Recurrent Low-grade Serous Ovarian Cancer Research Articles

First results of the NOGGO PERCEPTION: Phase II investigational study of pembrolizumab in combination with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer.

e17550 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This clinical trial is a multi-center, single-arm phase 2 study to evaluate pembrolizumab therapy concomitant to platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin & carboplatin plus gemcitabine) and as maintenance in recurrent LGSOC cases. Eligible for the trial are LGSOC patients with progression or recurrence at least six months after most previous platinum-containing therapy and in good general performance (ECOG 0/1). The primary objective is the 12 months progression free survival (PFS) rate. Secondary end-points include overall survival, response rate (RR), PFS and RR according to Ki67 expression levels, time to first subsequent therapy and its response, safety and quality of life. The trial is planned according to Simon’s two-stage design with total sample size up to 33 patients. The null hypothesis is PFS-rate of at least 12 months of 20%. During the first stage 18 patients were enrolled and since 5 patients showed PFS of 12 months the study has been continued within stage 2 to enrol additional 15 patients. The trial can be claimed as successful, if at least 11 patients show PFS after 12 months. Assuming a true PFS-rate of 40%, this trial has 5% type I error rate and 80% power. Results: Data from 18 patients enrolled into this trial from FPI up to the time of interim analysis have been analyzed. 5 patients had reached the primary endpoint. 6 patients progressed or died before they reached the primary endpoint. At this time, 10 patients are still undergoing treatment and 7 patients may still reach the primary endpoint. Patients have a median age of 60 years (range: 43-81), ECOG score of 0 was recorded in 16 patients (88.9%) and most received one prior line of chemotherapy (61.1%, range: 1-5). 14 patients (77.8%) received carboplatin + PLD and 4 patients (22.2%) received carboplatin + gemcitabine as chemotherapy. 10 patients (55.6%) had at least one SAE. 3 patients (16.7%) had at least one SAE with relation to study treatment. 1 SAE resulted in a fatal outcome but was assessed not be related to study treatment. Conclusions: The interim analysis showed positive results, strengthening the hypothesis that pembrolizumab is an effective agent capable of extending progression-free survival in the studied patient population. Clinical trial information: NCT04575961 .

Abstract 6279: Estrogen signaling in low-grade serous ovarian carcinoma

Abstract High level of estrogen in the blood of women has been linked to the progression and possibly development of ovarian cancer. Almost all low-grade serous ovarian cancer (LGSOC) expresses estrogen receptor alpha (ERα protein encoded by the gene ESR1) and develops during reproductive age of women. However, recent studies suggested that a higher expression of ERα correlates with better survival. In a phase II clinical trial, hormonal therapies have been shown to be associated with a clinical benefit rate of 61% for recurrent ER-positive LGSOC patients. The study also indicated that women with recurrent LGSOC who received hormonal therapies had a significantly longer progression-free survival but not overall survival. Endocrine therapies have proven to be effective in treating breast cancer. Unfortunately, in ovarian cancer clinical trials (GOG0281 and PARAGON), these treatments have not achieved comparable results, with an objective response rate of only approximately 14%. To understand the ESR1 regulation in LGSOC, we have performed RNAseq and ChIPseq analyses of LGSOC tumor tissues. We also forced over-expression of ESR1 in LGSOC cell lines. Using RNAseq data, we aligned the sequencing reads to all the known ESR1 transcript variants. We found that ESR1 transcript variant 1, 2, 3 and X11 were the major transcripts expressed. Variants 1, 2 and 3 encode the regular 66 kDa ESR1 protein, while the X11 variant encodes a 52 kDa ESR1 protein. Both 66 kDa and 52 kDa ESR1 proteins were also detected in LGSOC tumor tissues by western blots. To further explore the function of ESR1 66kDa in LGSOC, we over-expressed ESR1 variant 1 in two LGSOC cell lines (HOC-7 and HCC5075) by transfecting with an expression plasmid. Total proteins were extracted from the mock control and transfected cells for functional proteomic analysis by reverse phase protein arrays (RPPA). From the RPPA data, overexpressing ESR1 in LGSOC cell lines suppressed DNA repair pathways but activated cell cycle and mitosis pathways. To further delineate the ESR1 DNA binding sites in LGSOC, we performed ChIPseq analysis of these tumor samples as well as two ovarian cancer cell lines that express ESR1 protein. Our results demonstrated that ESR1 regulated “cistromes” in ER positive ovarian carcinoma is very different from that in ER positive breast cancer as much less ESR1 binding sites were found in LGSOC. There are ESR1 binding sites common to both types of cancers, but we found quite a few unique ESR1 binding sites. We are trying to integrate the ChIPseq and RNAseq data and hopefully identify, for the first time, an ovarian cancer specific ERα cistrome. ER expression may not always correlate with activation of ESR1 signaling pathways, which may be one of the reasons underlying endocrine therapy resistance in ovarian cancer. The results of an integrated analyses will also give us insight on the management of ER positive LGSOC by identifying new genetic targets that may be used in combination with endocrine therapy. Citation Format: Yvonne TM Tsang, Chun Wai Oscar Ng, David Gershenson, K-Kwok wong. Estrogen signaling in low-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6279.

Abstract A091: The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors

Abstract KRAS mutations (mt) occur in up to 98% of pancreatic ductal adenocarcinoma (PDAC) and represent a key initiating event in PDAC carcinogenesis. Therapeutic efforts targeting the RAS/RAF/MEK/ERK (MAPK) pathway with MEK-only inhibitors have been unsuccessful in substantially modifying PDAC prognosis. Thus, novel strategies are needed to overcome putative mechanisms of resistance to MEK inhibition such as focal adhesion kinase (FAK) pathway activation. Another hallmark of PDAC is its high stromal density, which is thought to limit the penetration of cytotoxic drugs and T cells into the tumor and has been shown to be correlated with FAK hyperactivation, altogether supporting co-targeting the MAPK and FAK pathways to achieve deep and durable responses for patients with PDAC. Avutometinib is a RAF/MEK clamp that potently inhibits MEK kinase activity and induces dominant negative RAF-MEK complexes preventing phosphorylation of MEK by ARAF, BRAF and CRAF. This unique mechanism allows avutometinib to block MEK signaling without the compensatory re-activation of MEK that appears to limit the efficacy of MEK-only inhibitors. Preclinically, avutometinib has shown strong anti-proliferative potency across tumor cell lines carrying KRAS mt including PDAC cell lines. Clinically, avutometinib in combination with the FAK inhibitor (FAKi) defactinib received breakthrough therapy designation for the treatment of patients with recurrent low-grade serous ovarian cancer. Here, we tested the combination of avutometinib and FAK inhibition with standard of care chemotherapy in PDAC mouse models. In a KRAS/p53 pancreatic cancer mouse model, we found that whereas the combination of avutometinib + FAKi induced tumor inhibition and increased survival, addition of chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) to avutometinib/FAKi induced tumor regression. These results support the ongoing clinical study of avutometinib and defactinib in combination with standard of care chemotherapy (gemcitabine/nab-paclitaxel) for patients with front-line metastatic PDAC (NCT05669482). Other combinations being explored preclinically include avutometinib with G12D inhibition (G12Di) in KRAS G12D PDAC, which accounts for 28% of patients with PDAC. In 3D culture, avutometinib was synergistic with the G12Di MRTX1133 in reducing viability of a panel of KRAS G12D PDAC cell lines. In mouse models, avutometinib enhanced anti-tumor efficacy of MRTX1133 in a KRAS G12D pancreatic cancer patient-derived xenograft model. Furthermore, in KRAS mt PDAC cell lines, avutometinib was synergistic with the autophagy inhibitors chloroquine or apilimod. Indeed, dual treatment with avutometinib + MRTX1333 synergistically decreased proliferation and increased autophagic flux in KRAS G12D PDAC cell lines, supporting testing the triple combination of avutometinib + G12Di + autophagy inhibitor in patients with KRAS G12D pancreatic cancers. In conclusion, we show that avutometinib is a unique RAF/MEK clamp with the potential to become the backbone of therapy for pancreatic cancers. Citation Format: Silvia Coma, Xiuting Liu, Noah L. Pieper, Wen-Hsuan Chang, Kirsten L. Bryant, Channing J. Der, David G. DeNardo, Jonathan A. Pachter. The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A091.

Low-grade versus high-grade serous ovarian cancer: comparison of surgical outcomes after secondary cytoreductive surgery.

Retrospective series have shown secondary cytoreductive surgery improves oncological outcomes in recurrent low-grade serous ovarian cancer. We aim to compare surgical procedures and complications between patients with low-grade and high-grade recurrent serous ovarian cancer. This retrospective single-institution study includes patients with recurrent low-grade and high-grade serous ovarian cancer undergoing surgery between January 2012 to December 2021. Patients were propensity matched 1:3 for residual tumor at first surgery, presence of ascites and performance status. Complexity of surgery and postoperative complications were analyzed. A total of 116 patients undergoing secondary cytoreductive surgery were included with 29 patients (25%) having low-grade ovarian cancer. The median age of the patients was 54 years (range: 19-85) and 57 years (range: 29-78) in low-grade and high-grade ovarian cancer, respectively (p=0.13). Stages III/IV at diagnosis were more frequent in patients with high-grade ovarian cancers (p<0.001). Peritoneal involvement was higher in low-grade compared with high-grade ovarian cancer as shown by the higher rate of diaphragmatic (41.4% vs 21.8%, p=0.05), abdominal wall (41.4% vs 18.4%, p=0.02) and pelvic (51.7% vs 21.8%, p=0.01) peritonectomy. Multiple bowel resections were higher in low-grade ovarian cancer (24.1% vs 8.0%, p=0.04), while high-grade ovarian cancer had a higher rate of nodal recurrences (73.2%% vs 37.9%, p=0.03). Overall, surgical complexity was higher in low-grade ovarian cancer (58.6% vs 36.8%; p=0.05), with higher median estimated blood loss (400 vs 200 mL; p=0.01) compared with high-grade. Complete cytoreduction was achieved in 26 patients (89.7%) with low-grade and 84 (96.6%) with high-grade (p=0.16) ovarian cancer, with no significant differences in postoperative complications. Secondary cytoreductive surgery in low-grade serous ovarian cancer patients was associated with higher complexity, multiple bowel resections, and higher median estimated blood loss than in high-grade serous ovarian cancer. The comparable rate of postoperative complications suggests that secondary cytoreductive surgery in this group of patients is feasible in expert centers.

Treatment of Recurrent Low-grade Serous Ovarian Cancer With MEK Inhibitors: A Systematic Review.

Low-grade serous ovarian cancer (LGSC) represents 5% of all epithelial ovarian cancers. They are characterized by indolent growth and KRAS and BRAF mutations, differing from high-grade serous ovarian cancer both clinically and molecularly. LGSC has low response rates to traditional systemic therapies, including chemotherapy and hormonal therapy. The objective of this systematic review was to appraise the literature describing the efficacy of MEK inhibitors in the treatment of LGSC. A comprehensive search was conducted of the following databases: Medline ALL, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Sciences, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICFRP), and International Standard Randomized Controlled Trials Number (ISRCTN) Registry. All studies investigating MEKi in the treatment of LGSC in the adjuvant or recurrent setting for patients 18 years of age or older were included. All titles/abstracts were then screened by 2 independent reviewers (A.K. and C.C.). The full-text articles were then screened. All disagreements were resolved by a third independent reviewer (T.Z.). Two independent reviewers (A.K. and C.C.) extracted data from the studies deemed eligible for final review. A total of 2108 studies were identified in the initial search. Of these, a total of 4 studies met the eligibility criteria for systematic review. In these studies, 416 patients were treated with an MEKi alone. All patients included in the studies were being treated for LGSC in the recurrent setting. Varied results and efficacy of the MEKi were reported in each study. The results highlighted in this systematic review demonstrate varied responses to MEKi for recurrent LGSC. Further research is needed in this field comparing the efficacy to current therapies, as well as to further evaluate the safety and toxicity profile with long-term use of MEKi.

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer.

We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31-0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43-1.59). Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC).

5515 Background: LGSOC is a RAS/MAPK pathway driven cancer that constitutes ≤10% of ovarian cancer. There are no FDA approved treatments specifically for LGSOC. Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition, and defactinib, a small molecule inhibitor of FAK, has shown synergistic antitumor activity with avutometinib in preclinical models. The combination of avutometinib and defactinib has demonstrated a high rate of confirmed and durable responses (overall response rate [ORR] = 46%) in recurrent LGSOC (Banerjee S, ESMO 2021). Methods: A registration-directed phase 2, adaptive, multicenter, randomized study was initiated to evaluate avutometinib ± defactinib in patients with KRAS mutant (mt) and KRAS wild-type (wt) recurrent LGSOC to identify the optimal regimen based on confirmed ORR by blinded independent central review (Part A) and determine the efficacy of the optimal regimen (Part B) (NCT04625270). Pts were randomized to avutometinib 4 mg orally (PO), twice weekly, 3 weeks on, 1 week off (mono) or avutometinib 3.2 mg PO twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off (combo). Key inclusion criteria include histologically confirmed recurrent LGSOC, known KRAS status and prior systemic therapy with platinum chemotherapy. Unlimited additional prior lines, including prior MEK inhibitor, were permitted. Here we present efficacy results from Part A (evaluable patients, N=59) and safety data from all pts enrolled (N=121). Results: In Part A, the median number of prior systemic regimens was 3 for mono, and 4 for combo. In evaluable patients, a confirmed ORR of 7% (2/30) was observed for mono (13% KRAS mt, 0% KRAS wt), and an ORR of 28% (8/29) was observed for combo (27% KRAS mt, 29% KRAS wt). Two of 4 patients previously treated with a MEK inhibitor showed a confirmed partial response (PR) on the combination arm. A high disease control rate (PR or SD ≥ 8 weeks) was observed for both mono (90%) and combo (93%). The majority of treatment related adverse events (AEs, any grade) for combo (N=57) were mild to moderate. The most common Grade ≥3 AEs for combo were blood CPK increase (15.8%), fatigue (5.3%), diarrhea (3.5%), dermatitis acneiform (1.8%), and rash (1.8%). A similar AE profile was observed for mono (N=64). Most AEs were manageable/reversible. On the combo arm, 90.6% (±20%) of planned doses were given and 9% (n=5) of pts discontinued due to AEs [asymptomatic elevated blood CPK (n=3) and fatigue (n=2)]. Conclusions: The interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status. No new safety signals were observed, and most AEs were mild to moderate. Enrollment continues in Part B for the combination of avutometinib and defactinib. Clinical trial information: NCT04625270 .

Trametinib for patients with recurrent low-grade serous ovarian cancer: A cost-effectiveness analysis

ObjectiveThe GOG 281/LOGS trial found that trametinib prolonged progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer (LGSOC), compared with standard of care (SOC). The current study aimed to evaluate the cost-effectiveness of trametinib versus standard of care for recurrent LGSOC from the US payer perspective. MethodsA Markov model was adopted to compare the cost and effectiveness of trametinib and standard of care group in patients with recurrent LGSOC. Life years (LYs), quality-adjusted LYs (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, and probabilistic sensitivity analyses were performed to explore the model robustness. ResultTrametinib group provided an additional 0.58 QALYs (1.14 LYs) and an incremental cost of $248,214 compared with the SOC group. The incremental cost-effectiveness ratio was $424,097 per QALY. The results of one-way sensitivity analyses suggested that our model was sensitive to the hazard ratio of OS and PFS between trametinib and SOC group, utility of PFS and the cycle cost of trametinib. Probabilistic sensitivity analyses revealed that there was 6% probability of the trametinib group being cost-effective at a willingness-to-pay (WTP) threshold of $150,000 per QALY. ConclusionsFrom the US payer perspective, trametinib is not cost-effective for patients with recurrent LGSOC at the assumed WTP threshold of $150,000 per QALY. Based on the value standpoint, price reduction of trametinib is expected to improve the cost-effectiveness of trametinib in patients with recurrent LGSOC.

Advancements in Low-Grade Serous Carcinoma of the Ovary and Peritoneum.

Low-grade serous ovarian cancer (LGSOC) is a rare form of epithelial ovarian cancer that generally exhibits a protracted course and is less sensitive to chemotherapy than high-grade serous ovarian cancer. Over the past decade, it has become clear that patients with LGSOC have a clinically distinct course and are molecularly and histologically unique from patients with high-grade serous ovarian cancer. Endocrine therapy is frequently used for the treatment of patients with recurrent LGSOC and is now also part of the standard upfront treatment of this disease, with an ongoing phase III clinical trial seeking to determine if chemotherapy can be eliminated altogether from the initial treatment of LGSOC. Tumors are frequently found to exhibit alterations affecting the mitogen-activated protein kinase (MAPK) pathway, recently leading to developments in the use of targeted treatments for those patients with recurrent disease. LGSOC is a clinically, histologically, and molecularly unique form of epithelial ovarian cancer. Recent advances in the understanding of endocrine and molecular drivers of this disease have led to changes in both the treatment of newly diagnosed and recurrent disease, with ongoing studies focused on refining upfront therapy and seeking novel targeted combinations for those patients with recurrent disease.

ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of VS-6766 (RAF/MEK clamp) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC).

TPS5615 Background: Low-grade serous ovarian cancer (LGSOC) constitutes up to 10% of all ovarian cancer and has clinical and molecular characteristics distinct from high-grade serous ovarian cancer. Approximately a third of patients (pts) with recurrent LGSOC harbor KRAS mutations (mt) and pts with KRAS wild-type (wt) LGSOC may have mutations in NRAS, BRAF, or other RAS pathway-associated genes. Prior clinical studies with single agent MEK inhibitors have shown response rates of 16-26% in recurrent LGSOC. VS-6766 is a unique small molecule RAF/MEK clamp that inhibits both RAF and MEK activities by trapping them in inactive complexes. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Focal adhesion kinase (FAK) activation is a putative resistance mechanism to RAF and MEK inhibition, and defactinib, a small molecule inhibitor of FAK, has shown synergistic anti-tumor activity with VS-6766 in preclinical models, including organoids from LGSOC pts. Furthermore, FAK inhibition combined with VS-6766 induces tumor regression in a KRAS mt ovarian cancer xenograft model. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof-of-concept study, durable objective responses (ORR = 46%; 11/24) have been reported in recurrent LGSOC pts, including pts who have had a prior MEK inhibitor (Banerjee ESMO 2021) and the combination of VS-6766 + defactinib has received FDA Breakthrough Therapy Designation for recurrent LGSOC. These initial preclinical and clinical results support the ongoing phase 2 ENGOT-ov60/GOG-3052 in recurrent LGSOC. Methods: This is an international phase 2, adaptive, multicenter, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 vs VS-6766 in combination with defactinib currently open to enrollment (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS mt and KRAS wt LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS mt and KRAS wt LGSOC. The minimum expected enrollment is 104 pts, 52 pts with KRAS mt and 52 KRAS wt (64 pts in Part A and 40 pts in Part B). Pts will be randomized to receive VS-6766 (4.0 mg orally (PO), twice weekly 3 wks on, 1 wk off) or VS-6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 wks on, 1 wk off) till progression. Key inclusion criteria include histologically confirmed LGSOC, known KRAS mutation status, prior systemic therapy including platinum for metastatic disease and up to 1 prior line of MEK inhibitor therapy permitted. Part A of this study has completed enrollment and Part B is currently enrolling pts. Clinical trial information: NCT04625270.

PERCEPTION: Phase II investigational study of pembrolizumab combination with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer— A NOGGO trial.

TPS5613 Background: Low-grade serous ovarian cancer (LGSOC) represents a minority within the group of invasive epithelial ovarian malignancies. Recent analyses showed a very limited responsiveness to chemotherapy in LGSOC. Since bevacizumab many years ago, none other agents have been approved in LGSOC. There is a high demand of new therapy combinations with modern substances to improve the response rate and prognosis in this group of patients. Immune check-point inhibitors provide a new possibility which showed to be effective in different malignant diseases as well as in selected ovarian cancer patients. In this study, the standard chemotherapy is going to be combined with pembrolizumab in recurrent LGSOC cases with therapy free interval (TFI) over 6 months after last platinum-based chemotherapy. To the authors knowledge no comparable studies have been performed or planned. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: PERCEPTION/NOGGO-ov44 (NCT04575961) clinical trial is a multi-center, single-arm phase 2 study to evaluate pembrolizumab therapy concomitant to platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin, carboplatin plus gemcitabine or carboplatin monotherapy) and as maintenance in recurrent low-grade serous ovarian cancer cases. LGSOC patients with progression or recurrence at least six months after most previous platinum-containing therapy and in good general performance (ECOG 0 or 1) are eligible to participate in this clinical trial. The primary objective is the 12 months progression free survival (PFS) rate. Secondary end-points include overall survival, response rate (RR), PFS and RR according to Ki67 expression levels, time to first subsequent therapy (TFST) and its response, safety and quality of life. The trial is planned according to Simon’s two-stage design with total sample size up to 33 patients. The null hypothesis is PFS-rate after 12 months of 20%. In the first phase 18 patients will be enrolled and if at least 5 patients show PFS after 12 months the study is going to be continued with an additional 15 patients. The trial is claimed successful, if at least 11 patients show PFS after 12 months. Assuming a true PFS-rate of 40%, this trial has 5% type I error rate and 80% power. Clinical trial information: NCT04575961.

Rare Ovarian Cancer's First Positive Trial.

The MEK1/2 inhibitor trametinib increases progression-free survival from 7.2 months to 13 months in women with recurrent low-grade serous ovarian cancer. The drug also boosts the overall response rate from 6% to 26%.

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial

SummaryBackgroundLow-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.MethodsThis international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting.FindingsBetween Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9–15·0) compared with 7·2 months (5·6–9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36–0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths.InterpretationTrametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.FundingNRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.

Abstract P046: ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC)

Abstract Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Citation Format: Susana N. Banerjee, Bradley J. Monk, Els Van Nieuwenhuysen, Kathleen N. Moore, Ana Oaknin, Michel Fabbro, Nicoletta Columbo, David M. O’Malley, Robert L. Coleman, Jonathan Pachter, Andrew Koustenis, Gloria Patrick, Lorna Leonard, Rachel Grisham. ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC) [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 P046.

Abstract P121: Dual RAF/MEK inhibitor VS-6766 for treatment of solid tumors with diverse MAPK pathway alterations

Abstract The RAS/RAF/MEK/ERK (MAPK) pathway shows frequent mutations in cancer which often confer worse prognosis. Whereas KRAS mutations (mt) are prevalent in pancreatic cancer (PDAC; 98%), colorectal cancer (CRC; 45%) and non-small cell lung cancer (NSCLC; 31%), melanoma shows frequent mutations in BRAF (60%) and NRAS (28%). Although several BRAF and MEK inhibitors (MEKi) are FDA approved, there is still a need for agents with improved response rate, duration of response, and tolerability. VS-6766 is a unique dual RAF/MEK inhibitor. In contrast to MEKi, VS-6766 is a potent allosteric inhibitor of MEK kinase activity, which promotes a dominant negative RAF/MEK complex preventing phosphorylation of MEK by wildtype BRAF, BRAF V600E and CRAF. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of MEKi. In 3D proliferation assays in vitro, VS-6766 inhibited cell proliferation across multiple MAPK pathway alterations, including KRAS (G12C, G12D, G12V, G13D and Q61K), BRAF (V600E and class 2), NRAS and NF1 mt. Cell lines with KRAS G12V mt (n = 10; IC50 = 10 - 400 nM, average = 120 nM) were generally more sensitive than cell lines with KRAS G12D mt (n = 9; IC50 = 150 – 12,000 nM; average = 2.4 mM). Cell lines with NRAS mt also appeared to be especially sensitive to VS-6766 (average IC50 = 80 nM). Overall, VS-6766 inhibited proliferation of cell lines representing multiple cancers including NSCLC, PDAC, CRC and melanoma. VS-6766 effectively suppressed RAS pathway signaling (pMEK, pERK, DUSP4, pEphA2) throughout a 48-hour period among a panel of KRAS mt NSCLC cell lines. In a genetically engineered mouse tumor model of KRAS G12V mt/Trp53 KO NSCLC, which has previously been shown to be CRAF-dependent (Sanclemente et al., 2018), VS-6766 (0.1 mg/kg QD) induced regression of all tumors, whereas the MEKi trametinib at the same dose did not induce significant tumor growth inhibition. In KRAS mt NSCLC (H358) and ovarian cancer (TOV21G) xenograft models, VS-6766 significantly inhibited tumor growth (tumor growth inhibition, TGI = 70% and 69%, respectively), whereas the equivalent dose of trametinib was much less effective in inhibiting tumor growth (TGI = 13% and 29%, respectively). Clinically, intermittent dosing of VS-6766 as monotherapy has shown partial responses in patients with KRAS or BRAF mt gynecological malignancies (3/5) and KRAS mt NSCLC (3/10) (Guo, 2020). Interestingly, in NSCLC, responses occurred especially in patients with KRAS G12V mt tumors, which correlates with the greater anti-proliferative potency of VS-6766 observed across KRAS G12V mt NSCLC, CRC and PDAC cell lines. These data support the recent initiation of two registration-directed studies evaluating VS-6766 ± defactinib (FAK inhibitor) for the treatment of recurrent low-grade serous ovarian cancer (NCT04625270) and recurrent NSCLC with KRAS G12V or other KRAS mutation (NCT04620330), and suggest potential utility of VS-6766 for treatment of additional tumor types and oncogenic mutations in the MAPK pathway. Citation Format: Silvia Coma, Sanjib Chowdhury, Monica Musteanu, Mariano Barbacid, Jonathan A. Pachter. Dual RAF/MEK inhibitor VS-6766 for treatment of solid tumors with diverse MAPK pathway alterations [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 P121.

ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC).

TPS5603 Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Clinical trial information: NCT04625270.

Molecular results and potential biomarkers identified from MILO/ENGOT-ov11 phase 3 study of binimetinib versus physicians choice of chemotherapy (PCC) in recurrent low-grade serous ovarian cancer (LGSOC).

5519 Background: Lower responses to chemotherapy and the unique molecular profile of LGSO led to the adoption of MEK-inhibitors for this disease. Updated analysis from the MILO/ENGOT-ov11 phase III study of binimetinib vs PCC in recurrent LGSOC showed response rate of 24% in those treated with binimetinib (JCO, 2020; NCT01849874). Here we present results of the post-hoc tumor tissue biomarker analysis performed with MILO/ENGOT-ov11. Methods: Mutational/copy number analysis was performed via Foundation Medicine on archival tissue obtained prior to randomization. Unbiased univariate analysis was used to test association between mutation status and outcomes in binimetinib and PCC treated patients. Outcomes examined were progression free survival (PFS), binary response by local RECIST 1.1 (complete or partial response [CR/PR] vs. stable [SD] or progressive disease [PD]), and ordinal response. Kaplan-Meier was used to estimate PFS. Cox regression, binary logistic regression, and ordinal logistic regression were used to examine relationship between mutation status and outcomes. Results: MILO/ENGOT-OV11 enrolled 341 patients from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or PCC. Based on January 1, 2020 data cut-off the data is as-is, amongst those patients treated with binimetinib with molecular results available, PFS data is available for 144 and response rate (RR) data for 135. There were 47 mutations detected in ≥5% of patients, most commonly KRAS (33%). Patients harboring a KRAS mutation had 3.4 times the odds of responding to treatment with binimetinib as patients without KRAS mutation (95% CI 1.57,7.67; p-value 0.002). There was no difference in effect of KRAS G12V mutation vs other KRAS mutation on PFS (PFS HR 1.06; 95% CI:0.53, 2.12; p value 0.9). In the 135 patients with binimetinib RR data, other MAPK mutations were identified as follows; NRAS in 11(8.1%), BRAFV600E in 8(5.9%), RAF1 in 2 (1.5%), NF1 in 7 (5.2%). In patients with MAPK mutation (as defined above) the RR was 41% vs 13% in those without MAPK mutation. PFS was significantly better in patients treated with binimetinib harboring MAPK mutation vs those without (HR 0.5; 95% CI 0.31, 0.79; p = 0.003). In patients treated with PCC there was a nonsignificant trend towards improved PFS in those with MAPK mutation vs those without (HR 0.82; 95% CI 0.43,1.59; p = 0.6). A test for interaction between treatment and MAPK pathway was not significant by Cox regression model (p = 0.32). Conclusions: While this hypothesis generating analysis is limited by multiple testing, higher response rates and longer PFS were seen in those patients with LGSOC treated with binimetinib who harbored MAPK mutations, most commonly in KRAS. Somatic tumor testing should be routinely performed in patients with recurrent LGSOC to aid in clinical decision making. Clinical trial information: NCT01849874.

Bevacizumab Enables Surgery in Previously Inoperable Patients with Advanced Low-Grade Serous Ovarian Cancer

Low grade serous ovarian cancer (LGSOC) accounts for 10% of ovarian cancer cases and is characterised by an early age of onset and an indolent disease course. In contrast to high grade serous ovarian cancer (HGSOC), LGSOC is relatively resistant to cytotoxic chemotherapy and so aggressive surgery is preferred, especially at first presentation. Bevacizumab is effective in advanced ovarian cancer, and several singleinstitution studies have reported activity in patients with recurrent LGSOC. Bevacizumab is contraindicated in patients with extensive malignant bowel involvement due to the risk of perforation, which can be fatal. We present two patients with advanced LGSOC and extensive bowel serosal disease who safely received combination chemotherapy and bevacizumab in the first line setting and demonstrate that surgery was specifically facilitated by the bevacizumab component of this regimen.

Survival outcomes for patients with recurrent low-grade serous ovarian carcinoma

Objective: Low-grade serous ovarian cancer (LGSOC) is a rare ovarian tumor. Management of recurrences is not well established today. We describe clinical and biological features and treatments for patients with recurrent LGSOC.

Abstract IA24: Low-grade serous ovarian cancer: Recent advances and future directions

Abstract Low-grade serous ovarian cancer accounts for approximately 10% of epithelial ovarian cancer cases and is histologically, clinically, and molecularly distinct from high-grade serous ovarian cancer. Patients often present at a younger age and can have a protracted clinical course with median survival approaching 10 years. Prior retrospective studies have shown lower response rates to chemotherapy than are typically seen for patients with high-grade serous ovarian cancer in both the upfront and recurrent setting. However, patients with low-grade serous ovarian cancer also tend to be hormone receptor positive, with approximately 90% of patients being estrogen receptor and/or progesterone receptor positive. This has led to considerable interest in the use of hormonal therapies such as aromatase inhibitors and tamoxifen. Based on prior retrospective studies showing response, hormonal therapies are now routinely used for treatment of recurrent low-grade serous ovarian cancer. Given the generally well-tolerated side effect profile of hormonal therapies, the limited response rates to chemotherapy, and the high prevalence of hormone receptor positivity in low-grade serous ovarian cancer, there has also been considerable interest in the use of hormonal therapies in the first-line treatment of this disease. Dr. Gershenson and colleagues presented a large retrospective study showing a significant improvement in progression-free survival for patients with advanced low-grade serous ovarian cancer treated with maintenance hormonal therapy following upfront surgery and adjuvant chemotherapy. Hormonal therapy is now a standard-of-care management option following surgery and chemotherapy. These findings have led others to question if chemotherapy could potentially be omitted from upfront treatment altogether. The upcoming randomized phase III study, NRG-GY019, seeks to answer this question by randomizing patients with stage II-IV low-grade serous ovarian cancer treated with primary debulking surgery to either 6 cycles of carboplatin and paclitaxel chemotherapy followed by letrozole maintenance therapy or to letrozole maintenance therapy alone. With the recent FDA approval of bevacizumab in the front-line setting for treatment of all patients with advanced ovarian cancer, triplet therapy with carboplatin, paclitaxel, and bevacizumab has recently also become an option for selected patients with advanced low-grade serous ovarian cancer, a strategy specifically supported in low-grade serous ovarian cancer based on retrospective studies showing activity of bevacizumab in combination with chemotherapy in the recurrent setting. There has also been considerable interest in the use of targeted therapies for the treatment of recurrent low-grade serous ovarian cancer, with most efforts thus far targeting the MAP kinase pathway. Thirty-five to 45% of patients with advanced disease harbor a hotspot KRAS mutation and a smaller percentage a BRAF V600E mutation. Following promising results seen in a phase II study of selumetinib, two large phase III studies randomized patients with recurrent disease to treatment with single-agent MEK inhibitor vs. either standard-of-care chemotherapy or hormonal therapy, with results of both studies expected to be reported soon. Additional early-stage studies have shown promising results with targeted therapy combinations, but further development has been limited by toxicity and associated compliance issues. Newer strategies and trials currently in development concentrate on novel hormonal therapies such as the progesterone antagonist onapristone, and hormonal combination strategies such as CDK 4/6 inhibitors in combination with letrozole or fulvestrant. Citation Format: Rachel N. Grisham. Low-grade serous ovarian cancer: Recent advances and future directions [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 IA24.