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PURPOSE To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials. METHODS Plasma samples were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria. RESULTS A total of 162 plasma samples were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma samples (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.77; P < .01) and overall survival (HR, 0.54; 95% CI, 0.3 to 0.96; P = .03) compared with an increase. These differences were more marked if there was a >50% decrease in mVAF for both progression-free survival (HR, 0.29; 95% CI, 0.13 to 0.62; P < .001) and overall survival (HR, 0.23; 95% CI, 0.09 to 0.6; P = .001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients. CONCLUSION A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials.

Table S1. All TEAEs at least possibly related to one or more of the study drugs by dose level. Table S2. Statistical summary of the PF-05212384 PK parameters obtained by NCA using the available rich sampling data of cycle 1 after drug administration at day 1. Table S3. Statistical summary of the PF-05212384 PK parameters obtained by NCA using rich sampling data collected until day 4 after drug administration at day 1 cycle 1 and 2.

Purpose:This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel.Patients and Methods:Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression.Results:Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0–2). Median number of administered cycles was 6 (range, 2–16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2–G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results.Conclusions:Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.

Purpose: This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. Patients and Methods: Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression. Results: Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0–2). Median number of administered cycles was 6 (range, 2–16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2–G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results. Conclusions: Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.

BackgroundRecent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes.MethodsBlood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNAC3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor.ResultsA total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (ΔcholineC3) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNAC3 and ΔcholineC3 was prognostic for both OS and PFS. Multivariable analyses show ΔcholineC3 was a prognostic factor for PFS independent of ΔctDNAC3, cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS.ConclusionsThis is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and ΔcholineC3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding.Trial registration numberNCT03702309.

M4076 is a potent and selective oral inhibitor of ataxia-telangiectasia mutated (ATM), a key kinase of the DNA damage response (DDR) involved in double-strand break repair. Preclinically, M4076 when combined with DNA damage-inducing therapy or other DDR inhibitors caused unrestricted cell cycle progression and DNA damage accumulation, resulting in tumor cell death. Part 1A of this ongoing open-label study (NCT04882917) evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and maximum tolerated dose (MTD) of M4076 monotherapy in patients (pts) with advanced solid tumors. Dose escalation was guided by safety, along with Bayesian analysis, PK, and PD. In total, 22 pts received M4076 at 4 different dose levels (100-400 mg once daily [QD]); 21 pts (95.5%) discontinued treatment (progressive disease: 11 [50%], adverse events [AEs]: 5 [22.7%]). Dose-limiting toxicities (DLTs) were reported in 4 pts. Overall, 6 pts had ≥1 treatment-related AE (TRAE) of Grade ≥3 (including one Grade 4 hypersensitivity). The most common TRAEs were rash and anemia (Table 1). MTD was determined at 300 mg QD. As per preliminary PK across cohorts, M4076 was rapidly absorbed with median Tmax ~0.5-2 h and mean elimination half-life (t1/2) ~2-10 h; exposure increased in a dose-related manner, with minimum accumulation after multiple QD doses. At ≥200 mg QD, unbound steady state plasma concentration exceeded in vivo pCHK2 IC90 throughout the dosing interval. PD evaluation was based on the modulation of γ-H2AX (a direct ATM target) in ex vivo bleomycin stimulated CD45+ lymphocytes, by flow cytometry. Preliminary analyses showed a trend of reduction of γ-H2AX levels from day 1 to day 2, reaching 80-100% of target inhibition on day 2 with the dose range 100-400 mg QD. The MTD of M4076 was determined, and target exposure and engagement were achieved without significant hematological toxicity. Future investigations on M4076 as combination therapy are planned. Table 1. Safety overview Dose (Safety set) Patients with TRAEs (Grade ≥3) DLT analysis set (Patients with ≥80% of the planned dose or DLT per investigator) DLT DLT AE terms 100 mg(n = 2) No n = 2 No NA 200 mg(n = 7) n = 1 (decreased lymphocyte count, maculo-papular rash) n = 5 Yes(n = 1) Grade 3 maculo-papular rash (TRAE, required drug withdrawal; resolved) 300 mg(n = 9) n = 3 (anemia, spontaneous bacterial peritonitis) n = 7 Yes(n = 1) Grade 1 maculo-papular rash; Grade 2 fever (TRAEs, required treatment discontinuation; resolved) 400 mg(n = 4) n = 2 (nausea, maculo-papular rash, hypersensitivity) n = 4 Yes(n = 2) Grade 3 maculo-papular rash (TRAEs, required dose reduction/interruption and/or concomitant medication; resolved) MedDRA version 23.0, NCI-CTCAE version 5.0. Data cutoff: 2 Nov 2022 AE, adverse event; DLT, dose-limiting toxicity; NA, not applicable; TRAE, treatment-related AE Citation Format: Lillian L. Siu, Timothy A. Yap, Sofia Genta, Gregory Pennock, Christine Hicking, Xiaoli You, Jatinder K. Mukker, Giuseppe Locatelli, Anthony W. Tolcher. A first-in-human phase I study of the ATM inhibitor M4076 in patients with advanced solid tumors (DDRiver Solid Tumors 410): Part 1A results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT171.

Simple Summary Immune checkpoint inhibitor-induced insulin-dependent diabetes mellitus (ICI-induced IDDM) is an emerging form of autoimmune diabetes. We describe the characteristics of 34 patients who developed ICI-induced IDDM across five Canadian cancer centres. We observed that presentation with hyperglycemic crisis is common and that patients treated with combination immunotherapy regimens develop ICI-induced IDDM earlier than those treated with monotherapy. Our results suggest that ICI-induced IDDM is irreversible but is associated with high tumor response rates and prolonged survival. The data generated by this study may help clinicians manage ICI-induced IDDM. Abstract Immune checkpoint inhibitor (ICI)-induced insulin-dependent diabetes mellitus (IDDM) is a rare but potentially fatal immune-related adverse event (irAE). In this multicentre retrospective cohort study, we describe the characteristics of ICI-induced IDDM in patients treated across five Canadian cancer centres, as well as their tumor response rates and survival. In 34 patients identified, 25 (74%) were male and 19 (56%) had melanoma. All patients received anti-programed death 1 (anti-PD1) or anti-programmed death ligand-1 (anti-PD-L1)-based therapy. From ICI initiation, median time to onset of IDDM was 2.4 months (95% CI 1.1–3.6). Patients treated with anti-PD1/PD-L1 in combination with an anti-cytotoxic T lymphocyte antigen 4 antibody developed IDDM earlier compared with patients on monotherapy (1.4 vs. 3.9 months, p = 0.05). Diabetic ketoacidosis occurred in 21 (62%) patients. Amongst 30 patients evaluable for response, 10 (33%) had a complete response and another 10 (33%) had a partial response. Median overall survival was not reached (95% CI NE; median follow-up 31.7 months). All patients remained insulin-dependent at the end of follow-up. We observed that ICI-induced IDDM is an irreversible irAE and may be associated with a high response rate and prolonged survival.

Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively (p < 0.001).

9579 Background: High-risk melanoma has variable prognosis. Adjuvant immuno- (IO) and targeted therapy (TT) are approved for stage III-IV resected disease. However, a significant proportion of patients (pts) are cured by local treatment alone or relapse despite adjuvant therapy. Liquid biopsy with ctDNA assays have been used to predict response to treatment and identify pts at higher risk of progression/death. Personalized ctDNA assays are a highly sensitive approach that may enhance upfront risk stratification and early detection of relapse. Methods: Serial ctDNA Monitoring as a predictive Biomarker in advanced neoplAsms (SAMBA) is a Princess Margaret prospective ctDNA kinetics study (NCT03702309) in high-risk melanoma pts. Plasma is collected pre-op (pre-local treatment, if feasible), post-op (after surgery), and every 3-6 months (m) until radiological progressive disease (rPD). Personalized amplicon based NGS assays by Inivata (RaDaR) were used to detect somatic variants in ctDNA identified through whole-exome sequencing of matched tumor tissue. Progression free survival (PFS) and overall survival (OS) from the time of surgery were estimated with the Kaplan Meier and compared with the log-rank test. Results: As of December 2021, 82 of 100 planned pts have been enrolled. A total of 191 samples from 47 pts have been analyzed. Median age was 66 years (27-87), 33 were male (70%). Seven (15%), 30 (64%) and 10 (21%) were stage II/III/IV respectively. All pts had surgery and 8 (17%) adjuvant radiation. No systemic therapy was given to 11 pts (23%); 30 (64%) had IO and 6 (13%) TT. rPD occurred in 13 pts (28%). Median follow up was 24 months. A median of 48 variants were included in the personalized ctDNA panel design (35-52). ctDNA was detected (ctDNA+) at any time point in 12/47 pts (26%), of which 5/12 (42%) were BRAF and NRAS wt on tissue. Median PFS was 4.9 months (m) for ctDNA+ pts and not reached (NR) for ctDNA- pts at post-op (HR = 2.71 CI 0.60-12.31, p = 0.179). Median OS was 23.1 m vs NR in ctDNA+ vs ctDNA- pts (HR = 8.9, CI 1.45-54.77, p = 0.004). Two ctDNA+ pts had neoadjuvant IO and became ctDNA- before surgery. One, free of disease after 12 m, had ctDNA- in 4 follow up samples. The other pt was ctDNA+ in the post-op sample and relapsed within 3 m. Four of 45 (9%) pts had ctDNA+ at post-op. Two of them, including a pt who had neoadjuvant IO, did not receive adjuvant therapy and had rPD within 3 m. The other 2 pts received adjuvant IO; ctDNA cleared and pts remain free of disease at 12 and 34 m. Three pts with rising ctDNA over time experienced rPD after a median of 4 m (2-7). Conclusions: Personalized ctDNA analysis with RaDaR may improve risk of death stratification and selection of pts who could benefit from adjuvant treatment. Detection of ctDNA may precede rPD. Follow-up will continue in pts with rising ctDNA who have not yet had rPD. Pts accrual and sample collection are ongoing, and additional data will be presented. Clinical trial information: NCT03702309.

2546 Background: ctDNA kinetics with tumor-informed assays can predict treatment outcome in patients (pts) treated with anti-PD1 IO ( Bratman et al, Nature Cancer 2020). We evaluated whether early ctDNA kinetics with a tumor-naïve assay were associated with clinical outcomes in advanced solid tumor patients treated on early phase IO trials. Methods: Advanced solid tumor pts treated with investigational IO agents at the Princess Margaret Phase I program were enrolled. Baseline (B) and pre-cycle 2 (C2) (3-4 weeks after first dose) plasma samples were prospectively collected via an institutional liquid biopsy program (LIBERATE, NCT03702309). ctDNA was assessed using the tumor-naïve 425-gene Geneseeq Prime panel in a clinical laboratory. Mutations in each gene detected in ctDNA were measured as Variant Allele Fraction (VAF). Mean VAF from all mutations was calculated. Radiological response was measured per RECIST criteria and correlated using ROC curves. Hyperprogression (HPD) was defined using VHIO criteria ( Matos et al, CCR 2020). Survival outcomes were estimated using the Kaplan Meier method. Results: From 12/2017 to 3/2020, 162 plasma samples from 81 pts with 25 different tumor types were collected. Pts were treated within 25 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. Median age was 58y (range 21 – 79), 54% female, 76% ECOG1. Sarcoma and colorectal (11%, each) followed by breast (8%) and melanoma (7%) were the most frequent tumors. Median follow up was 10.3 months (m) (1.8-46.9). CR 4% (n = 3), PR 6% (n = 5), HPD 11% (n = 9). Clinical benefit (CB) rate (CR+PR+SD > 6 months) was 20% (n = 16). ctDNA was detected in 122/162 samples (75.3%) (60 at B, 62 at C2). The most frequent mutations were TP53 (32%), PI3KCA (12%), PKHD1 (11%), and KRAS (9%). Mean VAF at B below median was not associated with OS (HR = 0.68 95%CI 0.4-1.16; p = 0.16) or PFS (HR = 0.93 95%CI 0.56-1.54; p = 0.77). Mean VAF change (difference between mean VAF at B and at C2) was associated with response (AUC = 0.99) and CB (AUC = 0.86). A decrease in mean VAF from B to C2 was seen in 24 pts (37.5%) and was associated with longer PFS (median PFS 2.7 vs 1.8 m; HR: 0.43, 95%CI 0.24-0.77; p < 0.01) and OS (median OS 10.8 vs 9.1 m; HR: 0.54; 95%CI 0.3-0.96; p = 0.03) compared to an increase in mean VAF. These differences were more marked if there was > 50% decrease in mean VAF from B to C2 (n = 11, 17%) compared to decrease < 50% or increase: median PFS 3.6 vs 1.8 m (HR: 0.29, 95%CI 0.13-0.62; p < 0.01) and median OS not reached vs 9.6 m (HR: 0.23, 95%CI 0.09-0.6; p < 0.01). No differences in mean VAF change were seen between HPD and PD pts. Conclusions: In a pan-cancer solid tumor early phase trial IO cohort, a decrease in ctDNA within 4 weeks of treatment was associated with increased CB, OS and PFS. HPD pts did not show greater increases in ctDNA. Tumor-naïve ctDNA assays may be useful to identify early treatment benefit in phase I/II trials with IO.

11563 Background: Selinexor has demonstrated clinical activity in a variety of tumors including STS. Selinexor dosing at 60mg twice a week or 80mg once a week in later phase trials was associated with gastrointestinal and hematologic toxicities requiring frequent dose interruption and reduction. Preclinical in vivo studies show that selinexor use in a split-dose regimen or sustained-release formula is associated with less toxicity. This phase 1b study aimed to evaluate the safety and tolerability of split-dose selinexor in patients (pts) with advanced STS. Methods: Eligible pts with advanced STS of any histologic subtype, and ECOG performance status (PS) ≤ 1 were treated with split-dose selinexor (40mg, 20mg, 20mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15 and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. Antiemetic prophylaxis (oral dexamethasone and ondansetron) was given to all pts. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAE) by CTCAE v5.0. The secondary endpoint was assessment of quality of life (QoL) using the EORTC QLQ-c30 tool v3. Descriptive analyses of Global Health Status (GHS) QoL scores at screening (baseline) and cycle 2 day 1 (C2D1) were performed. Radiologic tumor assessments (by RECIST v1.1) were performed every 8 weeks while on treatment. Results: Nineteen pts [12 female and 7 male; ECOG 0/1, 8/11; median age 61 years (range 41 – 83)] were enrolled. The most frequent of 12 STS subtypes was leiomyosarcoma (n = 7, 37%). Among 18 patients evaluable for toxicity, there were no grade ≥ 3 TRAE. The most common grade ≤ 2 TRAE were dysgeusia (n = 11, 61%), nausea (n = 11, 61%), fatigue (n = 10, 56%) and vomiting (n = 10, 56%). Grade ≤ 2 hematologic TRAE were thrombocytopenia (n = 6, 33%), neutropenia (n = 4, 22%) and anemia (n = 1, 6%). Dose reduction was required in 3 pts (17%) due to intolerable grade 2 TRAE (fatigue, nausea, thrombocytopenia). No serious adverse event due to selinexor was noted. QoL scores were evaluable for 15 pts. The mean (± SEM) change in GHS QoL score from baseline to C2D1 was -10.6 (± 4.8). Among 16 pts evaluable for radiologic response, the best response was stable disease (SD) in 10 pts (63%), and progressive disease (PD) in 6 pts (37%). Durable clinical benefit (SD for > 16 weeks) was seen in 5 pts (31%; 95%CI 11.0 – 58.7%) The median PFS was 3.6 months (95%CI 1.7 – 7.3). Conclusions: Split-dose selinexor was well tolerated in this heterogeneous group of pts with advanced STS and warrants further interrogation. Updated toxicity, safety, efficacy and QoL data will be presented at the meeting. Clinical trial information: NCT04811196.

Objective Around 15% of epithelial ovarian cancer (EOC) patients (pts) harbor a germline BRCA1 or 2 mutation, showing different features than BRCA wild-type pts. The clinical and pathological features of an Italian BRCA mutated EOC cohort were described. Methods We retrospectively analyzed clinical, pathological and mutational data from a cohort of Italian BRCA mutated EOC pts. treated in 15 MITO centers between 1995 and 2017. Results Three-hundred thirty-one pts. were recorded. Two-hundred forty (72%) and 91 (27.5%) pts. harbored a BRCA1 and BRCA2 mutation, respectively. Median age at diagnosis was 52 years. The most frequent diagnosis was a high grade serous FIGO III or IV EOC and platinum doublet in first-line was administered to almost all pts. Fifty-three % of them had no residual disease (R = 0) at surgery. Median progression-free-survival (mPFS) after first-line chemotherapy was 29 months. Expected percentage of pts. alive at 5 years was 72.5% (CI 60.2–80.8%) and R = 0 predicted a significantly longer overall survival (OS). Sixty-six pts. (19,9%) had both an EOC and a breast cancer (BC) diagnosis. The first diagnosis was BC in 81,8% of cases with a mean interval between the two diagnoses (IBTDs) of 132.4 months. Mutational data show that the founder mutation c.5266dupC in BRCA1 was the most frequently recorded. Conclusions This is the largest Italian BRCA mutEOC cohort. The only predictor of longer OS was R = 0. EOC pts. that developed subsequently a BC are long-term survivors.

Background Central nervous system (CNS) spreading from epithelial ovarian carcinoma (EOC) is an uncommon but increasing phenomenon. We previously reported in a small series of 11 patients a correlation between Androgen Receptor (AR) loss and localization to CNS. Aims of this study were: to confirm a predictive role of AR loss in an independent validation cohort; to evaluate if AR status impacts on EOC survival. Results We collected an additional 29 cases and 19 controls as validation cohort. In this independent cohort at univariate analysis, cases exhibited lower expression of AR, considered both as continuous (p p p p = 0.005 for Progression Free Survival (PFS) and p = 0.002 for brain PFS (bPFS) respectively). Comparison of AR expression between primary tissue and paired brain metastases in the combined dataset did not show any statistically significant difference. Conclusions We confirmed AR loss as predictive role for CNS involvement from EOC in an independent cohort of cases and controls. Early assessment of AR status could improve clinical management and patients’ prognosis.

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.

Epithelial ovarian cancer (EOC) is the most common cause of death among gynecological malignancies. Despite surgical and pharmacological efforts to improve patients' outcome, persistent and recurrent EOC remains an un-eradicable disease. Chimeric associated antigens (CAR) T cells are T lymphocytes expressing an engineered T cell receptor that activate the immune response after an MHC unrestricted recognition of specific antigens, including tumor associated antigens (TAAs). CART cells have been shown to be effective in the treatment of hematologic tumors even if frequently associated with potentially severe toxicity and high production costs.In this review, we will focus on preclinical and clinical studies evaluating CART activity in EOC in order to identify possible difficulties and advantages of their use in this particular setting.The pattern of diffusion within the peritoneal cavity, the tumor microenvironment and the high rate of TAAs make EOC a particularly interesting model for CART cells use. Data from preclinical studies indicate a potential activity of CARTs in EOC, but robust clinical data are still awaited. Further studies are needed to determine the best methods of administration and the most effective CAR type to treat EOC patients.

Background: The molecular mechanisms underlying primary versus acquired resistance to anti-PD-1/L1 antibodies have not been comprehensively evaluated across different tumor types. Methods: The Immune Resistance Interrogation Study (IRIS; NCT04243720) is a prospective, investigator-initiated study at the Princess Margaret Cancer Centre, aimed to perform extensive multi-omic characterization of solid tumors with primary resistance (disease progression on first imaging; or stable disease T mutation in 6 patients (17%), followed by TERT promoter -124C>T mutation in 5 patients (14%), FGF19/FGF4/FGF3 and CCND1 amplifications in 4 pts each (11%), and MDM2 amplification, CDK4 amplification and CDKN2A loss, detected in 3 pts each (9%). Pts with acquired resistance had a higher frequency of TP53 mutations (9/13 = 69%) compared to primary resistance pts (7/22 = 32%), p=0.04; however this was not significant when corrected for multiple testing. Interestingly, amplifications in CDK4, CCND1, FGF 19/FGF 3/FGF 4, MDM2 and mutations in NF1 were only identified in pts with primary resistant tumors. Conclusions: No significant differences in disrupted genes and variants were observed in the current analysis. However, this can be due to the small number of pts analyzed thus far. Accrual to this study is ongoing. A comparison of alterations in oncogenic pathways is planned to further define the genomic landscape of pts with primary versus acquired resistance to anti-PD1/PDL1 blockade. Citation Format: Sofia Genta, Farnoosh Abbas Aghababazadeh, Ming S Tsao, Aaron R Hansen, Marcus O Butler, Albiruni R Razak, Philippe L Bedard, Ben X Wang, Pugh J Trevor, Sevan Hakgor, Jeffrey Woo, Benjamin Haibe-Kains, Lillian L Siu, Anna Spreafico. Immune resistance interrogation study (IRIS): Initial report of next generation sequencing (NGS) results in patients with primary versus acquired resistance to anti-PD1/L1 antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA021.

Cancer derives from alterations of pathways responsible for cell survival, differentiation and proliferation. Dysfunctions of mechanisms protecting genome integrity can promote oncogenesis but can also be exploited as therapeutic target. Poly-ADP-Ribose-Polymerase (PARP)-inhibitors, the first approved targeted agents able to tackle DNA damage response (DDR), have demonstrated antitumor activity, particularly when homologous recombination impairment is present. Despite the relevant results achieved, a large proportion of patients fail to obtain durable responses. The development of innovative treatments, able to overcome resistance and ensure long-lasting benefit for a wider population is still an unmet need. Moreover, improvement in biomarker assays is necessary to properly identify patients who can benefit from DDR targeting agents. Here we summarize the main DDR pathways, explain the current role of PARP inhibitors in cancer therapy and illustrate new therapeutic strategies targeting the DDR, focusing on the combinations of PARP inhibitors with other agents and on cell-cycle checkpoint inhibitors.

TPS2679 Background: Immune checkpoint inhibitors (ICI) have demonstrated efficacy in a wide variety of cancers. Nevertheless, only a small proportion of patients derive a durable benefit. Mechanisms underlying primary and acquired resistance are still incompletely understood. They comprise tumor-intrinsic factors such as genomic and transcriptomic changes; upregulation of immunosuppressive subsets; T cell exhaustion; and promotion of an immune-tolerant tumor microenvironment. The collection of tumor biopsy at disease progression (PD) is challenging both in clinical and research settings as this often occurs at the time of treatment discontinuation. However, the analysis of these samples can lead to novel strategies to prevent or reverse immune resistance. Thus, the current approach to begin a profiling study with patients at the time of PD on ICI enables access and interrogation of such samples. Methods: IRIS is a prospective, investigator-initiated trial at the Princess Margaret Cancer Centre that aims to extensively characterize the genomic, transcriptomic, epigenetic and immunophenotypic profiles of tumors with primary versus acquired resistance to ICI-based therapy. Primary resistance is defined as PD at the first on-treatment imaging, whereas acquired resistance is defined as PD occurring after an initial partial or complete response or following disease stability lasting ≥6 months. Additional objectives include the evaluation of radiomic parameters on standard radiological imaging, investigation of fecal microbiome, generation of patient-derived organoids and facilitation of data and sample sharing with the research community. The planned samples size is 100 patients. A one-time fresh tumor biopsy, blood and stool samples and archival tissue (when available) are collected at the time of PD on ICI (baseline) from all the participants. Longitudinal blood samples are obtained every 2-3 months (around the time of tumor imaging) until PD in patients receiving a subsequent treatment. Subjects who are not amenable for therapy undergo blood collections at the time of further PD. Molecular characterization of tumor samples includes: DNA/RNA sequencing, Assay of Transposase Accessible Chromatin (ATAC)-sequencing, Cellular Indexing of Transcriptomes and Epitopes (CITE)-sequencing, multiplexed immunohistochemistry and flow cytometry. Results of NGS performed on the first biopsy core are returned to patient and physician. Key eligibility criteria include diagnosis of solid tumor, progression to ICI as the most recent line of treatment and disease amenable to core needle biopsy. The IRIS trial, activated in October 2020, is currently open to enrollment. As of January 2021, 21 patients have been enrolled and a total of 92 tissue cores, 42 blood and 20 stool samples have been collected. Clinical trial information: NCT04243720.

9557 Background: Melanoma has a high probability of central nervous system (CNS) spread. Although first line nivolumab and ipilimumab resulted in 56% response rate and 29.2 months median overall survival (OS) in patients with melanoma brain metastases (MBM), there is paucity of data for patients who develop MBM after prior systemic therapy. As this subgroup is often underrepresented in clinical trials, we aimed to evaluate the OS of non-treatment naïve patients who develop MBM and identify factors related to survival. Methods: In this single-center, retrospective study, consecutive melanoma patients with > 90 days from exposure to either immune checkpoint inhibitor (ICI), targeted therapy (TT), or chemotherapy, to CNS relapse were included. OS was defined as the time between CNS relapse and death by any cause. The Log-Rank method was used to calculate OS. Cox regression analysis was used to identify differences between subgroups. Variables with a p value < 0.1 were included in a multivariate model. A p value < 0.05 was considered statistically significant. Results: Between 2012 and 2018, 135 patients were identified. Median age was 57 (29-92) years, 92 (68%) were male, and median number of prior systemic therapies was 2 (1-6). One-hundred and nine (81%) patients had cutaneous melanoma; acral lentiginous melanoma (ALM) comprised 11 (8%) patients. Molecular studies were available for 123 patients, of whom 61 (50%) were BRAF V600 mutant. Eighty-nine (66%) patients had prior ICI, of whom 33 (37%) had prior exposure to both anti-PD1 and anti-CTLA-4, either as monotherapy or combination. Amongst the BRAF V600 mutant population, 48 (79%) had prior TT. Radiotherapy was given to 112 patients, of whom 55 (49%) had SRS. Median follow-up was 41 (95% CI 30-51) months. Median OS was 6.4 (95% CI 5.3-7.5) months. Patients with ALM, > 3 MBM, ECOG 2-4 and active treatment at CNS relapse (< 30 days from last dose of treatment to MBM diagnosis) were at increased risk of death, whilst subsequent treatment with ICI was related to better survival (Table). On multivariate analyses, age ( p = 0.007), subtype ( p = 0.04), number of MBM ( p = 0.01), active treatment at CNS relapse ( p < 0.001) and subsequent ICI ( p = 0.002) remained statistically significant. Exploratory analyses suggested subsequent treatment with anti-PD1 + anti-CTLA-4 (n = 42) compared favourably to subsequent anti-CTLA-4 only (n = 21) (13 x 7 months, p = 0.004), and was independent of prior ICI. Conclusions: Previously treated melanoma patients who develop MBM have a poor prognosis, but subsequent ICI therapy seems to be associated with better OS. Further clinical investigation to identify optimal anti-PD1-based therapies is warranted for non-treatment naïve patients who develop MBM.[Table: see text]

TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors. Methods: In this phase 1, multicentric, dose escalation and dose expansion study we evaluate the safety and tolerability of AMG 650 monotherapy in patients with advanced/metastatic solid tumors (NCT04293094). The main objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on emerging safety, efficacy, and pharmacodynamics (PD) data prior to reaching the MTD. Key inclusion criteria include the presence of measurable disease and diagnosis of advanced/metastatic triple negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), serous-like endometrial cancer or other solid tumors with documented TP53 mutations. In the dose expansion phase, participants with locally advanced or metastatic TNBC or HGSOC will be treated with the preliminary RP2D identified from the dose exploration part of the study. Primary endpoints include the incidence of Dose Limiting Toxicities (DLTs),Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment-related Adverse Events and the evaluation of the number of participants who experience a clinically significant change from baseline in vital signs, electrocardiogram and laboratory tests parameters. Secondary endpoints include Objective Response Rate, Duration of Response, Progression-free Survival, Clinical Benefit Rate, Time to Response, Time to Progression, Overall Survival (OS), Maximum Plasma Concentration (Cmax) of AMG 650, Time to Maximum Plasma Concentration (Tmax) of AMG 650 as well as Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval for AMG 650. Continuous monitoring of toxicity is conducted. The study began enrolling pts in March 2020 and is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com Clinical trial information: NCT04293094.

2640 Background: Endocrine immune-related adverse events (irAEs) are frequent with immune checkpoint inhibitors (ICIs); however, ICI-related insulin-dependent diabetes mellitus (IDDM) is a rare but serious endocrine irAE. We describe the characteristics of patients who developed ICI-related IDDM across five academic Canadian cancer centres. Methods: In this multicentre, retrospective study, we included both patients who developed IDDM and patients with non-IDDM (NIDDM) or pre-DM who became insulin-dependent while on treatment with ICI. We collected data on primary tumor type, ICI regimen (single agent or combination), time to development of IDDM from ICI initiation, comorbidities, laboratory parameters at the time of IDDM diagnosis, tumor response and survival. A p value < 0.05 was considered statistically significant. Results: We identified 27 patients between July 2016 and August 2019. Median age was 60 (39-79) years, 20 (74%) were male, 15 (55%) had melanoma and 4 each (15%) non-small cell lung cancer (NSCLC) and renal cell carcinoma. Seven (26%) patients had prior NIDDM or pre-DM; 5 (18%) had an auto-immune disease (2 psoriasis, 2 inflammatory bowel disease, and 1 systemic lupus erythematosus). Laboratory parameters at presentation and management of IDDM are presented in the Table. Mean A1c was not statistically different between patients with or without prior NIDDM or pre-DM (8.4% vs. 8.6%; p = 0.9). All IDDM events were irreversible; 1 (4%) patient died of diabetic ketoacidosis. At time of IDDM diagnosis, 17 (63%) patients were receiving single agent anti-PD1 and 10 (37%) anti-PD1-based combinations (7 anti-CTLA-4, and 3 other compounds). Median time for development of IDDM from ICI initiation was 2.7 months (95% CI 0.2-5.3). Patients receiving combination ICI developed IDDM earlier than those treated with single agent (1.4 vs 4.8 months; p = 0.05). Amongst patients with metastatic disease (n = 24), 9 (38%) had a complete response and 7 (29%) had a partial response. Two patients (8%) were treated in the adjuvant setting; 1 (4%) received consolidation ICI. IDDM led to ICI discontinuation in 12 (44%) patients. After a median follow up of 21 months from ICI initiation, median survival was 30 months (95% CI NE) and was not reached in patients with melanoma and NSCLC. Conclusions: ICI-related IDDM is a rare and typically irreversible irAE that occurs early in the course of treatment and develops earlier with combination ICI. In this cohort, patients who developed ICI-related IDDM had a high tumor response rate and prolonged survival, especially melanoma and NSCLC patients. Prospective evaluation of autoantibodies to predict development of IDDM is ongoing.[Table: see text]

e15038 Background: Recurring oncogenic non-V600E BRAF mts have been identified in many cancer types. Preclinical data indicate that some BRAF non-V600E mts can be targeted with BRAF + MEK inhibitors. BEAVER is an investigator-initiated study designed to test the safety and efficacy of binimetinib and encorafenib (B+E) in patients (pts) with non-V600E BRAF mts. Methods: Key eligibility criteria are: pts with advanced solid tumors with BRAF non-V600E activating (class 1 and 2) or inhibitory (class 3) mts, and no prior BRAF/MEK inhibitors. Pts receive binimetinib (45mg PO BID) and encorafenib (450mg PO daily) on a 28-day cycle until intolerable toxicity or progression. The primary objective is OR rate (ORR) as per RECIST 1.1. In this Simon 2-stage trial, ≥1 of 7 pts need to have an objective response (OR) before commencing second stage of study (26 pts total). Secondary objectives include: safety, DCR, PFS, and OS. Exploratory objectives include: genomic profiling of tumors, evaluating circulating tumor DNA dynamics and development of patient derived xenograft (PDX) models. Results: From June 2019 to Feb 2021, 12 pts were screened and 9 pts enrolled; 9 are evaluable for safety and 8 for efficacy. Tumor types were melanoma and colon (n=2 each), as well as gallbladder, lung, breast and uterine cancers (n=1 each). Median age was 62 yrs (range 40-72). Median number of prior treatments was 2 (range 0-6). 1 pt had a class 1, 3 pts had class 2, and 5 pts had class 3, non-V600E BRAF mts. The median number of cycles was 2 (range: 1-7). Common treatment-related adverse events were mostly grade ≤ 2, and included: Blurred vision (78%), fatigue (67%), nausea (44%), vomiting (33%), and rash (33%). Dose reductions were required in 4/9 pts (44%) due to: blurred vision (22%), central serous retinopathy (11%), malaise (11%) and increased lipase (11%). Drug-related grade 3 AEs occurred in 2/9 pts and included: malaise (11%), confusion (11%), fatigue (11%) and increased lipase (11%). All eye toxicities were reversible with dose interruption. ORR was 12.5% (1/8) with one unconfirmed PR in a melanoma pt (BRAF G469S), treated for 6.5 months. One gallbladder cancer pt (BRAF D594N) had SD, and 6 pts had PD as best response. Genomic profiling was performed on archival tumors for 8 pts. Two PDX models were established. Responses to B+E in PDX models mirrored responses in 2 corresponding pts who had PD. Genomic and molecular profiling of pt tumors and corresponding PDXs identified multiple potential mechanisms of B+E resistance including: activation of EGFR and Akt pathways and inactivation of NF1 and Rb1. Conclusions: Preliminary data confirmed the safety of B+E and showed preliminary evidence of anti-tumor activity in advanced cancer pts with non-V600E BRAF mts. This study met the criterion for advancing to stage 2. Enrolment in the BEAVER trial and correlative biomarker analyses are ongoing. Clinical trial information: NCT03839342.

// Gloria Mittica 1, 2, * , Eleonora Ghisoni 1, 2, * , Gaia Giannone 1, 2 , Massimo Aglietta 1, 2 , Sofia Genta 1, 2 and Giorgio Valabrega 1, 2 1 Department of Oncology, University of Turin, Turin, Italy 2 Division of Medical Oncology-1, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy * These authors contributed equally to this work Correspondence to: Giorgio Valabrega, email: giorgio.valabrega@ircc.it Keywords: endometrial cancer, immunotherapy, tumor infiltrating lymphocytes (TILs), polymerase epsilon (POLE)-ultra-mutated, microsatellite instability (MSI) Received: June 08, 2017 Accepted: July 26, 2017 Published: August 08, 2017 ABSTRACT Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. Materials and Methods: We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords ‘endometrial cancer’ and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. Results: POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Conclusions: Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

// Gloria Mittica 1, 2, * , Rebecca Senetta 3, * , Giulia Scotto 1 , Massimo Aglietta 1, 2 , Furio Maggiorotto 4 , Eleonora Ghisoni 1, 2 , Sofia Genta 1, 2 , Renzo Boldorini 5 , Claudia Manini 6 , Isabella Morra 7 , Roberta Buosi 8 , Anna Sapino 3, 9 , Paola Cassoni 9, * and Giorgio Valabrega 1, 2, * 1 Department of Oncology, University of Turin, Turin, Italy 2 Division of Medical Oncology-1, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy 3 Unit of Pathology Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy 4 Division of Gynecologic Oncology, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Italy 5 Department of Health Science, University of Eastern Piedmont “Amedeo Avogadro”, Novara, Italy 6 Unit of Pathology, Giovanni Bosco Hospital, Turin, Italy 7 Unit of Pathology, Citta della Salute e della Scienza, Turin, Italy 8 Division of Oncology, Santo Spirito Hospital, Casale Monferrato, Italy 9 Department of Medical Sciences, University of Turin, Turin, Italy * These authors have contributed equally to this work Correspondence to: Giorgio Valabrega, email: giorgio.valabrega@ircc.it Keywords: androgen receptor, ovarian cancer, brain metastases Received: November 24, 2016 Accepted: March 17, 2017 Published: April 12, 2017 ABSTRACT Brain metastases are uncommon localizations in epithelial ovarian cancer (EOC), their reported incidence is increasing and no predictive biomarkers have been identified yet. Goals of this study were: i) to define a possible association between Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR),human EGF receptor 2 (HER2) and brain progression in EOC patients, and ii) to identify differences in ER, PR, AR and HER2 protein expression from primary EOC and its matched resected brain metastasis. A retrospective series of 11 EOC with matched brain metastasis surgically removed was collected. For comparison, a “Control dataset” of 22 patients, without evidence of brain involvement after an adequate follow up was matched. ER, PR, AR and HER2 status were analyzed by means of immunohistochemistry forCases (both primary and metastatic lesions) and Controls. Univariate analysis showed that AR status was significantly associated with brain localization, both considered as discrete variable (cut-off: 10%, p =0.013) and as continuous one ( p =0.035). Multivariate analysis confirmed this trend ( p =0.053). When considered as continuous variables, ER and AR showed greater expression in primary tumors in comparison with brain metastases ( p =0.013 and p =0.032, respectively). In our series, AR predicts brain involvement, with a 9.5 times higher propensity for AR-negative EOC. Moreover, brain dissemination is probably the result of progressive dedifferentiation of primary tumor, shown by reduction of ER and AR expression in metastases. Further studies are required, in order to anticipate and improve multimodal treatment of brain metastases.

Endometrial cancer (EC) is the most frequent gynecological cancer. In patients with relapsed and advanced disease, prognosis is still dismal and development of resistance is common. In this context, endometrial Cancer Stem Cells (eCSC), stem-like cells capable to self-renewal and differentiation in mature cancer cells, represent a potential field of expansion for drug development. The aim of this review is to characterize the role of eCSC in EC, their features and how they could be targeted. CSC are involved in progression, invasiveness and metastasis (though epithelial to mesenchimal transition, EMT), as well as chemoresistance in EC. Nevertheless, isolation of eCSC is still controversial. Indeed, CD133, Aldheyde dehydrogenase (ALDH), CD117, CD55 and CD44 are enriched in CSCs but there is no universal marker nowadays. The most frequently activated pathways in eCSC are Wingless-INT (Wnt)/β-catenin, Notch1, and Hedghog, with a high expression of self-renewal transcription factors like Octamer binding transcription factor 4 (OCT), B Lymphoma Mo-MLV Insertion Region 1 Homolog (BMI1), North American Network Operations Group Homebox protein (NANOG), and SRY-Box 2 (SOX2). These pathways have been targeted with selective drugs alone or in combination with chemotherapy and immunotherapy. Unfortunately, although preclinical results are encouraging, few clinical data are available.

Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. The results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. Our preliminary data suggest that CIK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting.

The role of poly ADP ribose polymerase inhibitors in ovarian cancer is rapidly evolving. Three different poly ADP ribose polymerase inhibitors (olaparib, niraparib and rucaparib) have been already approved as maintenance after response to platinum-based chemotherapy; two of them (olaparib and rucaparib) also as single agents. Veliparib, a novel PARPI, showed promising results in preclinical and early clinical settings. The aim of this review is to discuss veliparib’s mechanisms of action, to provide a clinical update on its safety and activity in ovarian cancer, and to highlight future perspectives for its optimal use. Veliparib favorable toxicity profile encourages its use either as monotherapy or in combination. Its peculiar neuroprotective and radio-sensitizing effect warrant further investigation.

Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development of a new class of drugs: CDK inhibitors (CDKis). The aim of this review is to give an overview on CDKis preclinical, early clinical activity and future development in EC. Use of CDKis has a strong preclinical rationale but we have poor clinical data. Similar to breast cancer, most ongoing trials are investigating synergistic associations between CDKis and ET. These trials will probably help in defining the best clinical setting of CDKis in ECs, which are the best partner drugs, and how to manage CDKis toxicities with a focus on potential biomarkers of response.

Increasing evidence suggests that epigenome plays a central role in cancer development making it a promising target for anticancer treatments. Here, we review two new classes of epigenome-targeting agents: the bromodomain and extraterminal domain proteins (BET) inhibitors and the enhancer of zeste homolog (EZH2) inhibitors. Clinical research evaluating BET and EZH2 inhibitors is still at an early stage; however, both classes of drugs have demonstrated activity among different hematologic malignancies and solid tumors. Several studies on BETi and EZH2i are ongoing to better define their potential role in cancer treatment, which patients are most likely to benefit and if the association with other drugs can improve their efficacy.

Objective Relapsed epithelial ovarian cancer (EOC) is frequently treated with pegylated liposomal doxorubicin (PLD). Unfortunately, most patients do not benefit from treatment. Prediction of response is crucial to optimize PLD use and avoid unnecessary toxicities. We aimed at assessing the value of topoisomerase II alpha (TOP2A) expression as predictive marker of response to PLD-based therapy in patients with relapsed EOCs. Methods We retrospectively analyzed Formalin Fixed Paraffin Embedded (FFPE) tissues from 101 patients with platinum resistant (PR) or partially platinum-sensitive (PPS) EOCs treated with PLD-based chemotherapy beyond second line in three referral cancer centers between January 2010 and June 2018. TOP2A expression was measured by immunohistochemistry (IHC): images of each sample were acquired by optical microscope and analyzed by using automatic counter software. Correlation between TOP2A expression and response to PLD was assessed. Since no cut-off for positivity has been validated yet, we dichotomized TOP2A expression based on a cut-off of 18% (mean value in this study). Results TOP2A expression beyond cut-off was not prognostic for primary platinum-free interval in our series (p = 0.77) neither for optimal cytoreduction (p = 0.9). TOP2A > 18% was associated with a longer time to progression (TTP) following PLD-treatment, although not statistically significant (p = 0.394). No difference was observed between PR and PPS patients’ groups (p = 0.445 and p = 0.185, respectively). Not unexpectedly, patients with TOP2A expression > 18% treated with PLD monotherapy achieved a longer TTP compared with PLD-doublet therapy (p = 0.05). Conclusions Our data suggest that TOP2A status might predict activity of PLD in patients with PR/PPS EOCs.

Background Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn’t exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS. Methods We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed. Results At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS.

Background Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. Objectives The study aimed to highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. Methods We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google. com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Results Olaparib, Niraparib and Rucaparib are already approved for the treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). Conclusion PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC.

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the "turn off" signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC.