusters of genes that change over time with chemotherapy treatment of the responsive model 60577, while the chemoresistant model HGS2 displayed limited alteration of gene expression. We integrated RNAseq and ECM structure and texture data, and showed the structure index was correlated with 144 core matrisome genes. To identify potential therapeutic targets, we then focused our study on genes that remained highly expressed in resistant tumors post chemotherapy, but were originally low or decreased with treatment in the sensitive tumors. Members of the LOX and P4HA family were found amongst these genes. We confirmed by immunohistochemical analysis that expression of LOX, LOXL2, P4HA1 and P4HA2 was downregulated by chemotherapy in the 60577 chemo-sensitive tumors while their levels remained relatively unaffected in the resistant HGS2 tumors. This study refines our understanding of the mechanisms of microenvironmental chemoresistance in HGSOC, highlighting putative therapeutic targets to increase the efficacy of platinum-based chemotherapy in ovarian cancer. 1 Maniati, E. et al. Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment. Cell Rep 30, 525-540.e527, doi:10.1016/j.celrep.2019.12.034 (2020). Citation Format: Panoraia Kotantaki, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Frances R. Balkwill. Chemotherapy-induced extracellular matrix remodeling in HGSOC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5957.

The treatment of high-grade serous ovarian cancer and high-grade endometrioid ovarian cancer has seen significant improvements in recent years, with BRCA1/2 and homologous recombination status guiding a personalized approach which has resulted in improved patient outcomes. However, for other epithelial ovarian cancer subtypes, first-line treatment remains unchanged from the platinum–paclitaxel trials of the early 2000s. In this review, we explore novel therapeutic approaches being adopted in the treatment of clear cell, mucinous, carcinosarcoma and low-grade serous ovarian cancer and the biological rational behind them. We discuss why such disparities exist, the challenges faced in conducting dedicated trials in these rarer histologies and look towards new approaches being adopted to overcome them.

Supplementary Data from The Tumor Microenvironment of Clear-Cell Ovarian Cancer

Introduction/Background Advanced clear cell gynaecological cancers (CCGC) have poor prognosis with objective response rates (ORR) to second-line chemotherapy between 0–8%. Preliminary clinical activity with PD-1 inhibitors have been described in CCGC. We investigated pembrolizumab monotherapy for advanced CCGC. Methodology PEACOCC is a Phase II, multicentre, single-arm trial in patients with advanced CCGC who had ≥1 prior line of chemotherapy with progression (PD) at study entry. Pembrolizumab 200 mg iv q21 days was given until PD (RECIST v1.1), unacceptable adverse event (AE), 2 years (y) pembrolizumab completed, patient or clinician decision. Primary endpoint was progression-free survival (PFS) rate at 12 weeks (w) (H0≤15%; H1≥33%; 5% 1-sided α; 90% power). Secondary endpoints included ORR, duration of response (DOR), PFS, overall survival (OS) and safety. Results 49 patients were enrolled with 48 evaluable. Median age 58.5 y (32–77 y), ECOG 0/1 54.2%/45.8%, 85.4% ovarian CCGC. Median number of prior systemic therapy 2 (1–6); 19 patients (39.6%) had received anti-angiogenic therapy. 42 patients completed median of 4 cycles pembrolizumab (1–25), 6 patients (12.5%) continue pembrolizumab. 16.7% patients had Grade(G)3 treatment-related AE (TRAE) of hyperthyroidism, acute kidney injury, raised alanine aminotransferase, raised alkaline phosphatase, anaemia, encephalitis and diabetic ketoacidosis. There were no G4 or G5 TRAE. 3 patients (6.3%) discontinued pembrolizumab due to TRAEs. The PFS rate at 12w was 43.8% (90%CI:31.5–56.6) exceeding the pre-stated lower bound of 15%. Best ORR was 25.0% (90%CI:15.1–37.3) [1 complete, 11 partial], with 1 y DOR rate 47.7% (95%CI:14.1–75.6). After a median follow-up of 2.1 y, median PFS was 12.2w (95%CI:5.9–32.9) and median OS 71.0w (95%CI:29.1–137.6). Conclusion The PEACOCC trial suggests that pembrolizumab is effective in heavily pre-treated patients with advanced CCGC: 43.8% patients were alive and progression-free at 12w. Clinical outcomes were durable with limited toxicity. These promising results justify consideration of pembrolizumab monotherapy as a new standard-of-care for advanced CCGC.

Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating "TGFβ remodeling of the extracellular matrix" as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.

Abstract Treatment of advanced Clear Cell Ovarian Cancer (CCOC) with immune checkpoint inhibition (ICI) is currently undergoing evaluation in a Phase II clinical trial. ARID1A mutations, which occur in up to 57% of CCOC, influence immune cell infiltration in pre-clinical models, but more information is needed on how it alters the tumor microenvironment (TME) of human CCOC. Methods: FFPE samples from 36 cases of FIGO III-IV CCOC were analyzed. Of the 36 cases; 21 were ARID1A wildtype (ARID1Awt), 14 ARID1A mutant (ARID1Amut) and 1 mixed. Immunohistochemistry was performed for immune markers (CD3, CD8, CD4, CD45RO, FOXP3, CD20, CD68, CD1a, Mast Cell Tryptase, Eosinophil Derived Neurotoxin, alpha-SMA) alongside PD1, PDL1, PDL2 and quantified using QuPath. The malignant cell area (MCA), leading edge (LE) and stroma were measured separately to provide information on immune marker location within the TME. Collagen was identified by Masson's Trichrome with structural analysis using the FIJI plugin TWOMBLI. Statistical analysis was performed on PRISM. Results: In this study we found significant differences between the TME of ARID1Awt and ARID1Amut tumors in terms of both immune infiltrate, collagen density and structure. ARID1Awt tumors had more collagen, with longer fibers and more branchpoints across the MCA, LE and Stroma (<0.05). Within the LE and Stroma of ARID1Awt tumors, collagen fibers formed a more diffuse isotropic matrix (<0.05). There were significant differences at the 0.05 level for all immune markers between ARID1Awt and ARID1Amut tumors apart from CD68. The LE of ARID1Amut was the most immune rich region, with the largest populations of CD3 and CD45RO T-cells, CD20 B-cells and Mast Cells. The LE of ARID1Awt tumors had the largest populations of CD4 and FOXP3 T-Cells. There were significantly more CD8 T-cells within the MCA of ARID1Amut tumors and significantly more at the LE and within the stroma of ARID1Awt (p=<0.001). Across the MCA, LE and stroma of both groups, there was significantly more PDL2 than either PD1 or PDL1 (p=<0.0001). In ARID1Amut tumors there was significantly more PDL1 expression within the MCA compared to ARID1Awt tumors, which had more PD-1 at the LE and significantly more PDL2 within both the MCA and LE (p=<0.05). Conclusion: There are significant differences in the collagen matrix, immune cell populations and the PD1-PDL1-PDL2 axis between ARID1Awt and ARID1Amut advanced CCOC tumors. This may influence response to ICI and other therapies. Citation Format: Michael-John Devlin, Rebecca S. Kristeleit, Jacqueline McDermott, Eleni Maniati, Florian Laforêts, Panoraia Kotantaki, Rowan Miller, Frances Balkwill. Impact of ARID1A mutation on the tumor microenvironment of advanced clear cell ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2748.

PURPOSE:Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS:Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS:Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION:The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.

Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer globally and commonly presents with locally advanced disease, which has a recurrence rate of around 50% despite aggressive multi-modality treatment involving surgery, radiotherapy and chemotherapy or EGFR inhibition where appropriate. As understanding of the underlying cancer biology and the complex interactions within the tumor microenvironment improves, there is gathering interest in and evidence for the role of immunomodulating agents in the management of HNSCC. Immune checkpoint inhibitors, which aim to hinder the inhibitory interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1, have demonstrated durable improvements in patient outcomes in advanced / metastatic HNSCC, with both pembrolizumab and nivolumab being granted FDA approval in 2016. There are numerous ongoing clinical trials exploring the role of checkpoint inhibitors both as single agents and in combination, administered with established treatment modalities such as chemotherapy and radiotherapy, as well as alongside other novel immune modulators. These trials are not limited to advanced / metastatic HNSCC, but also to the neo-adjuvant or adjuvant settings. As studies complete and more results become available, the role immunotherapy agents will have within the treatment strategies for HNSCC may change, with increasing biomarker selection resulting in personalized therapy aiming to further improve patient outcomes.

5581 Background: 10 year survival for ovarian cancer (OC) in the UK has improved from 18% (1971) to a predicted survival of 35% (2011). Historical data show pts with advanced CCOC have worse survival compared to other histological subtypes of epithelial OC. We sought to determine treatment type and outcome of CCOC pts at 2 UK gynaecological cancer centres. Methods: Medical records of pts with CCOC treated between 2002 and 2017 were reviewed. Data collected comprised pt and tumour characteristics, treatment and outcome. Results: 115 pts, median age 56 (29-86) years (y) with CCOC were identified: stage (S) I (62), II (16), III (23), IV (8) and unknown (6). 91 pts had pure CCOC and 24 had mixed histopathology: endometrioid (83%), serous (12%), other (5%). Endometriosis co-existed in 43 (37%) pts; 34 pure CCOC, 8 mixed endometrioid. BRCA mutations were present in 4/19 tested and MMR loss in 2/8 tested. 21/23 pts with a thromboembolic event and 9/10 pts with hypercalcaemia (2.72-3.63mmol/L) had advanced or recurrent disease. 19 pts had a prior or synchronous malignancy, most commonly endometrial (8) or breast (6). Primary refractoriness to first line treatment occurred in S I (3%), III (13%) and IV (100%) CCOC with median overall survival (OS) of 224 days (d). Recurrence rates were 22% (S I), 38% (S II) and 61% (S III). Molecular targeted agents (MTA) were used in 29 treatments; bevacizumab (45%), nintedanib (17.5%), PARP combination (10%), PI3K/mTOR inhibitor (10%), other novel agent (17.5%).33pts had 2nd line treatment with overall response rate (ORR) of 30% and progression free survival (PFS) 258d. 12/33pts treated with a regimen containing a MTA had PFS 358d vs 228d for those without. ORR in the 3rd line was 14% with PFS 185d. The OS rate at 1y was 98% (S I), 100% (S II), 86% (S III) and 0% (S IV) and at 5y was 81% (S I), 50% (S II) and 23.5% (S III). Conclusions: Late stage CCOC has a phenotype distinct to early stage with a propensity to be treatment resistant, recur, have paraneoplastic manifestations and poor survival. The 2nd line ORR of 30% in our cohort is higher than expected and may reflect increased MTA use. 21% and 25% pt had a BRCA variant or MSI loss suggesting benefit of testing CCOC.

Abstract Background: Patients (pts) with advanced gynecological (GYN) cancers have limited therapeutic options and the prognosis is poor. Early phase trials may be a suitable option for pts with good performance status. Increasingly, molecular characterisation guides pt selection for early phase trials. We sought to determine the outcome of GYN pts treated in a phase 1 unit and examined the role of molecular selection to inform therapeutic decision making. Methods: Medical records of all pts with a GYN malignancy treated within an early phase trial between 2010 and 2016 were reviewed. Data comprising patient and tumor characteristics, prior treatment, trial therapy and outcome were analysed. Results: 81 pts with a median age of 60 years (range 20-75) with a diagnosis of ovarian (OC, 54), endometrial (EC, 15) or cervical/vulval (CC, 12) cancer were identified. The median number of prior therapies for advanced disease was 3 (OC) and 2 (EC and CC) (overall range 1-6). 9 pts (11%) entered a second and 1 pt a third phase 1 study on disease progression. Next Generation Sequencing (NGS) using a targeted panel was performed in 32 pts (40%) with an actionable mutation identified in 9 including; KRAS (3pts), PIK3CA (2pts) and EGFR (2pts). Germline BRCA (gBRCA) testing was performed in 35 OC pts (65%) with 24 gBRCA mutations identified. Pts were allocated, in order of priority, where available, to (1) a trial selected on the basis of NGS or gBRCA (‘genomic’ 35%), (2) a ‘tumor specific’ cohort within an early phase trial (15%) or (3) a ‘generic’ study (51%). For the whole cohort there was an overall response rate (ORR) of 18% with 41% stable disease (SD) and median progression free survival (PFS) and overall survival (OS) of 13 and 46 weeks respectively. Outcomes were best for pts in the genomic group. Both PFS and OS were significantly longer with genomic selection (p < 0.01 for both, Mantel-cox test) with median PFS of 29.7, 14.2, 8.0 weeks and OS of 84.1, 69.7, 33.6 weeks for genomics, tumor specific and generic studies respectively. The ORR was also greatest for the genomic cohort (32%) compared to the tumour specific (7%) and generic (11%) groups. Within the heavily pre-treated EC and CC cohorts there was an OS of 30 and 42 weeks respectively. 24% of EC pts had an ORR with a further 24% with stable disease (SD). There was only 1 response (9%) in the CC cohort, however SD was seen in 64%. The OS for the OC was 55 weeks with an ORR of 20% and 46% SD. Conclusions: Early phase trials represent a good option for pts with advanced GYN malignancies. Whilst applicable to all GYN cancers, this is particularly relevant for EC and CC pts as standard treatment options are limited. For OC patients (median 3 prior lines of chemotherapy in this cohort) where standard treatment options exist, early access to phase 1 genomic trials may result in improved response rates and allow further standard options to be given subsequently. NGS is feasible in real time and may have a positive impact on outcome. Citation Format: Rowan E. Miller, Michael John Devlin, Nicholas Brown, Kin Woo, Tami Grunewald, Arran Speirs, Miriam Mitchison, Michelle Lockley, Mary McCormack, Jonathan Ledermann, Martin Forster, Tim Meyer, Rebecca Kristeleit. Guidance by molecular selection improves the outcome of early phase treatment for gynecological (GYN) cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2726. doi:10.1158/1538-7445.AM2017-2726

2532 Background: BAL101553 (prodrug of BAL27862) is a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a previous study (NCT01397929, Lopez et al. JCO 34, 2016; abstr 2525), 2-h IV infusion on Days 1, 8, 15 (q28d) of BAL101553 up to 80 mg/m2 (maximum administered dose, MAD) showed vascular toxicities, including transient hypertension, which appeared to be Cmax related. The recommended Phase 2 dose (RP2D) was 30 mg/m2 weekly IV. Based on nonclinical models, antiproliferative effects of BAL27862 are driven by AUC. This trial explores whether once daily oral administration of BAL101553 reduces Cmax-related toxicity and improves the therapeutic window (NCT02490800). Methods: Patients (pts) with advanced solid tumors who failed standard therapy, received QD oral BAL101553 (28-d cycles) in a 3+3 dose-escalation design to determine the MTD. Adverse events were assessed by CTCAEv4 grade (G); tumor response by RECIST 1.1; serial PK on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 19 pts (9M/10F; median age 67 y) received doses of 2, 4, 8, 16 or 30 mg oral BAL101553 QD. The MAD was 30 mg with DLTs of reversible G2 hallucination and asymptomatic, reversible G3 electrolyte imbalances. No DLTs were observed at ≤ 16 mg. Dosing is ongoing between 16 and 30 mg QD to determine the MTD. BAL27862 exposures after oral QD dosing of BAL101553 compared to weekly 2-h infusions suggested high relative oral bioavailability. The BAL27862 weekly AUC at the oral MAD (30 mg QD) compared to the RP2D of 30 mg/m2 for 2-h IV was more than 5-fold higher (19,656 vs 3,584 ng*h/mL) and Cmax was 1.5-fold lower (171 vs 266 ng/mL). Both Cmaxand AUC were dose-proportional, with low/moderate variability. Oral BAL101553 had no effects on blood pressure and showed no vascular toxicity. 5 pts had stable disease (2 pts [cholangiocarcinoma, neuroendocrine pancreatic cancer] > 4 cycles). Conclusions: Daily oral BAL101553 enables higher weekly exposures of BAL27862 with lower Cmax levels compared with a 2-h weekly infusion, due to the absence of Cmax related vascular toxicity. Doses up to 16 mg QD are well tolerated. The MAD has been identified as 30 mg QD; definition of the MTD is ongoing. Clinical trial information: NCT02490800.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer globally, originating from the epithelial surface of the upper aerodigestive tract from the lips to the larynx.It commonly presents with locally advanced disease, with a recurrence rate of around 50% despite aggressive multimodality treatment involving surgery, radiotherapy and chemotherapy or EGFR inhibition as appropriate.Improvements in understanding the underlying cancer biology and its evolution within the complex interactions of the tumor microenvironment, there is gathering interest in and evidence for the use of immunomodulating agents in the management of HNSCC.Immune checkpoint inhibitors, primarily programmed cell death protein 1 (PD-1) inhibitors to date, which inhibit the inhibitory interaction between PD-1 and its ligand PD-L1, have demonstrated durable improvements in patient outcomes in advanced/metastatic HNSCC, with both nivolumab and pembrolizumab being granted FDA approval in 2016.There are numerous clinical trials ongoing exploring the role of checkpoint inhibitors both as single agents and in combination, administered with established modalities such as chemotherapy and radiotherapy, as well as alongside other novel immune modulators.These trials are not limited to advanced/ metastatic HNSCC, but also explore neoadjuvant or adjuvant settings.As studies complete and more data become available, immunotherapy agents are likely to have expanding roles within the treatment algorithms of HNSCC, and with greater biomarker development have the potential to further improve patient outcomes via a personalized therapy approach.

5597 Background: Patients (pts) with advanced endometrial (EC), cervical and vulval (CVC) cancer have limited therapeutic options and poor prognosis. Early phase trials may be a suitable option for pts with good performance status aided by molecular selection. We sought to determine the outcome of EC and CVC pts treated in a phase 1 unit. Methods: Medical records of pts with EC and CVC treated within an early phase trial between 2010 and 2016 were reviewed. Data comprised pt and tumor characteristics, prior therapy, trial therapy and outcome. Results: 38 pts, median age 59 years (21-74) with EC (19) or CVC (19) were identified. Median prior therapies for advanced disease: 1 (1-3). Histological subtypes: endometrioid (4), high grade serous (HGS 7), carcinosarcoma (CS 4), clear cell (1), and adenosquamous (3) for pts with EC; adenocarcinoma (5), squamous (11), clear cell (2) and neuroendocrine (1) for CVC pts. 20 pts (53%) had Next Generation Sequencing (NGS) using a targeted panel with actionable mutations identified in 10 (KRAS (4), PIK3CA (6) and EGFR (1)). Pts were allocated in order of priority to a trial (1) on the basis of NGS (‘genomic’ 8%), (2) within a ‘tumor specific’ expansion cohort (45%) or (3) a ‘generic’ study (47%). The overall response rate (ORR) was 21% with 34% stable disease (SD) and median progression free survival (PFS) and overall survival (OS) of 11 and 42 weeks respectively, with 10 pts still on study. Within the EC cohort ORR was 21% with 32% SD and PFS and OS of 9 and 38 weeks respectively. For the CVC cohort ORR was 21% with 37% SD and PFS and OS of 12 and 42 weeks respectively. Outcomes were better for the pts in the genomic and tumour specific groups. Both PFS and OS were longer with median PFS of 42, 32 and 8 weeks and OS of 91, not reached and 37 weeks for genomic, tumor specific and generic trials respectively. Conclusions: Early phase trials represent a good option for pts with advanced EC and CVC with meaningful clinical benefit observed even in this small cohort. Encouraging RR and PFS were observed in these pts with limited standard treatment options. This includes pts with difficult to treat histological subtypes such as HGS and CS EC and clear cell and adenocarcinoma CVC. NGS is feasible in real time and increasing use may benefit pts further.