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Background In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum‐based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor). Methods Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III–IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression‐free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA‐sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD‐L1 expression was scored by immunohistochemistry (IHC). Results A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss‐of‐function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD‐L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD‐L1 protein expression in the GR group. Conclusions Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4., In patients with suboptimally‐debulked, advanced high grade serous ovarian cancer (HGSOC), the spectrum of responses to first line platinum‐based chemotherapy (PtC) vary from durable to non‐existent, highlighting an unmet medical need for those with poor responses. Our study molecularly characterizes a cohort of HGSOC patients with distinct responses, either good or poor, to PtC. The good and poor responders have median progression‐free intervals of 32 and 3 months, respectively, and molecular analysis of tumors identifies differences in DNA damage response pathways and immunity, namely, tumors from poor responders to first line PtC have a distinct molecular profile characterized by actionable drug targets including PARP4.

BackgroundEGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advancedEGFRm NSCLC was evaluated.MethodsThis Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19delEGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy.ResultsFrom dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9–80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5–15.2) and median response duration was 9.2 months (95% CI: 3.7–14.0).ConclusionsDurvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients withEGFRm NSCLC.

Background: Loss of function in the tumor suppressor gene, PTEN, activates PI3K/AKT signaling, driving tumor growth. Somatic mutations in PTEN occur in 5-10% of estrogen-receptor-positive (ER+) breast cancer (BC), and PTEN loss/inactivation is associated with an aggressive BC phenotype and poor outcome. Capivasertib, a pan-AKT kinase inhibitor, has shown antitumor activity in solid tumors. In ER+ BC, suppression of PI3K/AKT signaling results in a compensatory increase in ER-dependent transcription, potentially limiting the efficacy of AKT inhibitors when given as monotherapy. We therefore investigated concurrent inhibition of AKT and ER with combination therapy of capivasertib and fulvestrant in PTEN-mutant ER+ metastatic BC (MBC). Methods: In an expansion cohort (part F) of a Phase I study (NCT01226316), oral capivasertib 400 mg twice daily, 4 days on 3 days off, and fulvestrant at labeled dose, was administered to ER+ MBC patients (pts) with tumors harboring a deleterious PTEN alteration (identified in tissue/plasma by local next-generation sequencing [NGS], with central NGS and immunohistochemistry [IHC] performed retrospectively). Pts were enrolled in fulvestrant-naïve (FN) or fulvestrant-resistant (FR) cohorts (max 24 pts/cohort). Key objectives included safety and efficacy based on 24-week clinical benefit rate (CBR). Results: At data cut-off, 31 pts (12 FN; 19 FR) received treatment. Median number of prior metastatic regimens was 7. FN pts had higher rates of visceral disease (100%) and prior chemotherapy receipt (median 4 [range 0-8]) than FR pts (84%; median 2 [1-7]), respectively]. CBR and median progression-free survival (PFS) were 17% and 2.6 months in FN pts, and 37% and 4.1 months in FR pts, respectively (Table). Twenty-four patients (77%) had PTEN mutations and 7 (23%) had PTEN gene deletions determined by local NGS. Central plasma NGS confirmed 79% (19/24) of the PTEN mutations, and IHC confirmed complete loss of the PTENprotein in 85% (22/26) of cases. Treatment-related grade ≥3 adverse events (AEs) occurred in 32%, most frequently diarrhea and maculopapular rash (both n=2 pts). Treatment-related AEs resulted in dose reduction in 2 pts. Table. Clinical efficacyFN, n=12FR, n=19ORR, % (95% CI)8 (0.2, 39)21 (6, 46)CBR, % (95% CI)17 (2, 48)37 (16, 62)Confirmed response, n (%)1 (8)4 (21)Stable disease ≥24 weeks, n (%)2 (17)3 (16)Median PFS, months (95% CI)2.6 (1.2–4.2)4.1 (1.5–6.7)Median duration of response, months (95% CI)5.5 (NC–NC)6.9 (1.4–NC)Data cut-off was 21 March 2019. Median time from last fulvestrant administration to study entry in FR pts (n=19) was 13.8 months (range 0.7–28.2). CBR was defined as confirmed responders and those with stable disease ≥24 weeks. NC, not calculable (because of limited pt numbers); ORR, objective response rate Conclusions: Capivasertib plus fulvestrant is clinically active in heavily pretreated PTEN-mutated ER+ MBC, including in pts with prior resistance to fulvestrant. Efficacy appeared marginally better in FR than FN pts, possibly due to enrichment of pts with more aggressive disease in the FN cohort. Further analyses of the relationship between genomic features, such as concurrent mutations with drug activity, will be reported. Citation Format: Lillian M Smyth, Gerald Batist, Funda Meric-Bernstam, Peter Kabos, Iben Spanggaard, Ana Lluch, Alison Schram, Andrea Varga, Andrea Wong, Helen Ambrose, Alan Barnicle, T. Hedley Carr, Elza C de Bruin, Carolina Salinas-Souza, Andrew Foxley, Joana Hauser, Justin PO Lindemann, Rhiannon Maudsley, Robert McEwen, Michele Moschetta, Martine Roudier, Gaia Schiavon, Pedram Razavi, Udai Banerji, Sarat Chandarlapaty, José Baselga, David M Hyman. Capivasertib (AZD5363) in combination with fulvestrant in PTEN-mutant ER+ metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-05.

Purpose:Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods:Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results:Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions:This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Uncontrolled proliferation is a hallmark of cancer and can be assessed by labelling breast tissue using immunohistochemistry for Ki67, a protein associated with cell proliferation. Accurate measurement of Ki67-positive tumour nuclei is of critical importance, but requires annotation of the tumour regions by a pathologist. This manual annotation process is highly subjective, time-consuming and subject to inter- and intra-annotator experience. To address this challenge, we have developed Proliferation Tumour Marker Network (PTM-NET), a deep learning model that objectively annotates the tumour regions in Ki67-labelled breast cancer digital pathology images using a convolution neural network. Our custom designed deep learning model was trained on 45 immunohistochemical Ki67-labelled whole slide images to classify tumour and non-tumour regions and was validated on 45 whole slide images from two different sources that were stained using different protocols. Our results show a Dice coefficient of 0.74, positive predictive value of 70% and negative predictive value of 88.3% against the manual ground truth annotation for the combined dataset. There were minimal differences between the images from different sources and the model was further tested in oestrogen receptor and progesterone receptor-labelled images. Finally, using an extension of the model, we could identify possible hotspot regions of high proliferation within the tumour. In the future, this approach could be useful in identifying tumour regions in biopsy samples and tissue microarray images.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.

Background: Estrogen receptor positive (ER+) breast cancer is routinely treated with endocrine therapies targeting the ER axis. However, primary and secondary resistance ultimately limits the use of these agents. Fulvestrant (FULV) is the first-in-class selective ER degrader (SERD) clinically effective in patients with ER+ breast cancer, both naïve and resistant to tamoxifen and aromatase inhibitors. FULV has low oral bioavailability, and its dose-dependent pharmacodynamic (PD) activity and clinical efficacy is limited by the currently approved maximal feasible dose (MFD) of 500 mg, which is administered monthly as two intramuscular injections. AZD9496 is an orally bioavailable, nonsteroidal, selective and potent degrader and antagonist of ER in preclinical models. This pre-surgical, window of opportunity study (NCT03236974) compared PD changes and the PD/pharmacokinetic (PK) relationships of AZD9496 with FULV in patients with newly diagnosed ER+ HER2- breast cancer awaiting curative intent surgery.Methods: In this open-label, multicenter study, patients were randomized 1:1 to receive oral AZD9496 250 mg BID from Day 1 for 5-14 days or FULV 500 mg administered intramuscularly on Day 1 only. On-treatment image-guided core tumor biopsies were taken between Days 5 and 14. The primary objective was to compare the effects of AZD9496 and FULV on ER expression in tumor tissue using pre-dose biopsies as baseline. Secondary objectives were changes in progesterone receptor (PR) and Ki-67 biomarkers, AZD9496 and FULV plasma concentrations during treatment, and safety. Immunohistochemistry was used to determine ER and PR H-scores, and Ki-67 index, and treatment effects were compared using an analysis of covariance model. Blood samples for PK analysis were taken at on-treatment biopsy and 1-2 hours afterwards. Adverse events (AEs) were monitored from screening through to a follow-up visit 28 days after the last study dose.Results: Of the 49 women enrolled, 46 received treatment (AZD9496 n=22; FULV n=24) and of these, 35 paired biopsies were evaluable (AZD9496 n=15; FULV n=20). The least square mean estimate for the reduction in ER H-score after AZD9496 treatment was 24% (80% CI: 34.4, 14.3), and after FULV treatment was 36% (44.9, 27.7), with a least square mean difference between AZD9496 and FULV of 12% (p=0.86). AZD9496 was not superior to FULV in terms of ER modulation at the tested dose. AZD9496 also reduced PR H-scores and Ki-67 levels from baseline (by 33.3% and 39.9%, respectively). These effects were not statistically superior to FULV at the tested dose (PR: -68.7%, p=0.97; Ki 67: 75.4%, p=0.98).Plasma exposure of AZD9496 (AUC -40%, Cmax -25%) was lower than predicted based on PK data from the previous phase 1 study, whereas FULV exposure was consistent with historical data. No clear exposure-response relationship for plasma concentration at biopsy and PD markers for AZD9496 or FULV were observed.The median treatment duration of AZD9496 was 9.5 days (range: 6-15), and the relative dose intensity was 100% (range: 90-125); no patients discontinued AZD9496. AZD9496 and FULV were both well tolerated, and no new safety findings were identified. No grade ≥3 toxicities or serious AEs occurred. Conclusion: AZD9496 250 mg BID reduced ER, PR and Ki-67 expression, and as such, is the first pre surgical study to demonstrate an oral SERD impacting its key biological targets. These reductions were not superior to the FULV clinically approved dose, which performed as expected based on historical data. Pre-surgical studies represent an important method to test the proof of mechanism of novel SERDs early in clinical development. Citation Format: John FR Robertson, Abigail Evans, Stephan Henschen, Cliona Kirwan, Ali Jahan, Laura Kenny, J. Michael Dixon, Peter Schmid, Ashutosh Kothari, Omar Mohamed, Peter A Fasching, Kwok-Leung Cheung, Rachel Wuerstlein, Danielle Carroll, Teresa Klinowska, Justin PO Lindemann, Alexander MacDonald, Richard Mather, Rhiannon Maudsley, Michele Moschetta, Myria Nikolaou, Martine P Roudier, Tinnu Sarvotham, Gaia Schiavon, Diansong Zhou, Li Zhou, Nadia Harbeck. A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2- primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-01.

There is no approved therapy specifically for the treatment of papillary renal cell carcinoma (PRCC). Advances in molecular profiling of PRCC have identified a segment of PRCC with 10% MET mutation rates (Linehan et al 2016). Chromosome 7 gain is a hallmark of PRCC and thought to occur at 50% frequency in PRCC (Jiang et al 1998). We undertook a retrospective analysis of archival tumors to evaluate MET pathway aberrations for correlation with efficacy in a phase II study of savolitinib (volitinib, AZD6094, HMPL-504) in patients with PRCC (NCT02127710). Archival diagnostic tumor samples were mandated for central confirmation of PRCC diagnosis, histological subtyping, and for exploratory biomarker analysis. Eighty-four archival tumors were obtained and profiled using four methods: H&E stain for PRCC histological subtype, immunohistochemistry (IHC) for c-Met protein expression (Ventana, CONFIRM), fluorescent in situ hybridization (FISH) for MET gene amplification (Abbott, VYSIS), and Next Generation Sequencing (NGS) as an orthogonal method for confirmation of MET amplifications, detection of HGF gene amplifications, MET mutations, chromosome 7 ploidy, and other exploratory genomic biomarkers (Foundation Medicine Inc., T7 panel). Eight patients with a confirmed partial response (PR) to savolitinib were used to define MET-driven PRCC. Retrospective analysis demonstrated that only NGS, not IHC, FISH or histological subtype, identified all PRs. NGS detected any one of the following biomarkers alone or in combination in PRs: chromosome 7 copy number gain, MET or HGF gene focal amplification, MET kinase domain mutations. The frequency of these biomarkers in the phase II population were 31.5%, 10%, 1%, and 7.5%, respectively and captured all responders (18% ORR); however, 42% of non-responders (PD and SD) were also classified as MET-driven by NGS. Focal MET amplifications were confirmed with MET FISH testing, but FISH was unable to identify gains in chromosome 7. IHC was not as sensitive as NGS (57% vs 100%) but had a higher specificity. Molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. Citation Format: Melanie M. Frigault, Sabina Signoretti, Aleksandra Markovets, Daniel Stetson, William Howat, Martine Roudier, Vincent Haddad, Brian Dougherty, Toni K. Choueiri, J. Carl Barrett. MET gene copy number gains evaluated by NGS is more predictive than other methods to enrich for papillary RCC patients sensitive to savolitinib, a selective MET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4541.

2538Background: Knowledge of the success rates in obtaining baseline and on treatment tumour biopsies with sufficient evaluable tumour tissue is valuable in guiding strategies for evaluation of PD ...

5561Background: Patients with advanced high grade serous ovarian cancer (SOC) who undergo a suboptimal debulking primary surgery typically have adverse clinical outcomes. However, a spectrum of sen...

Introduction The prevalence of urate crystals in residual tissue samples from coronary arteries, aortic valves and prostate glands was assessed. Methods Alcohol-fixed coronary arteries from 55 explanted hearts, alcohol-fixed aortic valves collected from 75 valve replacement surgeries and 40 frozen, unfixed prostate specimens resected during cancer surgery were examined for birefringent crystals with polarising microscopy. Results In the 55 explanted hearts, 6 (10.9%) contained a coronary artery with birefringent crystals. One of the 75 aortic valves (1.4%) contained negatively and positively birefringent crystals. Nineteen of the 40 (47.5%) prostates contained birefringent crystals. Conclusions We found that a remarkable percentage of coronary arteries and prostate specimens contained birefringent crystals. Crystal presence is an obvious prerequisite for possible crystal induced-inflammation in these tissues, just as similar crystals elicit a gouty inflammatory cascade in synovial joints. Further studies are necessary to determine whether urate crystals may play this role in these tissues and, if so, to establish whether urate-lowering therapy may be beneficial in prostatitis and coronary disease.