Abstract This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m 2 , however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m 2 . Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.
Objectives: Dostarlimab, an immune-checkpoint inhibitor, blocks the interaction between programmed cell death protein-1 (PD-1) and its ligands (PD-L1 and PD-L2). In the phase 3 RUBY trial (NCT03981796), dostarlimab+carboplatin-paclitaxel (CP) significantly improved PFS and OS vs placebo+CP in patients (pts) with primary advanced or recurrent endometrial cancer (pA/rEC). The first interim analysis (IA1) of RUBY Part 1 revealed no significant exposure–response (ER) relationship for PFS or for the 5 most common adverse events (AEs), except for rash (deemed not clinically relevant).1 Here, we report ER data from IA2 to assess the ER relationship between dostarlimab and OS, and between dostarlimab and dostarlimab-related AEs.Methods: Due to limited pharmacokinetic (PK) sample accrual after IA12, no further PK analyses were performed at IA2. Population PK model predictions from IA12 were used at IA2. OS, defined as time from randomization to date of death by any cause, was analyzed using Cox regression. Covariates included mismatch repair status (mismatch repair deficient/microsatellite instability-high vs mismatch repair proficient/microsatellite stable), disease status in EC, prior external pelvic radiotherapy, baseline ECOG performance status, geographic location, and histology. Logistic regression was used to describe the relationship between the occurrence of dostarlimab-related AEs and dostarlimab exposure. Safety analysis was based on the 5 most common AEs of any grade at any time, assessed by investigators as related to dostarlimab (fatigue, nausea, rash, diarrhea, and arthralgia). AE analysis was completed for 3 periods: cycles 1–6 (chemotherapy phase [dostarlimab/placebo+CP]), cycle 7 and greater (monotherapy phase [dostarlimab/placebo alone]), and all cycles.Results: In total, 232 pts treated with dostarlimab+CP with ≥2 quantified dostarlimab concentrations were included in the OS analysis. Cox regression of OS showed no significant ER relationship based on dostarlimab cycle 1 exposure. Geographic location, histology, and mismatch repair status were identified as significant covariates (P < 0.05) for OS; however, patient numbers were small in these exploratory analyses and should be interpreted with caution. Among the most common AEs, only rash and arthralgia exhibited significant (P < 0.05) ER relationships. The increase in predicted probabilities for rash and arthralgia for pts with high vs low exposure was limited, ranging from 5.6%–10.4% for rash and 4.3%–17.7% for arthralgia, depending on the exposure metric and time period assessed, making the relationship flat in nature.Conclusions: Consistent OS benefits were demonstrated across the exposure metrics evaluated and no clinically meaningful ER relationships between dostarlimab exposure and safety were observed. Therefore, dose adjustment based on any covariate is not warranted. These data support the recommended therapeutic dose of dostarlimab in combination with CP in pts with pA/rEC.Citations: [1] Kuchimanchi M, et al. ACoP 2023; Nov 5-8, 2023; National Harbor, MD. Poster PMX870.[2] Melhem M, et al. ACoP 2023; Nov 5-8, 2023; National Harbor, MD. Poster PMX864.
5581 Background: Advanced epithelial ovarian cancer (AEOC) is the fifth commonest cancer mortality among women in the United States. Despite 80% initial treatment response, most recur within two years and succumb from disease. Prolonging disease free interval with maintenance therapy is of interest. Options include Poly-(ADP) ribose polymerase inhibitors (PARPi’s) and Bevacizumab, an anti-angiogenesis agent; eligibility criteria are based on clinical trials. Here we examine national approach to front line maintenance therapy following treatment in AEOC with focus on PARPi use. Methods: Protocol for data collection was IRB approved and institutional IRB approved. A retrospective, observational cohort study using Flatiron Health electronic health record (EHR)-derived, de-identified database patients diagnosed with AEOC between March 2017-June 2020, following FDA approval of PARPi use in AEOC. Demographics were summarized using descriptive statistics by use of maintenance treatment, and associations were tested using ANOVA and Chi-squared tests. Trends in use and type of maintenance therapy were summarized by year. Time trends assessed by Cochran–Armitage tests. Results: 1196 patients met inclusion criteria: Age>18, Stage III-IV, 90-day gap rule, systemic therapy after diagnosis. Majority were >65, White, Stage III with ECOG 0 at diagnosis. Only 31.6% of patients received maintenance after frontline therapy. Single agent PARPi was most used (12.9%), and Olaparib was most used PARPi (57%). Use of maintenance therapy significantly differed by ECOG value at diagnosis (p=.005), region of practice (p=.003), use of surgery (p=<.001) and extent of debulking (p=.002). Maintenance therapy was used more often when ECOG low at diagnosis, optimal debulking achieved and with treatment in the Southern US. Maintenance therapy significantly increased by year (p=<0.001); highest in 2020 (46.9%). Type of maintenance therapy had a significantly different trend by year with PARPi becoming more common (p=<.001). Conclusions: Despite known high rates of response to maintenance PARPi and increased use over time, less than 50% of patients with AEOC receive this regimen. Reasons for low adoption of maintenance PARPi in this population with poor prognosis deserves further investigation. Olaparib, approved for single use in BRCA mutation carriers in the front-line maintenance setting was used more often than Niraparib, approved for all comers. [Table: see text]
<div>AbstractPurpose:<p>The relevance of the MET/hepatocyte growth factor pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease.</p>Patients and Methods:<p>PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib (60 mg once daily) in women with endometrial cancer with progression after chemotherapy. Coprimary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg, carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort.</p>Results:<p>A total of 102 patients were accrued. Among 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67%, and median PFS was 4.8 months. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56%, and median PFS was 4.0 months. In a separate cohort of 32 patients with uncommon histology endometrial cancer (including carcinosarcoma), response rate was 6% and 12-week PFS was 47%. Six patients were on treatment for >12 months, including two for >30 months. Common cabozantinib-related toxicities (>30% patients) included hypertension, fatigue, diarrhea, nausea, and hand–foot syndrome. Gastrointestinal fistula/perforation occurred in four of 70 (6%) patients with serous/endometrioid cancer and five of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic <i>CTNNB1</i> mutation [four partial responses (PRs) in 10 patients, median PFS 7.6 months] and concurrent <i>KRAS</i> and <i>PTEN/PIK3CA</i> mutations (three PRs in 12 patients, median PFS 5.9 months).</p>Conclusions:<p>Cabozantinib has activity in serous and endometrioid histology endometrial cancer. These results support further evaluation in genomically characterized patient cohorts.</p></div>
5524 Background: Recurrent/metastatic EC has a poor prognosis with no standard 2 nd line therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL & KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 & AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( > 30%) & 12-week progression-free-survival (PFS) ( > 55%). Activity was defined as > 7 partial responses (PRs) or > 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea & hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts & 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs & 24 instances of > 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs & 20 instances of > 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS > 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.
Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships.
Abstract Background: RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. Binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104. We previously reported results of the RGX-104 monotherapy dose escalation for which 26 patients with refractory solid tumors were treated in 5 dose cohorts. On-target AEs included hyperlipidemia and neutropenia. Flow-cytometry demonstrated MDSC depletion with associated T cell activation, which correlated with clinical benefit. A 40% disease control rate (DCR; SD+PR) was observed with a confirmed partial response (PR) by irRC (>79% reduction in index lesions) in a patient with platinum-refractory small cell lung cancer (SCLC). Methods: Here, we present the safety, biomarker and efficacy results of the docetaxel combination arm of the RGX-104 trial. Cohort 1- RGX-104 80 mg BID, and docetaxel at 35 mg/m2 days 1, 8, and 15 of a 28-day cycle; Cohort 2- RGX-104 80 mg BID, 5 days-on/2 days-off (5/2), and docetaxel at 28 mg/m2 on above schedule. Cohort 3- RGX-104 100 mg BID (5/2), and docetaxel as per cohort 2. Results: As of February 7, 2020, 11 patients with refractory solid tumors have been treated in 3 dose escalation cohorts with RGX-104 plus docetaxel. AEs were consistent with the individual toxicity profiles of docetaxel and RGX-104, with neutropenia being the most common AE and dose-limiting in cohort 1. The 5/2 dosing regimen in cohorts 2 and 3 resulted in significantly fewer episodes of neutropenia and no DLTs, while maintaining pharmacodynamic effects including >50% sustained MDSC depletion. A 66% DCR was observed in 9 evaluable patients including 2 patients in cohort 2 with PRs, a CPI-refractory SCCHN patient and a CPI-refractory melanoma patient, who remains on treatment at 36 weeks. A patient with melanoma in Cohort 3 had an initial assessment of SD and continues on study at 14 weeks. Clinical responses were associated with increases in T cell activation markers exceeding that generally observed with RGX-104 alone (up to a 5-fold increase in total CD8 T cells, a 7-fold increase in LAG-3+ CD8 T cells, and a 75-fold induction of serum IFNγ). Conclusion: The safety profile and marked pharmacodynamic and clinical activity of the RGX-104/docetaxel combination in CPI-refractory patients supports further development of this regimen. Consequently, the RGX-104/docetaxel regimen will be evaluated in a Phase 1b/2 expansion cohort in patients with relapsed/refractory ES-SCLC/high grade-neuroendocrine tumors. Citation Format: Emerson Lim, Erika P. Hamilton, Rebecca Redman, Michael A. Postow, Russell J. Schilder, Monica M. Mita, Alain C. Mita, Bartosz Chmielowski, James Strauss, Angela Jain, Shubham Pant, Olivier Rixe, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Kevin B. Kim, Eric K. Rowinsky, Michael Szarek, Foster Gonsalves, Isabel Kurth, Celia Andreu, Robert W. Busby, David Darst, Masoud Tavazoie, Syed Raza, Narayan Lebaka16, Robert Wasserman, Gerald Falchook. RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR): Initial results from the phase 1b RGX-104 plus docetaxel combination dose escalation cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT146.
Lymph node involvement has a significant impact on prognosis that may direct adjuvant therapy. The role of routine lymph node staging (LNS) is controversial given conflicting results in multiple studies. Our aims are to describe treatment patterns of LNS, identify factors impacting LNS, and quantify the contemporary trends.The National Cancer Data Base was queried for patients undergoing hysterectomy for endometrioid and serous uterine carcinomas from 2003 to 2012. For endometrioid tumors, LNS was considered indicated if at least 1 of 4 criteria was met. Multivariate logistic regression and Cox proportional hazards model were used.A total of 161,683 patients were identified who received hysterectomy for 155,893 (96.4%) endometrioid and 5790 (3.6%) serous carcinomas. Receipt of LNS was significantly associated with greater than 50% myometrial invasion (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.55-1.73), grades 3 to 4 (OR, 3.03; 95% CI, 2.83-3.25), and tumor size greater than 2 cm (OR, 1.17; 95% CI, 1.28-1.26). Of the 97,152 patients with endometrioid carcinoma who met criteria for comprehensive staging, 73,268 (75.4%) underwent LNS. Patients with endometrioid carcinoma meeting criteria for LNS were less likely to receive LNS if they were of African American race (OR, 0.92; 95% CI, 0.86-0.98), had Medicaid insurance status (OR, 0.75; 95% CI, 0.69-0.81), had Medicare insurance (OR, 0.82; 95% CI, 0.79-0.86), or received care at a community program (OR, 0.39; 95% CI, 0.33-0.46).Nationally, most patients with greater than 50% myometrial invasion, grades 3 to 4, and/or tumor size greater than 2 cm receive LNS, but this was significantly impacted by insurance status, demographic characteristics, and facility location/type.
