Linda Duska

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

BACKGROUND: A reliable model for predicting the outcome of primary cytoreductive surgery may be a useful tool in the clinical management of patients with advanced epithelial ovarian carcinoma. METHODS: Forty-one women with a preoperative computed tomographic (CT) scan of the abdomen and pelvis and a histologic diagnosis of Stage III or IV epithelial ovarian carcinoma following primary surgery performed by one of nine gynecologic oncologists were identified from tumor registry databases. All CT scans were analyzed retrospectively using a panel of 25 radiographic features without knowledge of the operative findings. Patient demographics, surgical findings and outcome, Gynecologic Oncology Group performance status, and pre-operative serum CA125 values were collected from patient medical records. Residual disease measuring < or = 1 cm in maximal diameter was considered an optimal surgical result. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each radiographic feature and clinical characteristic. Based on statistical probability of each factor predicting cytoreductive outcome, 13 radiographic features, in addition to performance status, were selected for inclusion in the final model. Each parameter was assigned a numeric value based on the strength of statistical association, and a total Predictive Index score was tabulated for each patient. Receiver operating characteristic (ROC) curve analysis was used to assess the ability of the model to predict surgical outcome. Statistical significance was evaluated using the Fisher exact test. RESULTS: Twenty of 41 patients (48.8%) underwent optimal cytoreduction to </= 1 cm residual disease. CT features of peritoneal thickening, peritoneal implants (>/= 2 cm), bowel mesentery involvement (>/= 2 cm), suprarenal paraaortic lymph nodes (>/= 1 cm), omental extension (spleen, stomach, or lesser sac), and pelvic sidewall involvement and/or hydroureter were most strongly associated with surgical outcome. Using the Predictive Index scores, a receiver operating characteristic curve was generated with an area under the curve = 0. 969 +/- 0.023. In the final model, a Predictive Index score >/= 4 had the highest overall accuracy at 92.7% and identified patients undergoing suboptimal surgery with a sensitivity of 100% (21/21). The specificity, or ability to identify patients undergoing optimal surgery, was 85.0% (17/20). The PPV of a Predictive Index score >/= 4 was 87.5% (21/24), and the NPV was 100%. The ability of this model to correctly predict surgical outcome was statistically significant (P < 0.001). CONCLUSIONS: In this model, a Predictive Index score >/= 4 demonstrated high sensitivity, specificity, PPV, and NPV, and was highly accurate in identifying patients with advanced epithelial ovarian carcinoma unlikely to undergo optimal primary cytoreductive surgery. The Predictive Index model may have clinical utility in guiding the management of patients with ovarian carcinoma.

BACKGROUND: Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab. METHODS: GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review. RESULTS: Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab. CONCLUSION: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT02715284.