Phase 1b study of batiraxcept in combination with durvalumab in patients with platinum-resistant ovarian cancer.

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum-resistant ovarian cancer.

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

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

PARP inhibition in the ovarian cancer patient: Current approvals and future directions.

Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed the therapeutic management of solid tumors, particularly ovarian cancer. Initially studied in BRCA deficient tumors, the Food and Drug Administration (FDA) indications have expanded to include other homologous recombination deficient tumors as well as biomarker-wildtype tumors. They have also gained momentum not only as a treatment strategy, but as a maintenance strategy as well. While PARP inhibitors were initially ev aluated in the recurrent setting, they have now moved to frontline therapy. This review will discuss the current FDA indications of the clinically available PARP inhibitors for treatment and maintenance therapies. We will then review the recently completed and ongoing clinical trials which may inform future clinical approvals.

Developmental sacral morphology: MR study from infancy to skeletal maturity.

PURPOSE: The primary aim of this study was to document the growth and spatial relationship of the sacrum in relationship to the lumbar spine and the ilium during childhood and adolescence. METHODS: MRIs of 420 asymptomatic subjects (50% female) with age range 0-19 years at the time of their MRI (mean ± SD 8.5 ± 5.5 years) were used to characterize the reference distributions of MRI anatomic measurements as a function of age and gender. Eight dimensional measurements and eight angles were measured using PACS tools. Reliability of the measurements was studied on a subset of N = 49 images (N = 24 males; mean ± SD age 6.8 ± 5.2 years). RESULTS: The dimensional measurements increase with age, often with a rapid "growth spurt" in the first few years of life, with a decreased but steady rate of growth continuing until the late teenage. An exception is the S1 canal width, which reaches near-adult size by age 5. Angle measures are less dependent on age or gender, and the associations with age are not necessarily uniformly increasing or decreasing. CONCLUSION: These data on the sacral morphology are a valuable information source for surgeons treating young patients for deformity of the spine and pelvis. Knowledge of normative data of children through growth may allow for adaptation of adult surgical techniques to this pediatric age-group of patients. These slides can be retrieved under Electronic Supplementary Material.

Disparities in gynecologic cancer genetics evaluation.

An estimated 2-5% of endometrial cancers and 15-20% of high-grade, non-mucinous epithelial ovarian cancers have an underlying hereditary cause. Appropriate risk assessment, genetic counseling, and germline genetic testing for cancer predisposition genes in both gynecologic cancer patients and their at-risk relatives is essential for effective delivery of tailored cancer treatment and cancer prevention. However, significant disparities exist within medically underserved and minority populations in the United States regarding awareness of, access to, and use of genetic services. The objectives of this review are to summarize the literature on genetic counseling and genetic testing of gynecologic cancer patients, the cascade genetic testing of their families following the identification of a germline mutation associated with susceptibility to cancer, to highlight disparities between populations, and to present some potential remedies.

A practical guide for the safe implementation of early phase drug development and immunotherapy program in gynecologic oncology practice.

The success of targeted and immune therapies in other malignancies has led to an exponential increase in the number of active and pending clinical trials using these therapeutic approaches in patients with gynecologic cancers. These novel investigational agents are associated with unique and potentially life-threatening toxicities and many require special multidisciplinary logistical considerations. The objective of this review is to describe a practical approach for the safe implementation of targeted and immune therapies in academic gynecologic oncology practices based on our experience at M.D. Anderson Cancer Center.

Assessment of treatment factors and clinical outcomes in cervical cancer in older women compared to women under 65 years old.

OBJECTIVE: This study aims to understand the treatment patterns and clinical outcomes of older women with cervical cancer compared to younger women. METHODS: Women undergoing care for cervical cancer between 2000 and 2013 at two academic institutions were identified. The cohort of older patients was defined as >65 years old at diagnosis. Patient charts were retrospectively reviewed, and clinical variables were extracted. Fisher's exact tests, logistic regression, and Kaplan-Meier analyses were performed. RESULTS: From 2000 to 2013 1119 women with cervical cancer were identified. Of these, 191 (17.0%) were >65 years old at the time of diagnosis. Older women were more likely to present with higher stage disease (p < 0.001). Controlling for stage, older women were less likely to undergo surgery during their treatment course (38% versus 70%, p < 0.001) and more likely to undergo radiation (77% versus 52%, p < 0.001), but no more likely to receive chemotherapy (p = 0.34). If they did undergo surgery, older women were less likely to have a pelvic lymph node dissection performed (41% versus 61%, p = 0.04), though the rate of positive pelvic lymph nodes was not different (p = 0.80). Overall survival was decreased in the older cohort (p < 0.001). A multivariate model identified age > 65 (HR 1.76, 95%CI 1.30-2.40), stage (HR 2.77, 95%CI 2.40-3.21), and ever undergoing surgery (HR 0.60, 95%CI 0.44-0.82) as independently associated with overall survival. CONCLUSIONS: Women over age 65 with cervical cancer are less likely to undergo surgical management and were observed to have a decreased overall survival, even when controlling for use of surgery and stage of disease.

Trends in the use of neoadjuvant chemotherapy for advanced ovarian cancer in the United States.

OBJECTIVE: Neoadjuvant chemotherapy and interval debulking surgery for the treatment of advanced ovarian cancer has remained controversial, despite the publication of two randomized trials comparing this modality with primary cytoreductive surgery. This study describes temporal trends in the utilization of neoadjuvant chemotherapy and interval debulking surgery in clinical practice in the United States. METHODS: We completed a time trend analysis of the National Cancer Data Base. We identified women with stage IIIC and IV epithelial ovarian cancer diagnosed between 2004 and 2013. We categorized subjects as having undergone one of four treatment modalities: primary cytoreductive surgery followed by adjuvant chemotherapy, neoadjuvant chemotherapy followed by interval debulking surgery, surgery only, and chemotherapy only. Temporal trends in the frequency of treatment modalities were evaluated using Joinpoint regression, and χ2 tests. RESULTS: We identified 40,694 women meeting inclusion criteria, of whom 27,032 (66.4%) underwent primary cytoreductive surgery and adjuvant chemotherapy, 5429 (13.3%) received neoadjuvant chemotherapy and interval surgery, 5844 (15.4%) had surgery only, and 2389 (5.9%) received chemotherapy only. The proportion of women receiving neoadjuvant chemotherapy and surgery increased from 8.6% to 22.6% between 2004 and 2013 (p<0.001), and adoption of this treatment modality occurred primarily after 2007 (95%CI 2006-2009; p=0.001). During this period, the proportion of women who received primary cytoreductive surgery and chemotherapy declined from 68.1% to 60.8% (p<0.001), and the proportion who underwent surgery only declined from 17.8% to 9.9% (p<0.001). CONCLUSION: Between 2004 and 2013 the frequency of neoadjuvant chemotherapy and interval surgery increased significantly in the United States.

The Role of Endometrial Biopsy in the Preoperative Detection of Uterine Leiomyosarcoma.

STUDY OBJECTIVE: To assess the sensitivity of preoperative endometrial biopsy in detection of uterine leiomyosarcoma (ULMS). STUDY DESIGN: Retrospective analysis of a prospectively collected database (Canadian Task Force III). SETTING: Two academic tertiary referral centers. PATIENTS: All cases of ULMS treated at participating institutions between January 2005 and August 2012 were identified following IRB approval. INTERVENTIONS: Abstracted data included demographics, preoperative evaluation, presenting symptom, surgical management, pathology and clinical outcomes. Chi-square tests were used for statistical analysis. MEASUREMENTS AND MAIN RESULTS: 329 cases were identified, of which 152 cases had complete pathologic data available for review. Sixty-eight (45%) of 152 patients had endometrial sampling prior to surgery. Patients with postmenopausal bleeding were significantly more likely to be biopsied preoperatively (51.6% vs 9.5%, p = <.0001). Of those sampled, 43 (63%) underwent endometrial pipelle biopsies and 25 (37%) had dilation and curettage. Endometrial sampling was significantly more likely to detect a concern for malignancy in patients who presented with postmenopausal bleeding (72.7% vs 32.3%, p = 0.002), however it was less likely to detect malignancy in patients with abnormal premenopausal bleeding (31.8% vs 64.3%, p = .02), compared to other presenting symptoms. Overall, 51.5% of patients with ULMS on final pathology had preoperative endometrial biopsies in which leiomyosarcoma or atypical spindle cell proliferation were diagnosed, whereas 35.5% of the pre-operative biopsies identified ULMS specifically. CONCLUSIONS: The sensitivity of an endometrial biopsy to detect ULMS is low, illustrating the difficulty of diagnosing ULMS preoperatively. As expected, the probability that an endometrial biopsy will detect ULMS or a related worrisome pathological finding is higher for patients with post-menopausal bleeding. Thus, benign endometrial biopsy results, particularly in pre-menopausal patients, should be interpreted with caution if there is suspicion for leiomyosarcoma. However, a positive or suspicious result can play an important role in the subsequent management of patients with ULMS, even if the absolute numbers of affected patients are small.

Laparoscopic Hysterectomy for Uterine Fibroids: Is it Safe?

As more complex cases and larger uterine specimens are able to be managed with minimally invasive surgery, the limitations of tissue retrieval with these methods are of increasing concern. Risks of morcellator-related injury, tissue dissemination, or fragmentation must be weighed against increased morbidity of abdominal approach to hysterectomy. In an effort to mitigate the risks of tissue morcellation, containment system use must be considered when fragmenting a specimen, either with power morcellation or a manual technique via the vagina or minilaparotomy.

Same-Day Discharge After Laparoscopic Hysterectomy for Endometrial Cancer.

PURPOSE: The aim of this study was to investigate the relationship between same-day discharge (SDD) and postoperative complications within 30 days of laparoscopic hysterectomy for endometrial cancer and endometrial intraepithelial neoplasia (EIN). METHODS: This single-institution retrospective cohort included all patients who underwent conventional and robotic-assisted laparoscopic hysterectomy for endometrial cancer or EIN in a large teaching hospital between 2011 and 2013. Temporal trends in frequency of SDD and rates of postoperative complications were investigated to assess whether adoption of routine SDD was associated with increased postoperative complications. Associations between SDD and postoperative complications were also investigated in univariate and multivariate models. RESULTS: Overall, 696 patients underwent laparoscopic hysterectomy. Of these, 37.1 % had pelvic lymphadenectomy, 3.0 % had para-aortic lymphadenectomy, and 9.3 % underwent omentectomy. The rate of SDD increased from 3.9 to 69.6 % during the study period (p < 0.001), and the frequency of postoperative readmission, unscheduled surgery, infection, and composite complications within 30 days of hysterectomy did not differ during the study period. The composite complication rate did not differ significantly between patients who underwent surgery before and after the adoption of routine SDD (rate ratio 0.7, 95 % CI 0.4-1.2, p = 0.24). After controlling for demographic, intraoperative, and comorbid factors, patients who underwent SDD were not at increased risk for postoperative complications. CONCLUSIONS: Adoption of routine SDD after laparoscopic surgery for endometrial cancer and EIN did not result in increased complication rates within our institution. A larger prospective study is required to definitively establish the safety of this approach.

Clinical outcomes of women with recurrent or persistent uterine leiomyosarcoma.

OBJECTIVES: This study aimed to identify prognostic factors influencing the outcome of recurrent or persistent uterine leiomyosarcoma (ULMS). METHODS: All patients with recurrent or persistent ULMS who underwent treatment at the participating institutions between January 2000 and December 2010 were identified from the tumor registry. The Kaplan-Meier method was used to generate overall survival data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS: One hundred fifteen (68.8%) patients who had recurrent/persistent disease were identified, 40 (34.8%) had persistent disease, and 75 (65.2%) had a recurrence. Median follow-up time was 24.9 months. The 5-year postrelapse survival rate was 15% and was not significantly different between women with recurrent or persistent disease (16% vs 13%; P = 0.1). Variables identified affecting the 5-year postrelapse survival rate included low number of mitosis at the time of diagnosis (<25, 25% vs 5%; P = 0.002), time to relapse from original diagnosis (≤6 vs >6 months, 8% vs 22%; P = 0.003)), and surgical treatment (17% vs 12%; P = 0.01). Age, stage, chemotherapy at time of original diagnosis or at the time of relapse, site of recurrence, and single versus multiple sites of recurrence were not associated with survival. In a multivariate Cox regression model, only low number of mitosis (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8, P = 0.02) was identified as a predictor of overall survival. CONCLUSIONS: The prognosis of patients with recurrent/persistent ULMS is, in general, poor. Women who have low number of mitosis at the time of diagnosis seemed to have better postrelapse survival.

GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation.

Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation.