Lucy Gilbert

Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer

To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer. Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined. Sixty-six patients, with a median of 3 prior lines of therapy (range, 1-8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1-2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months). The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations.

Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer

In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm). An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses. Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm.

Safety and Efficacy of 2D Brachytherapy vs. 3D Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer—A Single Institution Retrospective Study

Background: The treatment paradigm for locally advanced cervical cancer (LACC) has shifted from two-dimensional-brachytherapy (2D-BT) to three-dimensional-image-guided adaptive BT (3D-IGABT). In this retrospective study, we report our experience with the change from 2D-BT to 3D-IGABT. Methods: We reviewed 146 LACC patients (98 3D-IGABT and 48 2D-BT) who received chemoradiation between 2004 and 2019. The multivariable odds ratio (OR) for treatment-related toxicities and hazard ratios (HR) for locoregional control (LRC), distant control (DC), failure-free survival (FFS), cancer-specific survival (CSS) and overall survival (OS) are reported. Results: The median follow-up was 50.3 months. There was a significant decrease in overall late toxicities in the 3D-IGABT group compared to the 2D-BT group (OR 0.22[0.10–0.52]), late gastrointestinal (OR 0.31[0.10–0.93]), genitourinary (OR 0.31[0.09–1.01]) and vaginal toxicities (0% vs. 29.6%). Grade ≥ 3 toxicity was low in both groups (2D-BT: 8.2% acute, 13.3% late vs. 3D-IGABT: 6.3% acute, 4.4% late, NS). The five-year LRC, DC, FFS, CSS and OS for 3D-IGABT were 92.0%, 63.4%, 61.7%, 75.4% and 73.6%, compared to 87.3%, 71.8%, 63.7%, 76.3% and 70.8% for 2D-BT (NS). Conclusions: 3D-IGABT for the treatment of LACC is associated with a decrease in overall late gastrointestinal, genitourinary and vaginal toxicities. The disease control or survival outcomes were comparable to contemporary 3D-IGABT studies.

First-line lenvatinib plus pembrolizumab versus chemotherapy for advanced endometrial cancer: 1-Year follow-up after final analysis of the ENGOT-en9/LEAP-001 phase 3 trial

The phase 3 ENGOT-en9/LEAP-001 trial (NCT03884101) comparing first-line lenvatinib+pembrolizumab with carboplatin+paclitaxel did not meet pre-specified statistical criteria for overall survival or progression-free survival in participants with advanced/recurrent endometrial cancer. We report results after an additional year of follow-up (overall median 54.5 [range; 46.5-69.0] months). Eligible participants were adult females with stage III to IV or recurrent, histologically confirmed endometrial cancer. Measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and radiographically apparent disease per blinded independent central review was required. Participants were randomly allocated 1:1 to lenvatinib+pembrolizumab or chemotherapy (paclitaxel+carboplatin). The primary end points were overall survival and progression-free survival per RECIST version 1.1 by blinded independent central review. Secondary end points included objective response rate per RECIST version 1.1 by blinded independent central review and safety. The median overall survival (95% confidence interval [CI]) was 30.9 (range; 25.4-37.6) months with lenvatinib+pembrolizumab versus 29.4 (range; 26.2-34.8) months with chemotherapy in mismatch repair-proficient endometrial cancer (hazard ratio [HR] 0.99, 95% CI 0.82 to 1.21), 37.9 (range; 32.2-43.0) versus 32.3 (range; 27.2-35.7) months in all-comers (HR 0.91, 95% CI 0.77 to 1.09), and not reached in either treatment group in mismatch repair-deficient endometrial cancer (HR 0.60, 95% CI 0.39 to 0.93]). Corresponding results for progression-free survival were 9.6 (range; 8.2-11.9) versus 10.2 (range; 8.4-10.5) months (HR 1.01, 95% CI 0.83 to 1.22), 12.5 (range; 10.3-15.1) versus 10.2 (range; 8.4-10.4) months (HR 0.92, 95% CI 0.77 to 1.10]), and 31.8 (22.5 to not reached) versus 9.0 (range; 8.2-17.1) months (HR 0.62, 95% CI 0.41-0.93). Objective response rates were 50.6% versus 54.7%, 55.7% versus 55.5%, and 72.0% versus 58.0%, respectively. No new safety signals were identified. The results were consistent with those at the final analysis. The mismatch repair-proficient, all-comer, and mismatch repair-deficient populations continued to demonstrate antitumor activity for lenvatinib+pembrolizumab after an additional year of follow-up. These results should be interpreted with caution due to the exploratory nature of the analysis. ClinicalTrials.gov No. NCT03884101.

Quality-adjusted time without symptoms of disease progression or toxicity of treatment in patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel

In part 1 of the phase 3 RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer, dostarlimab plus carboplatin-paclitaxel significantly improved progression-free and overall survival vs placebo plus carboplatin-paclitaxel. Post hoc analyses examined the impact of adding dostarlimab to chemotherapy, compared with placebo plus chemotherapy, on quality-adjusted time without symptoms of disease progression or toxicity of treatment in this patient population. Patients were randomized 1:1 to receive dostarlimab/placebo plus chemotherapy every 3 weeks for 6 cycles, followed by dostarlimab/placebo monotherapy every 6 weeks for up to 3 years. Data from the first interim analysis (September 28, 2022) were used, and quality of life (QoL) was assessed with the EuroQoL 5-Dimensions 5-Level questionnaire. Quality-adjusted time without symptoms of disease progression or toxicity of treatment was calculated as the sum product of the restricted mean survival times spent in 3 mutually exclusive states: toxicity, time without symptoms of disease progression or treatment toxicity, and relapse, and utilized each state's corresponding QoL. In the dostarlimab and placebo arms, 241 and 246 patients were analyzed for safety, respectively. In the overall population, the mean (95% CI) duration of quality-adjusted time without symptoms of disease progression or toxicity of treatment was significantly longer in the dostarlimab arm (24.75 months [22.88 to 26.65 months]) than in the placebo arm (20.34 months [18.95 to 21.76 months]; the mean difference [95% CI] of 4.41 months [2.01 to 6.77 months], p < .001). Benefits in quality-adjusted time without symptoms of disease progression or toxicity of treatment after dostarlimab treatment were observed regardless of mismatch repair/microsatellite instability status or toxicity criteria used and were predominantly driven by the time without symptoms of disease. Dostarlimab plus carboplatin-paclitaxel treatment is associated with meaningful improvement in survival, avoidance of substantial toxicity, and maintenance of patient-reported QoL in patients with primary advanced or recurrent endometrial cancer.

First-Line Lenvatinib Plus Pembrolizumab Versus Chemotherapy for Advanced Endometrial Cancer: A Randomized, Open-Label, Phase III Trial

PURPOSE Lenvatinib plus pembrolizumab (len + pembro) significantly improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in previously treated advanced or recurrent endometrial cancer (aEC) in the phase III Study 309/KEYNOTE-775. We report results from the phase III, randomized, open-label European Network of Gynaecological Oncological Trial-en9/LEAP-001 study (ClinicalTrials.gov identifier: NCT03884101 ) that evaluated len + pembro versus chemotherapy in first-line aEC. METHODS Patients with stage III to IV or recurrent, radiographically apparent EC and no previous chemotherapy or disease progression ≥6 months after neo/adjuvant platinum-based chemotherapy were randomly assigned 1:1 to lenvatinib 20 mg once daily plus pembrolizumab 200 mg once every 3 weeks or paclitaxel 175 mg/m 2 plus carboplatin AUC 6 mg/mL/min once every 3 weeks. Primary end points were PFS and OS, evaluated in the mismatch repair-proficient (pMMR) and all-comers populations. Noninferiority was assessed for OS at final analysis (FA) for len + pembro versus chemotherapy (multiplicity-adjusted, one-sided nominal alpha, .0159; null hypothesis–tested hazard ratio [HR], 1.1). RESULTS Eight hundred forty-two patients were randomly assigned (len + pembro, n = 420 [pMMR population, n = 320]; chemotherapy, n = 422 [pMMR population, n = 322]). At FA (data cutoff, October 2, 2023), median PFS (95% CI) in the pMMR population was 9.6 (8.2 to 11.9) versus 10.2 (8.4 to 10.5) months with len + pembro versus chemotherapy (hazard ratio [HR], 0.99 [95% CI, 0.82 to 1.21]) and among all-comers was 12.5 (10.3 to 15.1) versus 10.2 (8.4 to 10.4) months (HR, 0.91 [95% CI, 0.76 to 1.09]; descriptive analyses). Median OS (95% CI) in the pMMR population was 30.9 (25.4 to 37.7) versus 29.4 (26.2 to 35.4) months with len + pembro versus chemotherapy (HR, 1.02 [95% CI, 0.83 to 1.26]; noninferiority P = .246, not statistically significant per multiplicity control strategy) and among all-comers was 37.7 (32.2 to 43.6) versus 32.1 (27.2 to 35.7) months (HR, 0.93 [95% CI, 0.77 to 1.12]). Grade ≥3 treatment-related adverse events occurred in 331/420 (79%) versus 274/411 (67%) treated patients. CONCLUSION First-line len + pembro did not meet prespecified statistical criteria for PFS or OS versus chemotherapy in pMMR aEC.