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Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort.Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens.Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent.BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents.

ObjectiveRadiofrequency ablation and microwave ablation are used to vaporize tumors not amenable to surgical resection. We sought to evaluate the safety and efficacy of radiofrequency and microwave ablation for the treatment of isolated lesions in patients with recurrent gynecologic malignancy.MethodsPatients with gynecologic malignancies treated with radiofrequency or microwave ablation at a university-affiliated cancer center from April 2007 to January 2020 were evaluated. Clinical records were reviewed for number of prior chemotherapy regimens, response to ablation, time to progression, and location of progression.ResultsThirty-two patients received ablative therapy for treatment of isolated recurrences. Seventeen (53%) patients had ovarian cancer, seven (22%) had endometrial cancer, and eight (25%) had cervical cancer. Thirteen (41%) patients received radiofrequency ablation and 19 (59%) received microwave ablation. Patients had a median of 2 (range 1–12) prior lines of chemotherapy. Sixteen (50%) patients achieved a partial or complete response with two patients experiencing no progression at time of submission. Six (19%) patients had stable disease and 10 (31%) patients had progression at time of initial follow-up imaging. Median progression-free survival for the cohort was 7.3 months (range 1.4–64.7). No significant improvement in median progression-free survival was seen with the addition of adjuvant systemic therapy to radiofrequency or microwave ablation (6.9 vs 7.7 months; HR 0.7, 95% CI 0.3 to 1.7). Clinical benefit, defined as absence of definitive progression at the site of ablation or new target lesions at 4 months, was seen in 22 (68.8%) patients. No major complications occurred, with two patients reporting pain or weakness at the site of ablation.ConclusionRadiofrequency and microwave ablation demonstrated that 68.8% (n=22) of patients experienced clinical benefit at 4 months. Ablative therapy may be considered for the treatment of isolated lesions in patients with recurrent gynecologic malignancies.

Advanced clear cell gynecologic malignancies remain among the most challenging diseases to manage. We evaluated ovarian and endometrial clear cell carcinoma (OCCC and ECCC) specimens using comprehensive sequencing technology to identify mutational targets and compared their molecular profiles to histologically similar clear cell renal cell carcinoma (ccRCC).Using next-generation sequencing (NGS), fragment analysis (FA), and in situ hybridization (ISH), 164 OCCC, 75 ECCC and 234 ccRCC specimens from 2015 to 2018 were evaluated and compared.The highest mutation rates in ECCC and OCCC were noted in: ARID1A (75.0%, 87.5%), TP53 (34.8%, 11.1%), PIK3CA (25.0%, 46.8%), PPP2R1A (8.7%, 16.7%), MSI-high (8.8%, 6.4%) and PTEN (8.3%, 7.1%). Among these mutations, there was no significant difference between OCCC and ECCC mutation prevalence except in TP53, with higher mutation rates in ECCC versus OCCC (34.8 vs. 11.1%, respectively, p0.05). ccRCC demonstrated different mutation profiles with higher mutation rates in VHL (80.3%), PBRM1 (43.9%), SETD2 (31.1%), and KDM5C (29.2%). By contrast, VHL, PBRM1, and SETD2 mutations were not found in ECCC and OCCC (0.0%). Compared to ccRCC and ECCC, OCCC was found to have a significantly higher tumor mutation burden (TMB) (19.1%).Gynecologic and renal CCC demonstrate separate and disparate somatic profiles. However, OCCC and ECCC are diseases with similar profiles. TMB and MSI analyses indicate that a subset of OCCC may benefit from immunotherapy. Prospective clinical trials are needed and are underway to examine targeted therapies in these gynecologic disease subtypes.

Background: Standard treatment of localized muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC); however, only 40-50% respond to NAC and approx. 50% experience relapse. Evaluation of treatment efficacy and early detection of relapse are therefore major clinical challenges. Methods: We present a clinical update of a previously described cohort of 68 patients who received NAC prior to RC (NAC cohort; Christensen et al. JCO 2019; median follow-up (FU) of 58 months) together with evaluation of a retrospectively collected cohort of 120 patients who did not receive NAC (no-NAC cohort; median FU of 71 months). Circulating tumor DNA (ctDNA) was analyzed before NAC (NAC cohort, n=63), prior to RC (NAC cohort, n=67; no-NAC cohort, n=115) and after RC (NAC cohort, n=66; no-NAC cohort, n=37) using Signatera™. RNA-seq was performed on 176 tumors. Results: Updated clinical FU for the NAC cohort showed that ctDNA-positive patients had significantly worse recurrence-free survival (RFS) compared to ctDNA-negative patients (before NAC: HR=16, 95%CI=3.6-70.5, p=0.0002; during surveillance after RC: HR=27.6, 95%CI=7.9-96.9, p Conclusion: Presence of ctDNA was associated with worse prognosis for both NAC and no-NAC treated patients. Transcriptomic analysis of primary tumors showed that anti-tumor immune responses may be associated with a particularly good outcome whereas EMT may be promoting more aggressive disease. Citation Format: Sia Viborg Lindskrog, George Laliotis, Karin Birkenkamp-Demtröder, Iver Nordentoft, Philippe Lamy, Elshaddai Z. White, Natalia Pajak, Tine G. Andreasen, Punashi Dutta, Meenakshi Malhotra, Shruti Sharma, Mark Calhoun, Adam ElNaggar, Minetta C. Liu, Mads Agerbæk, Jørgen B. Jensen, Lars Dyrskjøt. Utility of circulating tumor DNA and transcriptomic profiling in predicting outcome in muscle invasive bladder cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5600.

715 Background: Treatment response monitoring is key to effective disease management for patients with advanced (RCC) and can potentially improve clinical outcomes. Circulating tumor DNA (ctDNA) has shown promise as a biomarker in the early identification of treatment response in a variety of tumor types. Herein, we evaluated ctDNA-derived molecular residual disease (MRD) detection and dynamics in both clear cell (ccRCC) and non-clear cell (nccRCC) RCC patients treated with standard of care therapy and provide correlations with clinical outcomes. Methods: This was a multi-center retrospective analysis of real-world data obtained from commercial ctDNA testing (Signatera, Natera, Inc.), 41 patients (142 plasma samples) with high-risk resected or metastatic RCC were analyzed for ctDNA. Clinical data were collected on IMDC risk category, pathologic subtype, tumor stage and grade including the presence of sarcomatoid/rhabdoid features. Progression on radiological imaging was based on RECIST 1.1. criteria. Results: Of the 41 patients, 73% (30/41) had ccRCC and the remaining 27% (11/41) were nccRCC. Immunotherapy was administered as a single agent or in combination with other immune checkpoint inhibitor agents/targeted therapy in 78% (32/41) in either frontline or refractory settings. ctDNA detection at any time point was 70% (29/41) and patients were followed-up for a median of 26.4 weeks (range: 0.9-90.6) from the first ctDNA time point. Fourteen patients (34%) experienced disease progression during follow-up and all had ctDNA detected ahead of radiological progression (100% sensitivity) with a median lead time of 13.6 weeks (range: 1-39.7 weeks). Concordance between clinical outcome and ctDNA status (detected or not detected) was observed in 78% (32/41) of the patients, 12% (5/41) showed discordance, and imaging data is pending for 10% (4/41) at the time of analysis. Conclusions: Collectively, our study demonstrates high concordance between MRD status and subsequent clinical outcomes. MRD had 100% sensitivity for predicting subsequent radiographic progression with significant median lead time. MRD may serve as a valuable tool for monitoring patients on immunotherapy-based regimens for RCC.

563 Background: Muscle-invasive bladder cancer (MIBC) accounts for ~25–30% of all bladder cancer diagnoses. With neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) as standard-of-care, the 5-year survival rate ranges from 40%–60%. Bladder-sparing protocols (BSP) have emerged as a feasible alternative to RC for MIBC treatment, however better tools are needed. In this study, we evaluated the prognostic value of circulating tumor DNA (ctDNA) in predicting recurrence in patients who achieved pathological complete response (pCR). Methods: We analyzed a previously described cohort of 68 patients (656 plasma samples; Christensen et al., JCO 2019) with MIBC who received NAC prior to cystectomy. Patients had an updated median follow-up of 58.94 months (range: 7.19-81.77) post-cystectomy. ctDNA was analyzed at baseline (before NAC; N=64), and prior to cystectomy (N=65) using a commercially available assay (Signatera, Natera, Inc.). Additionally, exploratory RNA-Seq was performed on tumors from 59 patients (samples with >5M total counts were utilized). Pathway analysis was used to compare ctDNA-positive and ctDNA-negative patients who failed to achieve pCR. Results: Of the 64 patients with ctDNA results available at baseline, 59.4% (38/64) tested ctDNA-negative, and of these 84.2% (32/38) achieved pCR. Furthermore, 40.6% (26/64) tested ctDNA-positive, and only 34.6% (9/26) achieved pCR. Likewise, prior to cystectomy, 83.9% (52/62) of patients were ctDNA-negative, and 80.7% (42/52) achieved pCR, while none of the ctDNA-positive patients achieved pCR (positive predictive value 100%; negative predictive value 80.8%). Based on both ctDNA timepoints, the probability of ctDNA-negative patients to achieve pCR was significantly higher than ctDNA-positive patients ( p

721 Background: Current methodologies for monitoring treatment response are largely based on conventional scans and/or tumor biopsies, which may be limited in their ability to accurately assess disease burden at the molecular level. Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker and has shown to better assess treatment response in patients receiving immune checkpoint inhibitors (ICI). We conducted a prospective, pilot study to investigate the concordance of serial ctDNA detection and dynamics with radiographic response in patients with advanced GU malignancies undergoing ICI-based treatment. Methods: Twenty patients with histologically confirmed advanced GU malignancies (renal, urothelial, and prostate) were enrolled in the prospective study. All eligible patients received ICI treatment for at least 12 weeks and were followed by serial collection of blood samples every 6-8 weeks until disease progression. Conventional scans were performed approximately every 12 weeks until disease progression. Overall response rate (ORR) by investigator was reported and associated with ctDNA detection. Results: ctDNA analysis was performed on 122 plasma samples obtained from 20 patients (N=15 renal cell carcinoma; N=4 urothelial carcinoma; N=1 prostate cancer). Prior therapies to ICI-based treatment included chemotherapy (10%), hormonal therapy (5%) and anti-VEGF (5%). After study enrollment, patients received anti-PD-1 (95%), anti-CTLA-4 (30%) or anti-PD-L1 (5%) with an ORR of 70% as best response. With a median follow-up of 19 months (range: 4-48), progressive disease was observed in 7 patients. Nineteen patients had longitudinal plasma samples available and ctDNA detection at any time point was 45% (9/20). The overall concordance between ctDNA dynamics and radiographic response at 12 weeks was observed in 89% (17/19) of patients. Of these 17 concordant patients, one patient showed transient ctDNA positivity followed by clearance at the last two timepoints on treatment. The two patients with discordant results included the ones with CNS-only metastasis (ctDNA negative). Of the 7 patients who progressed on ICI, ctDNA was detected in five (71%); the remaining two had CNS-only metastases. The last patient had a single time point available on treatment that showed ctDNA-positivity and passed away 7 weeks after molecular evidence of disease. Conclusions: In this study, serial collection of blood samples for ctDNA analysis to monitor response to ICI-based therapiesin patients with advanced GU tumors was feasible. There was a high concordance rate between radiological imaging and ctDNA data, especially in extra-CNS disease. Further studies are needed to validate ctDNA as a tool to aid disease monitoring in patients treated with ICI.

e17501 Background: The role of immunotherapy in gynecologic malignancies continues to evolve. Use of immune checkpoint blockade (ICB) agents have consistently demonstrated less than a 15% response rate in ovarian, cervical, and subsets of endometrial cancer. Given the limited number of responders, a novel approach to treatment monitoring is needed to better sequence therapies. Circulating tumor DNA (ctDNA) surveillance in patients treated with ICB is one such approach that has been shown to predict clinical benefit. We sought to evaluate this approach in patients with recurrent gynecologic malignancies managed with ICB therapy. Methods: In this retrospective analysis of real-world data, plasma samples (n = 208) from 28 patients with recurrent/metastatic ovarian (n = 8), endometrial (n = 14), and cervical (n = 6) cancers were identified as having received ICB therapy. A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection of ctDNA in plasma samples. Serial time points were collected to monitor ctDNA levels in response to immunotherapy. Results: Response assessment results and longitudinal plasma samples were available for 19 patients. Pre-ICB plasma samples were available for 11 patients. Of these ctDNA was detected in 73% (8/11) of patients. All patients with progressive disease (10/10) had rising ctDNA levels that preceded radiological findings by a median of 2.8 months. One patient with rising ctDNA concentration presented with stable disease by imaging at the last follow-up. The remaining 8 patients demonstrated response to therapy that coincided with a declining or negative ctDNA level; 5 with partial response had a decline in ctDNA level prior to imaging (n = 3) or lack of ctDNA detection (n = 2), and 3 with complete response remained ctDNA negative, prior to imaging. Patients that exhibited a rise in ctDNA concentration (n = 11) (consecutive time points) while undergoing ICB therapy were associated with resistance to treatment (HR = 4.58 95%CI: 1.048-20.03, p = 0.04). TMB and MSI status (binary) were not predictive of response in univariate (p = 0.8, p = 0.9) analyses. Conclusions: ctDNA monitoring during the course of immunotherapy for relapsed gynecologic malignancies allows for accurate determination of therapeutic response and early prediction of disease progression. This enables timely assessment with imaging, and change in treatment plan. Our data suggest that patients with gynecologic malignancies may benefit from personalized, tumor-informed ctDNA testing to guide treatment decisions. Prospective studies are needed to establish the clinical utility of ctDNA monitoring in patients with gynecologic malignancies undergoing systemic therapies.

Background: A high unmet medical need exists for the treatment of patients who are unresponsive to or relapse following treatment with checkpoint inhibitors. Therefore, novel checkpoint inhibitors that can demonstrate clinical activity in this patient population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis. In nonclinical experiments using in vitro and animal models we have demonstrated that inhibition of PVRIG leads to enhanced activation of T and NK cells, and that knockout of PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will be safe and tolerable and demonstrate antitumor activity in pts with advanced solid tumors. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 weekly. Dose-limiting toxicities will be assessed within 21 days in cycle 1 of administration of COM701. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all the available standard therapy or is not a candidate for the available standard therapy, ECOG performance status 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose of COM701, symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701. Study Design: Single subject dose cohorts in initial 4 dose cohorts and 3+3 study design for subsequent cohorts. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. As of the date of this submission no DLTs have been reported in the initial 4 dose cohorts. Enrollment in cohort 5 is ongoing. Citation Format: Dan Vaena, Amita Patnaik, Erika Hamilton, Judy Olweny, John Hunter, Adeboye Henry Adewoye, Adam ElNaggar, Drew Rasco. Phase I study of COM701 (a novel checkpoint inhibitor of PVRIG) in patients with advanced solid tumors [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 CT168.

TPS40 Background: Novel checkpoint therapies are needed for the treatment of patients who relapse/refractory to treatment with checkpoint inhibitors. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with it's ligand, PVRL2. We have demonstrated in preclinical experiments that inhibition of PVRIG leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. We hypothesize that COM701 will be safe and tolerable and demonstrate antitumor activity in pts with R/R solid tumors. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with R/R solid tumors. The initial part of this study will evaluate the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all the available standard therapy or is not a candidate for the available standard therapy, ECOG performance status 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose of COM701, symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701. Study Design: Accelerated titration design consisting of single subject cohorts has been implemented for the initial cohorts. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. As of the date of this submission a third single subject dose cohort has been filled.