Utidelone monotherapy suggesting clinical efficacy in heavily pretreated platinum-resistant high-grade serous ovarian cancer: a case report

Background: We examined the association of platinum resistance with genetic mutations in high grade serous ovarian cancer (HSOC) patients undergoing high-throughput genomic tumor sequencing. Methods: Snap-frozen and fresh frozen paraffin embedded tissue samples were collected from HSOC patients enrolled on UNCseq (NCT01457196). UNCSeq is an institutional protocol which uses next generation sequencing to detect genetic mutations in a wide array of malignancies. Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Mutations with a quality score <100 were filtered from the data set, and only mutations rated to have a moderate to high impact were retained. Medical record review determined platinum sensitivity or platinum resistance. Tumors were defined as platinum sensitive or resistant if patients were noted to have > or < 6 months of disease free interval following completion of induction therapy, respectively. Results: Overall 39 HSOC cases met inclusion criteria; 32 tumors met criteria for platinum sensitive and 7 platinum resistant. 308 mutations were noted in at least one individual across all patients. The top observed mutations in platinum sensitive HSOC were TP53 (41%, n= 13), GucylA2 (19%, n=6), MLL2 (19%, n=6) and MTOR (16%, n=5). The top observed mutations in platinum resistant tumors were TP53 (71%, n=5), TET1 (43%, n=3), NF1 (43%, n=3) and MLL3 (43%, n=3). There was a trend toward more p53 mutations in resistant tumors (71% versus 41%, p=0.21) There was no difference in the total number of mutations per tumor in platinum sensitive and resistant patients, (3 vs. 4, p=0.516). Conclusions: We did not detect a difference in the number of genetic mutations in HSOC according to platinum sensitivity. Platinum resistant tumors had a trend toward higher frequency of TP53 mutations than platinum sensitive HSOCs. Furthermore, we identified 3 frequently mutated genes in platinum resistant HSOC: TET1, an epigenetic regulator, NF1, a tumor suppressor gene and MLL3, a histone modifier gene. Ongoing tumor sequencing of HSOCs on UNCseq will help to confirm these results. Citation Format: Tara Castellano, Leslie H. Clark, Naim Rashid, Victoria Bae-Jump. Genetic variation in platinum-sensitive and platinum-resistant high-grade serous epithelial ovarian cancer [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 412. doi:10.1158/1538-7445.AM2017-412

<h3>Introduction/Background*</h3> High-grade serous ovarian cancer (HGSOC) is the most lethal form of gynaecological malignancy. Despite initial chemosensitivity the majority of patients develop resistance to platinum chemotherapy and eventually die. Current treatment options for platinum resistant disease remain limited, therefore interest has turned towards the development of targeted therapeutics. The role of the PI3K/AKT/mTOR pathway, found activated in 70% of HGSOC cases, is well described in chemoresistant disease, in particular through activation of AKT in response to platinum treatment by the DNA damage response protein DNA-PK. Increasing numbers of PI3K/AKT/mTOR inhibitors are in development/clinical use for other cancer types. Our laboratory previously demonstrated that inhibition of AKT or DNA-PK re-sensitises clinically-acquired platinum resistant HGSOC cell lines to cisplatin. Here we aim to assess synergy between a panel of commercially available AKT and DNAPK inhibitors with cisplatin, and elucidate their mechanism of action within the PI3K/AKT/mTOR pathway. <h3>Methodology</h3> Platinum resistant immortalised HGSOC cell lines (PEO4, PEA2, OVCAR8, Kuramochi) were treated with cisplatin plus/minus AKT or DNA-PK inhibitors and Isobologram assays performed to establish synergy/antagonism between drug treatments. Cells were treated with inhibitors plus/minus cisplatin at different time points, protein lysates collected, and Reverse Phase Protein Array (RPPA) proteomics performed and analysed to establish mechanisms of action of inhibitors on the PI3K/AKT/mTOR pathway. <h3>Result(s)*</h3> Following treatment with cisplatin in combination with AKT or DNA-PK inhibitors, different levels of synergy were observed in platinum resistant HGSOC cell lines; strong synergy was noted for AKT inhibitors Afurosertib, Uprosertib, and Triciribine. Proteomic analysis revealed a response signature for AKT or DNAPK inhibition showing activation of AKT at S473 and decrease of downstream targets pS6_235/236 and 240/44, and p70S6K_T389. <h3>Conclusion*</h3> In the platinum resistant immortalised HGSOC cell lines tested, AKT inhibitors showed a synergistic effect when used in combination with cisplatin. Proteomic analysis confirmed targeting of the PI3K/AKT/mTOR pathway. With the aim of resensitising a resistant patient to their platinum-based chemotherapy a synergistic effect between the resensitising compound and chemotherapy agent is essential; this data suggests targeting of the PI3K/AKT/mTOR pathway in platinum-resistant HGSOC patients with AKT or DNAPK inhibition is a potentially useful therapeutic strategy.

5565 Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]

Background: Platinum-resistance is associated with a poor prognosis in HGSOC and has limited treatment options. Inhibition of CHK1 has shown activity in BRCAwt HGSOC. Here, we report the clinical activity and tolerability of the second generation CHK1 inhibitor, prexasertib, in platinum-resistant BRCAwt HGSOC (NCT02203513). Methods: Eligibility included platinum-resistant recurrent HGSOC women without germline or somatic BRCA mutation, ECOG PS 0-2, good end organ function, and measurable disease. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS) and safety. Prexasertib was given at 105 mg/m2 IV every 14 days in a 28-day cycle. CT scans were performed every 2 cycles for RECIST v1.1 evaluation, and safety evaluation using CTCAE v4.0 every cycle. CBC was performed on day 8 of cycle 1 for ANC nadir. Pretreatment clinical samples were collected for biomarker analysis including HR deficiency and circulating tumor cells (CTC). Results: Between January 2017 and November 2020, 49 patients (median age 64.1 years [IQR 56.8 - 69.9]) received at least one dose. 12 (24.5%) patients were primary platinum-resistant, and 37 (75.5%) were secondary platinum-resistant. All were heavily pretreated (median 4 prior systemic therapies [IQR 3 - 7]), including bevacizumab (79%), PARP inhibitors (44%), and both (2%). 39 patients were evaluable by RECIST and RR was 30.7%. The median PFS was 5.8 months (range 1.7-26.4 months). The median duration of response among PRs was 5.5 months (range 1-19.8 months). The clinical benefit rate (PR+CR+SD &amp;gt;4 months) was 84.6%. 10 patients were inevaluable due to: withdrawal of consent (n=2), intercurrent illness related to disease (tumor invasion of mainstem bronchus (n=1) or vaginal wall (n=1), small bowel obstruction (n=2), infection (n=2), failure to thrive (n=1), and pneumothorax secondary to thoracentesis (n=1) during cycle 1. The common (&amp;gt;10%) grade 3 or 4 adverse events (AEs) included neutropenia (85%, 42/49) based on the cycle 1 day 8 CBC at the time of ANC nadir, lymphocytopenia (46%, 23/49), thrombocytopenia (40%, 20/49), anemia (30%, 15/49), and febrile neutropenia (12%, 5/49). 83% (41/49) of patients received growth factors support to avoid subsequent treatment delays. There were no deaths on the study. No significant difference of RECIST response or PFS was observed in patients with high (≥2) vs low (&amp;lt;2) CTC at baseline. Conclusions: Prexasertib monotherapy resulted in clinical benefit in subgroups of heavily pretreated BRCAwt platinum-resistant HGSOC. Prexasertib was well tolerated with manageable grade 3/4 AEs. Further studies on predictive biomarkers are ongoing. Citation Format: Grant Zurcher, Ann McCoy, Brooke Solarz, Jay Nair, Min-Jung Lee, Jane B. Trepel, Christina M. Annunziata, Jung-Min Lee. A phase II study of prexasertib, a cell cycle checkpoint kinase 1 (CHK1) inhibitor, in platinum-resistant recurrent high-grade serous ovarian cancer (HGSOC) with BRCA wild-type (BRCAwt) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT113.

Differentially expressed genes in platinum-resistant high-grade serous ovarian cancer

Intracranial activity of mirvetuximab soravtansine in platinum-resistant high-grade serous ovarian cancer: Insights from a patient with central nervous system metastasis.

Background: Platinum-resistant (PR) ovarian cancer (OC) is a lethal disease for which effective therapies are limited. Preclinical data suggest that inhibitors of poly(ADP-ribose) polymerase (PARP) and ataxia telangiectasia and Rad3-related kinase (ATR) have synergistic antitumor activity in these tumors. We hypothesize that targeting two unique DNA repair pathways with combination therapy may increase response rates, durability of response, and lower off-target toxicities compared to standard treatments. This clinical trial examines PARP and ATR inhibition (PARPi-ATRi) in patients (pts) with recurrent OC (NCT03462342). Data from the PR arm of this trial are presented. Methods: Twelve patients were enrolled with PROC in the first stage of a Simon optimal two-stage design with alpha=0.10 and beta=0.10. Eligible pts had recurrent, PR high-grade serous OC, measurable disease, and no prior treatment with a targeted inhibitor of DNA repair. Pts may or may not have a somatic or germline mutation of BRCA1 or BRCA2. Pts received olaparib (O) 300mg orally twice daily on days 1-28 and AZD6738 (A) 160mg orally daily on days 1-7 of a 28-day cycle. Endpoints were safety (toxicity based on CTCAE v5.0), objective response rate (RECIST v1.1), and PFS (RECIST v1.1). If ≥1 patient of 12 treated has a partial or complete response, then 25 additional patients will be treated; if no responses are seen, the PR arm of this trial will be terminated. Results: Nine patients have been treated and 8 pts have had on-study imaging thus far. Median (M) age is 63 years (53-73); M ECOG, 0 (0-1); M prior lines of chemotherapy, 2.5 (1-4); M prior therapies after acquiring platinum resistance, 0.5 (0-2). BRCA1/2m status (positive/negative/unknown) is: gBRCA1 (1/5/4); gBRCA2 (0/6/4); sBRCA1 (1/7/2); sBRCA2 (0/8/2). No complete or partial responses were seen. Six of 8 patients achieved SD with a mean duration on study of 6.7 cycles (range 4-10 cycles), including 1 pt with gBRCA1m. Three of these 6 pts demonstrated 20-27% tumor regression of target lesions. Two patients had disease progression. Toxicities occurring in ≥50% of pts that were at least possibly related to combination therapy were nausea (grade (G) 1/2: 6, G3: 1); anorexia (G1/2: 5, G3: 1); fatigue (G1/2: 4, G3: 1), anemia (G1/2: 4, G3: 1). No G4 toxicities were observed and no pts discontinued therapy due to toxicity. Conclusions: Combination O and A is tolerable with mostly low-grade toxicity similar to that of olaparib single-agent. 75% of response-evaluable pts had stable disease, half of whom had substantial tumor regression. Duration of disease stability was clinically meaningful in this PR, largely g/sBRCA1/2 wild-type OC population. Biopsy samples will be evaluated by genomics and proteomics. Updated response data will be presented. Citation Format: Payal D. Shah, Haley Zarrin, Stephanie Wethington, Nawar Latif, Lainie Martin, Diego Rodriguez, Katie Elkins, Robert Giuntoli, Robert Burger, Janos Tanyi, Mark Morgan, Susan M. Domchek, Stephanie Gailliard, Deborah K. Armstrong, Fiona Simpkins. Combination ATR and PARP inhibitor (CAPRI) for recurrent, platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A72.

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

Glycosylated antitumor ether lipids (GAELs) are a promising class of investigational anticancer agents with potent antitumor activity against a range of cancers, including platinum-resistant high-grade serous ovarian cancer (HGSOC). We previously demonstrated that epithelial ovarian cancer (EOC) cell lines (HGSOC and endometrioid) and primary cells derived from patient ascites (HGSOC and clear cell) were sensitive to the cell-killing effects of D-glucosamine-derived GAELs via an apoptosis-independent mechanism. However, D-linked carbohydrates are metabolized by endogenous glucosidases in vivo, rendering the GAEL inactive. Thus, the aim of the current study was to synthesize a novel class of GAELs with L-linked carbohydrates and to evaluate their efficacy in EOC cell lines and patient samples. Out of seven novel compounds tested, L-rhamnose-GAEL was identified as the compound with the greatest efficacy for killing EOC cell lines and patient cells that were grown under adherent or nonadherent (3D) conditions. The drug-sensitive and drug-resistant syngeneic endometrioid EOC cell lines, A2780s and A2780cp, respectively, as well as the NIH:OVCAR-3 and COV362 HGSOC lines, were incubated with L-rhamnose-GAEL for 48 hours and the CC50 determined as 15 μM for A2780s, 22.5 μM for A2780cp, and 5 μM for NIH:OVCAR-3 and COV362 cells. Similar experiments were conducted with primary EOC cells, chemo-naïve EOC126 (clear-cell adenocarcinoma), and platinum-resistant EOC 183I (HGSOC). Cell viability decreased in a dose-dependent manner with CC50 of 12 μM for EOC126 and 22.5 μM for EOC183l. For comparison, when EOC126 and EOC183I were grown as 3D cultures the CC50for cisplatin was 20 μM and 40 μM, respectively. To evaluate the effect of using low-dose treatment of L-rhamnose-GAEL on primary EOC cells (chemo-naive and chemoresistant), cells were exposed to L-rhamnose-GAEL for 96 hours. These studies revealed that prolonged incubation led to low CC50 of 1-5 μM. These results showed that primary EOC cells derived from chemo-naïve and platinum-resistant patients were sensitive to the L-rhamnose-GAEL and offer a novel drug class capable of killing chemotherapy-resistant EOC cells. Citation Format: Mark W. Nachtigal, Frank Schweizer, Gilbert Arthur. Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A56.

Resistance to platinum-based chemotherapy is a major problem in the clinical management of recurrent HGSOC. While the use of poly ADP-ribose polymerase inhibitors (PARPi) have made an impact in BRCA1/2 mutated and homologous recombinant-deficient HGSOC, resistance and limited response-rates to PARPi persist. Alisertib (AL) an inhibitor of AAK can inhibit entry and progression of cells through mitosis as well as the interaction with N-myc and its degradation (Front. Oncol. doi:10.3389/fonc.2015.00189). In models of HGSOC from patients with recurrent platinum-resistant disease, cisplatin (CP) treatment does not lead to cell cycle traverse perturbations and significant accumulation of cells in G2-M. Since a defect in the G2-M DNA damage checkpoint is a potential mechanism of resistance to cisplatin, we sought to test the hypothesis that inhibition of AAK that is involved in centrosome maturation and entry into mitosis would enhance the anti-tumor activity of cisplatin in platinum-resistant HGSOC. To test this hypothesis, we treated HGSOC cell lines from patients with recurrent platinum-refractory disease with increasing doses of CP (1- 2.5 μM), of AL (0.05 μM) or the combination and evaluated effects on cell proliferation, apoptosis and generation of reactive oxygen species (ROS). The sequential treatment of four different HGSOC cell lines with CP for 3 hours followed by AL for 48 hours and recovery in drug-free medium for 96-120 hours led to a synergistic increase in apoptosis (p&amp;lt;0.01) and a synergistic decrease in cell survival (p&amp;lt;0.001) compared to treatment with either drug alone. The enhanced apoptosis and decreased cell survival with (CP→AL) treatment was accompanied by a significant increase (p&amp;lt;0.05) in ROS. In contrast, sequential treatment with AL followed by CP (AL→CP) led to an antagonistic response. The synergistic effect of (CP→AL) was accompanied by a modest increase in mRNA and protein levels of AAK. However, protein levels of N-myc protein, which interacts with AAK and is degraded, were not altered. Interestingly, (CP→AL) treatment did not elicit the synergistic cytotoxic response or increased ROS in immortalized normal human ovarian surface epithelium or normal human fallopian tube secretory epithelium cells. In platinum-refractory HGSOC cells that are wild-type for BRCA1/2 and resistant to olaparib, treatment with the combination of 0.01 μM AL and 1 μM olaparib for 48 hours resulted in an additive cytotoxic response. Based on the mutation landscape of the HGSOC cell panel evaluated, the synergistic cytotoxicity with the CP→AL treatment was independent of BRCA1/2 or TP53 mutation status. In summary, CP resistance in HGSOC due to a defective G2-M DNA damage response, can be potentially circumvented by sequential treatment with CP followed by AL. Citation Format: Ram N. Ganapathi, Eric J. Norris, Ashley P. Sutker, Hala Soliman, Mahrukh K. Ganapathi. Targeting aurora A kinase (AAK) in platinum-resistant high grade serous ovarian cancer (HGSOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1774.

5512 Background: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (HR = 0.57, one-sided log-rank p = 0.044, which met the one-sided significance level of 0.1 used for sample size calculation). Final overall survival (OS) and corresponding biomarker analyses are reported here. Methods: Patients (pts) with platinum-resistant high-grade serous ovarian cancer and unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting, were randomized 1:1 to gemcitabine/berzosertib versus gemcitabine alone. Randomization was stratified based on platinum free interval (PFI), PFI≤3 months versus &gt; 3 months. Crossover from gemcitabine to gemcitabine/berzosertib was allowed upon disease progression by RECIST 1.1. OS was a secondary endpoint while preplanned exploratory correlative studies included assessment of DNA repair pathways and replication stress (RS) alterations by targeted gene sequencing and/or immunohistochemistry (IHC). Results: Seventy pts were randomly assigned to treatment with gemcitabine/berzosertib (34 pts) or gemcitabine alone (36 pts); 15 pts crossed over from gemcitabine to gemcitabine/berzosertib. At the final OS analysis (92.9% maturity), median follow-up was 53.2 weeks in the gemcitabine/berzosertib and 43 weeks in the gemcitabine alone groups. Median OS in the intent-to-treat (ITT) population was 59.4 weeks in the gemcitabine/berzosertib group versus 43.0 weeks in the gemcitabine alone group (HR 0.79, 90% CI 0.52-1.2, one-sided p = 0.18). However, when patients who crossed over to gemcitabine/berzosertib were excluded from analysis, a significant OS benefit was observed with gemcitabine/berzosertib (HR 0.60, 90%CI 0.37−0.97); HR was 0.26 (90% CI 0.1−0.7) in pts with PFI≤3 months and 0.89 (90%CI 0.50−1.59) in pts with PFI &gt; 3 months. Furthermore, significant OS benefit was observed in pts with RS-low tumors (HR 0.39, 90%CI 0.17−0.91, defined as tumors harboring no genomic RS alterations related to loss of RB pathway regulation and/or oncogene-induced RS) but not in pts with RS-high tumors (HR 0.74, 90%CI 0.35−1.56). Additional targeted gene sequencing and IHC analyses as well as analyses adjusting for patient crossover will be reported at the meeting. Conclusions: In the ITT population, gemcitabine/berzosertib did not significantly improve OS versus gemcitabine alone. Pts with PFI≤3 months and pts with RS-low tumors may derive a survival advantage from addition of berzosertib to gemcitabine in the platinum-resistant setting. Clinical trial information: NCT02595892 .

5556 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are potential promising therapeutic targets due to their high expression level in many solid tumors including ovarian cancer. CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload and is administered by intravenous infusion Q2W. Methods: This phase 1 study includes the dose-escalation of Ia and the dose-expansion of Ib. The phase Ia started with accelerated titration (0.015, 0.03mg/kg) and then switched to 3+3 design (0.12, 0.15, 0.17, 0.18, 0.20mg/kg). Phase Ib dose-expansion study includes 4 cohorts, platinum-resistant high-grade serous ovarian cancer (HGSOC), other sub-types of ovarian cancer such as clear cell ovarian cancer (OCCC) and low-grade serous ovarian cancer, metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective is to assess the safety and preliminary efficacy. Results: As of December 8, 2023, 240 patients (phase Ia: n=40; phase Ib: n=200) have been enrolled including 136 HGSOC,17 OCCC, 24 TNBC and 63 other tumor types. Majority of adverse events were mild to moderate. Common (≥50%) treatment-related AEs (TRAEs) were neutropenia, WBC decreased, AST increased, pyrexia, ALT increased and nausea. Grade 3/4 TRAEs (≥5%) were neutropenia (49%), WBC decreased (26.8%), AST increased (5.9%), ALT increased (5.9%), anaemia (5.4%). 41 HGSOC patients at dose of 0.15mg/kg with ≤3 prior treatment regimens, regardless of FRα expression levels were evaluable for efficacy assessment. 13 patients achieved partial response (PR) and 29 patients achieved stable disease (SD). The objective response rate (ORR) and the disease control rate (DCR) were 31.7% and 70.7%, respectively. For 19 patients with FRα expression level 0 to 49%, 6 patients achieved PR and ORR was 31.6%. The longest treatment duration exceeds 13 months. Conclusions: The current result showed that CBP-1008 demonstrated manageable safety profile. Promising antitumor activity was observed in ovarian cancer patients at dose of 0.15mg/kg, especially in platinum-resistant HGSOC patients with ≤3 prior treatment regimens. CBP-1008 has the potential to provide a better treatment option for ovarian cancer patients regardless of FRα expression levels. Clinical trial information: NCT04740398 .

Single-agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%-40% of patients achieve stable disease. The primary objective was to estimate progression-free survival (PFS) after sequential versus combination cytotoxic T-lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum-resistant high-grade serous ovarian cancer (HGSOC). Patients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune-related PFS (irPFS). Sixty-one subjects were randomized to sequential (n=38) or combination therapy (n=23). Thirteen patients (34.2%) in the sequential arm receiveddurvalumab. There was no difference in PFS in the sequential arm (1.84months; 95% CI, 1.77-2.17 months) compared with the combination arm(1.87months; 95% CI, 1.77-2.43 months) (p=.402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient-reported outcomes were similar in both arms. There was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum-resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

5557 Background: Immune checkpoint blockade, e.g., anti-PD-1/PD-L1, demonstrated limited efficacy in HGSOC despite high levels of tumor-infiltrating lymphocytes, suggesting the innate, rather than adaptive, immune system may play a prominent role in anticancer response. Preclinical studies suggest CHK1i modulates the innate immune milieu. We previously showed clinical activity of prexasertib in BRCAwt, PR-HGSOC patients (pts). Here, we investigated the association of innate immunogenic features with CHK1i response. Methods: Prexasertib was given at 105 mg/m2 IV every 14 days in a 28-day cycle. Baseline (BL) fresh core biopsies were collected from pts enrolled in the biopsy (Bi) cohort for RNA sequencing. Computational immunogenomic analysis (CIBERSORT) was used for immune cell fractions quantification. Blood samples (BS) were obtained at BL and cycle 1 day 15 (C1D15) from pts enrolled in both Bi and non-Bi (nBi) cohorts for multiparametric flow cytometry (FC) analysis to evaluate dynamic changes in immune cell subsets. Mann-Whitney and Wilcoxon tests were used to compare unpaired and paired data, respectively. Results: 49 BRCAwt, PR-HGSOC pts were enrolled in the Bi cohort (n=25) and nBi cohort (n=24). 39 were evaluable per RECIST v1.1. 18/39 pts (46.2%) had a clinical benefit (CB), defined as progression-free survival≥6 months. Transcriptomic profiles of BL biopsies (n=15) met the quality control and assurance (Gene Similarity Index, Principal Component Analysis) for further in silico analysis. CIBERSORT analysis did not exhibit any differences in the immune cell fractions between CB and non-CB (NCB) groups at BL. FC analysis on paired BS (BL and C1D15) showed an increase of immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSCs, p&lt;0.001) and classical monocytes (CM, p=0.003) in the NCB group (18 paired BS). In the CB group (19 paired BS), CD141+ and CD1c+ dendritic cells (DCs) express higher rates of CD83, a marker of maturity and functionality (p&lt;0.001 and p&lt;0.001, respectively), despite no increase in the absolute number of DCs. At C1D15, a higher rate of M-MDSCs (median 7.8% vs. 5.52%; p=0.03) and CM (median 40.7% vs. 31.7%; p=0.03) were found in the NCB group (n=18) compared to the CB group (n=19); also, CM showed lower expression of HLA-DR in the NCB group (median 19.25% vs. 27.8%; p=0.02). Conclusions: Collectively, our data suggest the possible involvement of innate immunity in modulating CHK1i response. Increasing peripheral immunosuppressive cells and lower immunocompetence of the innate immune system may contribute to CHK1i resistance, whereas the functionality of DCs may be involved in the response. Enhancing innate immunity may represent a strategy to increase CHK1i response in this hard-to-treat population. Clinical trial information: NCT02203513 .

Introduction/BackgroundTP53 is a tumour suppressor gene frequently mutated in high grade serous ovarian cancer(HGSOC).The aim of this study is to investigate the expression of TP5-gene in cell-free DNA(cfDNA) in plasma...