Anne Knisely

Racial and sociodemographic disparities in the use of targeted therapies in advanced ovarian cancer patients with Medicare

To describe sociodemographic and racial disparities in receipt of poly ADP-ribose polymerase inhibitors (PARPi) and bevacizumab among insured patients with ovarian cancer. This retrospective study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify patients with advanced stage, high grade serous ovarian cancer diagnosed between 2010 and 2019. The primary outcome of interest was receipt of PARPi or bevacizumab at any time after diagnosis. χ The cohort included 6242 patients; 276 (4.4%) received PARPi, 2142 (34.3%) received bevacizumab, and 389 (6.2%) received both. Receipt of either targeted treatment increased over the study period. On univariate analysis, patients who received either targeted therapy were younger (63% vs 48% aged 74 years) were also less likely to receive PARPi or bevacizumab compared with those aged 65-69 years (all p<0.001). Sociodemographic and racial disparities exist in receipt of PARPi and bevacizumab among patients with advanced ovarian cancer insured by Medicare. As targeted therapies become more commonly used, a widening disparity gap is likely.

Transforming ovarian cancer care by targeting minimal residual disease

Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences.

Phase 1/2 trial of avelumab combined with utomilumab (4‐1BB agonist), PF‐04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies

AbstractBackgroundImmune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.MethodsThe primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival.ResultsForty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed.ConclusionsThe findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Surgical and Blood-Based Minimal Residual Disease in Patients with Ovarian Cancer after First-line Therapy: Clinical Outcomes and Translational Opportunities

Abstract Purpose: Minimal residual disease (MRD) after first-line treatment of advanced-stage ovarian cancer remains a long-standing barrier to cure. We investigated the prognostic and translational value of MRD detection by second-look laparoscopy (SLL) and ctDNA at the completion of first-line therapy. Experimental Design: Patients with high-grade epithelial ovarian cancer who had a complete clinical response to first-line therapy and underwent SLL and plasma collection for ctDNA were included. Progression-free survival (PFS) and overall survival (OS) were estimated based on MRD and clinicopathologic status. Spatial transcriptomics (GeoMx and Visium) and proteomics (CODEX) profiling were performed on serial samples from select patients. Results: Forty of 95 (42.1%) patients had surgically detected MRD, which was associated with worse PFS (median PFS 7.4 vs. 23.8 months; P &amp;lt; 0.001) and OS (median OS 33.9 vs. not reached; P &amp;lt; 0.001). SLL positivity was an independent negative prognostic factor for OS (HR, 4.40; 95% confidence interval, 1.37–14.21; P = 0.013) in multivariable analysis. Among 44 patients who underwent SLL and had ctDNA testing, 34% (15/44) were ctDNA-positive, which was associated with worse PFS (6.4 vs. 28.1 months; P &amp;lt; 0.001) and OS (32.4 months vs. not reached; P = 0.008). We demonstrated the feasibility of spatial multiomics in studying MRD and their ability to provide hypothesis-generating observations, implicating the upregulation of the hypoxia signaling pathway, expression of multiple druggable targets (CDK6, GLS, MSLN, ERBB2), and immune exclusion in MRD lesions. Conclusions: Approximately half of patients in clinical remission after first-line therapy have assessable MRD, which can inform prognosis, therapeutic target discovery, and clinical trials.

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

AbstractBackgroundSingle‐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).MethodsPatients 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).ResultsSixty‐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.ConclusionsThere 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.

Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma

Background Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture. Methods Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results 17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33–70) and 50% were females. Median number of lines of prior therapy was 2 (range 1–8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers. Conclusions TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.

Autologous Tumor Infiltrating Lymphocytes MDA-TIL in Treating Patients With Recurrent or Refractory Ovarian Cancer, Colorectal Cancer, or Pancreatic Ductal Adenocarcinoma

This phase II trial studies how well autologous tumor infiltrating lymphocytes MDA-TIL works in treating patients with ovarian cancer, colorectal cancer, or pancreatic ductal adenocarcinoma that has come back (recurrent) or does not respond to treatment (refractory). Autologous tumor infiltrating lymphocytes MDA-TIL, made by collecting and growing specialized white blood cells (called T-cells) from a patient's tumor, may help to stimulate the immune system in different ways to stop tumor cells from growing.

Durvalumab and Tremelimumab in Treating Participants With Recurrent or Refractory Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

This phase II trial studies how well durvalumab and tremelimumab work in treating participants with ovarian, primary peritoneal, or fallopian tube cancer that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether give durvalumab and tremelimumab in combination or sequential administration works better in treating participants with ovarian, primary peritoneal, or fallopian tube cancer.