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High grade epithelial ovarian carcinoma is an aggressive tumor. Treatment includes platinum therapy, however it recurs in most patients due to therapy resistance. In this project, we study the immunohistochemical (IHC) expression of five potential biomarkers/prognostic markers in high grade epithelial ovarian carcinoma: EGFR, HLA-G, CD70, c-MET, and NY-ESO1. A cohort of 274 patients is used. We compare the IHC expression with age, stage, ascites status, family history of cancer, disease free survival (DFS) and overall survival (OS). EGFR expression is significantly correlated with family history and worse OS. HLA-G is associated with worse OS. To confirm the results of EGFR and HLA-G, a second separated cohort of 248 patients is used. Positive EGFR expression again shows worse OS, while HLA-G expression has worse prognostic trend. CD70 has a worse OS trend. C-MET and NY-ESO1 do not have any clinical correlations. EGFR can potentially serve as target in future clinical immune therapy trials. [ABSTRACT FROM AUTHOR]

Background Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. Methods Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p  < 0.15; Ha: p  ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. Results Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. Conclusions The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings. Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prognostic and biologic significance of immune-related gene expression in high grade serous ovarian cancer (HGSOC). Methods: Gene expression dependent survival analyses for a panel of immune related genes were evaluated in HGSOC utilizing The Cancer Genome Atlas (TCGA). Prognostic value of LCK was validated using IHC in an independent set of 72 HGSOC. Prognostic performance of LCK was compared to cytolytic score (CYT) using RNAseq across multiple tumor types. Differentially expressed genes in LCK high samples and gene ontology enrichment were analyzed. Results: High pre-treatment LCK mRNA expression was found to be a strong predictor of survival in a set of 535 ovarian cancers. Patients with high LCK mRNA expression had a longer median progression free survival (PFS) of 29.4 months compared to 16.9 months in those without LCK high expression (p = 0.003), and longer median overall survival (OS) of 95.1 months versus 44.5 months (p = 0.001), which was confirmed in an independent cohort by IHC (p = 0.04). LCK expression was compared to CYT across tumor types available in the TCGA and was a significant predictor of prognosis in HGSOC where CYT was not predictive. Unexpectedly, LCK high samples also were enriched in numerous immunoglobulin-related and other B cell transcripts. Conclusions: LCK is a better prognostic factor than CYT in ovarian cancer. In HGSOC, LCK high samples were characterized by higher expression of immunoglobulin and B-cell related genes suggesting that a cooperative interaction between tumor infiltrating T and B cells may correlate with better survival in this disease. [ABSTRACT FROM AUTHOR]

To determine the clinical predictors of response rate, progression-free survival (PFS), and overall survival (OS) to pembrolizumab in advanced or recurrent, mismatch repair deficient (MMRd) or Microsatellite Instability-High (MSI-H) endometrial adenocarcinomas. A retrospective, single institution study was conducted among women with recurrent or advanced MMRd or MSI-H endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Logistic regression was used for univariable and multivariable analyses. PFS and OS were estimated using the methods of Kaplan and Meier and modeled via Cox proportional hazards regression. Log-rank test was used for intergroup comparisons based on body mass index (BMI). Among the 44 patients included in the analysis, the median BMI was 32.9 (range 18.5–51.8). Median cycles of pembrolizumab given was 11.5 (range 2–37). Median follow-up was 33 months (range 5–61) with a response rate of 63.6% and stable disease rate of 75%. When stratified by obesity status (BMI ≥ 30), disease control rate was 59.8% in patients with a BMI < 30 and 85.2% in patients with a BMI ≥ 30 patients (p = 0.05). On multivariable analysis, obesity was associated with increased rate of disease control (OR 4.03, 95%CI 1.09, 28) while prior smoking was associated with decreased rate of disease control (OR 0.18, 95%CI 0.03, 0.85). PFS was significantly increased among patients with a BMI ≥ 30 (p = 0.03) but OS was similar (p = 0.5). In this retrospective study, obesity is associated with increased rates of disease control and improved PFS in patients treated with pembrolizumab for recurrent or advanced MMRd/MSI-H endometrial adenocarcinomas. • Obesity is a known risk factor for many cancers, yet is associated with improved treatment response in some tumor types. • Obesity is associated with improved disease control in patients with MMRd endometrial cancer when treated with pembrolizumab. • PFS was significantly increased among patients with a BMI ≥ 30 but overall survival was similar. [ABSTRACT FROM AUTHOR]

Gynecologic tract melanoma (GTM) is a rare malignancy with historically poor outcomes. The current study examines patterns of care and oncologic outcomes in a large single-institution cohort from the contemporary therapeutic era. Patterns of care and predictors of outcomes were evaluated for all GTM patients without metastatic disease at diagnosis who were treated at our institution between 2009 and 2020 with >6 months of follow-up. Of the 124 patients included, anatomic subsites were vulvar (n = 82, 66%), vaginal (n = 34, 27%), or cervical (n = 8, 6%). Primary tumor was resected for 85% (n = 106) with surgical nodal evaluation for 60% (n = 75). Systemic therapy, most commonly immune checkpoint inhibitors (ICI, 58% systemic therapy), was used to treat all except one unresectable patient (17/18) and 33% (35/106) of resectable patients. Seven patients received neoadjuvant ICI. Fourteen patients received adjuvant radiation therapy to the pelvis (RT, 13% of those undergoing resection). With a median follow-up of 45 months, 100 patients (81%) recurred. Four-year actuarial outcomes were: 46% local control, 53% nodal control, 36% distant metastasis-free survival, 17% disease-free survival, 49% melanoma-specific survival and 48% overall survival. Mitotic rate > 10/mm2, nodal involvement and non-vulvar anatomic subsite were associated with poor outcomes. Patients treated after 2016 did not have significantly better outcomes than those treated earlier. Patients with GTM continue to have poor outcomes in the contemporary therapeutic era with particularly notable poor local disease control relative to other mucosal melanoma subtypes. More effective oncologic therapy is needed. • Gynecologic tract melanoma patients continue to have poor outcomes in the contemporary therapeutic era. • About half of patients will have primary disease progression with almost two-thirds developing distant metastasis. • High mitotic rate and vaginal or cervical disease predict for worse outcomes. • Radiation therapy may play a role in improving local disease control. [ABSTRACT FROM AUTHOR]

The purpose of the present study is to describe a cohort who received contemporary primary treatment for stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC), including patient characteristics and determinants of relapse and disease-free survival. The study included 99 patients: 1) with pathologically confirmed stage II-IV LGSOC of the ovary or peritoneum, 2) who underwent primary treatment consisting of cytoreductive surgery and either a) platinum/taxane chemotherapy followed by aromatase inhibitor maintenance therapy or b) aromatase inhibitor monotherapy, and 3) for whom there was availability of clinical data. Descriptive statistics were used to characterize clinicodemographic features. Subgroups were compared for PFS and OS. Multivariable Cox regression analyses were performed. Median PFS for the entire cohort was 56.8 months (95% CI, 41.3-NE), and median OS was 130.7 months (95% CI, 115.0–146.4). Forty-nine of 99 (49.5%) patients have relapsed to date. For these 49 patients, median time from diagnosis to relapse was 29.6 months (95% CI, 24.6–33.1) (range, 5.4–69.1 months). Only 1/49 (2%) patients who relapsed did so >5 years from diagnosis. Fifty (50.0%) patients have not experienced disease progression or relapse. Median follow-up time for these 50 patients is 86.2 months (range, 25.3–169.0). Thirty-three of the 50 (66.0%) have been followed for >5 years from diagnosis. On regression analyses, factors associated with improved patient outcomes—either PFS, OS, or both–included no gross residual disease, normal serum CA 125 at diagnosis, primary peritoneal site, and presence of extensive psammomatous calcifications. This is the first report to describe the clinicopathologic features and outcomes of women with stage II-IV LGSOC who received contemporary primary therapy. • Following contemporary primary therapy, 98% of women with stage II-IV LGSOC who relapsed did so within 5 years of diagnosis. • Fifty-one percent of women who received contemporary primary therapy had not relapsed at time of analysis. • This study delineates several clinicopathologic factors that may be associated with patient outcomes. [ABSTRACT FROM AUTHOR]

To evaluate the factors associated with response to neoadjuvant chemotherapy (NACT) and the ability to undergo interval tumor reductive surgery (iTRS) in patients with advanced ovarian cancer. We performed a retrospective review from April 2013 to March 2019 of patients with advanced stage ovarian cancer triaged to NACT based on our standard triage algorithm. Clinicopathologic and treatment data were analyzed for factors associated with response to NACT, outcomes at iTRS, and their impact on progression-free survival (PFS). 562 patients met inclusion criteria and triaged to NACT following laparoscopy (n = 132) or without laparoscopy (n = 430). 413 patients underwent iTRS (74%). Factors that correlated with a patient reaching iTRS included increasing age (p < 0.001), higher Charlson comorbidity index (p < 0.001), ECOG status 2 or 3 (<0.001), and laparoscopic assessment (<0.001). Patients with CA-125 ≤ 35 U/mL at iTRS had higher rates of complete gross resection (88% vs. 65%, p < 0.001) and improved PFS (16.8 vs. 12.7 months, p < 0.001). Patients receiving dose-dense paclitaxel (76% vs. 60%, p = 0.004) and CA-125 ≤ 35 U/mL at iTRS (85% vs. 66%, p < 0.001) had higher rates of complete radiographic response. On multivariate analysis, germline BRCA 1/2 mutation (p = 0.001), iTRS vs. no surgery (R0, p < 0.001; ≤1 cm, p < 0.001; >1 cm, p < 0.001), dose-dense chemotherapy (p = 0.01), and CA-125 ≤ 35 U/mL at iTRS (p = 0.001) were independent significant factors affecting PFS. Normalization of CA-125 at the time of iTRS following NACT may serve as a surrogate marker for prognosis in this high-risk population. Our NACT cohort experienced improved response rates and PFS with dose-dense therapy compared to conventional dosing. • Patients undergoing initial laparoscopic triage to NACT were more likely to undergo interval tumor reductive surgery. • Dose-dense therapy was associated with improved progression-free survival in our NACT cohort. • Normalization of CA-125 at the time of interval tumor reductive surgery was associated with improved outcomes. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) is more widely expressed than the estrogen or progesterone receptor in endometrial cancer (EC), including up to 90% of endometrioid type. Enzalutamide binds to the AR thereby nuclear translocation of receptors and blocking the association of the AR with DNA. We sought to evaluate the efficacy of paclitaxel, carboplatin and enzalutamide in a phase II study of advanced or recurrent endometrioid EC. Women with chemo-naïve, advanced-stage or recurrent endometrioid EC with measurable disease and adequate end organ function were eligible. Documented AR expression was not required. A safety lead in of the triplet was performed to confirm dose. In phase II, patients received 28 days of enzalutamide (160mg daily) as a single agent before starting triplet therapy. Pre- and post-treatment biopsies were obtained during the single agent lead in for evaluation of molecular markers including AR receptor expression and activation, expression of AR-related genes/proteins, and DNA copy number alterations and mutations. Patients then received carboplatin (AUC 6 IV Q3wk), paclitaxel (175 mg/m2), and enzalutamide (160mg daily). Response per RECIST 1.1 was assessed every 3 cycles for a maximum of 9 cycles. Evaluable patients received at least 6 cycles of triplet therapy. Progression free survival (PFS) was calculated from date of treatment initiation to earliest date of progression, death, or last contact. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Astellas Pharma Global Development, Inc. A total 81 patients were screened with 49 patients treated to date (safety lead in n=7; phase II n=42). Median age was 64 years (range 41-81) and the majority of patients had grade 2 histology (53.1%) and recurrent disease (81.6%). There were no dose-limiting toxicities observed during the safety lead in. Patients received a median of 9 cycles of triplet therapy (range 0-9). 8 patients (16.3%) did not receive chemotherapy due to rapid progression during single agent enzalutamide (n=3), unrelated death (n=2), withdrawal (n=2), and unrelated stroke (n=1). PFS for the entire cohort was 11.47 months (95% CI 9.86 - 17.94; Figure 1a) and 6-month PFS probability was 0.77 (95% CI 0.61-0.87). Among 35 evaluable patients, confirmed objective response rate was 71% (95% CI 54–85%), 6 months PFS probability was 0.83 (95% CI 0.66-0.92) and median PFS was 14.42 months (95% CI 11.2-25.5; Figure 1B). The most common adverse events were as expected for chemotherapy alone, including neutropenia (20%), anemia (18%), fatigue (18%), neuropathy (10%), hyperglycemia (14%), nausea (8%), and thrombocytopenia (8%). [Display omitted] The combination of enzalutamide, carboplatin, and paclitaxel was tolerable and had promising clinical outcomes in chemo-naïve advanced or recurrent endometrioid EC. Further analyses are ongoing regarding predictors of response and resistance to androgen-inhibitor therapy. NCT02684227. [ABSTRACT FROM AUTHOR]

Uterine leiomyosarcoma (ULMS) is a rare tumor with limited therapeutic options and no clearly established best treatment sequence strategy. The objective of this study was to evaluate treatment sequencing for ULMS following primary surgical management and determine predictors of survival. Women with a diagnosis of ULMS between 1/2013 and 1/2018 were identified. Clinical data was collected; for this analysis, only women treated with primary surgical management were included. Descriptive statistics were performed and predictors of overall survival (OS) and progression free survival (PFS) were analyzed using Cox regression and Kaplan-Meier methodology. 179 patients were included. Median age was 52 years (20-78), 94% had grade 3 tumors, and over half the total population were treated with adjuvant chemotherapy (n=100, 56%). In the subset of patients with early stage disease (126), 49% were treated with surgery only while 51% received adjuvant chemotherapy. There was no difference in PFS between early stage patients who did or did not receive adjuvant chemotherapy (p=0.60). For the overall cohort, the most common adjuvant therapy regimens were gemcitabine/docetaxel (gem/doce, 40.9%) or ifosphamide/doxorubicin (ifos/doxo, 11.4%).137 patients (76.5%) experienced recurrence, progression or death during their follow up. The median PFS was 1.76 years (95% CI: 1.27- 2.08). The median survival for those treated with surgery alone was 1.79 years, for those treated with gem/doce was 1.27 years, and other chemotherapy regimen was 0.43 years. Median survival was not estimated for the ifos/doxo regimen due to small patient number. Upfront therapy regimen significantly impacted PFS (Figure 1, p=0.003), but was not significantly associated with OS (p=0.069). The one-year PFS probability was 0.58 for gem/doce (95% CI 0.45-0.68) compared with 0.80 for ifos/doxo (95% CI 0.54-0.91). [Display omitted] Median PFS was 1.76 years, despite many women undergoing adjuvant therapy after surgery, most commonly with either gem/doce or ifos/doxo regimens. Primary treatment with ifos/doxo was associated with higher one-year PFS. This finding warrants additional evaluation to determine the optimal adjuvant therapy for these women. [ABSTRACT FROM AUTHOR]

Single agent immune checkpoint blockade (ICB) has demonstrated response rates of 5-15% in patients with recurrent high-grade ovarian cancer (HGOC), with another 15-40% of patients achieving stable disease. Combination ICB using ipilimumab and nivolumab resulted in improved response rates in a mixed population with platinum resistant and sensitive disease. The objective of the current trial was to evaluate sequential versus combination CTLA4 and PDL1 blockade strategies for extending progression free survival (PFS) in patients with platinum resistant/refractory HGOC. Patients were required to have pathologically confirmed platinum resistant or refractory epithelial ovarian cancer, no prior immunotherapy, and PS= 0-1 for enrollment. The current abstract includes data only on subjects with high grade serous ovarian cancer (HGSOC), as enrollment of patients with clear cell histology is still ongoing. The primary endpoint was PFS and response was assessed using modified RECIST v1.1. Unlimited numbers of prior regimens were allowed. Patients were adaptively randomized to sequential arm: tremelimumab (3mg/kg q4 weeks x 4 doses) followed by durvalumab (1.5g IV q4 weeks for up to 9 doses) upon progression, or the combination arm: tremelimumab (1mg/kg IV plus durvalumab 1.5g IV q4wk for up to 4 doses followed by durvalumab monotherapy for up to 9 doses). For the Bayesian adaptive randomization, the probability of being assigned to an arm was proportional to the likelihood the arm had better PFS, such that patients were more likely to be randomized to the more effective arm. A total of 61 subjects were adaptively randomized to sequential treatment (n=38) or combination therapy (n=23). 46 (79%) patients had wild-type breast cancer gene (BRCA). Median prior lines of therapy was 4 (range: 1-10). There was no difference in median PFS in the sequential arm (1.84 months; 95% CI: 1.77 – 2.17)) compared with the combination arm (1.87 months; 95% CI: 1.77 – 2.43), p=0.402. Similarly, median OS in the sequential and combination arms were 10.61 months (5.95 – 15.34) and 7.26 (4.24 – 15.57), respectively (p=0.810). In the sequential arm no objective responses were observed, although 12 patients (31.6%) exhibited stable disease. In the combination arm, 2 patients had partial response (8.7%) while one additional patient (4.4%) had stable disease. The adverse event profile was consistent with that previously reported for immune checkpoint therapy. [Display omitted] There was no difference in the median PFS between the combination and sequential durvalumab plus tremelimumab treatment strategy arms in a heavily pretreated population of patients with platinum resistant/refractory HGOC. Response rates were comparable to prior reports, though the combination regimen did not add significant benefit as has been previously described with combination of ipilimumab/nivolumab. Further exploration into subpopulations that may have increased benefit from ICB is warranted. [ABSTRACT FROM AUTHOR]