Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer.

PURPOSE: Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. METHODS: Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORR RESULTS: At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORR CONCLUSION: Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile

Niraparib maintenance treatment improves time without symptoms or toxicity (TWiST) versus routine surveillance in recurrent ovarian cancer: a TWiST analysis of the ENGOT-OV16/NOVA trial

Purpose: this study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. Patients and methods: mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation-gBRCAmut and non-gBRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. Results: in the gBRCAmut and non-gBRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gBRCAmut and non-gBRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. Conclusion: patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control

Incorporating the patient voice in sarcoma research: How can we assess health-related quality of life in this heterogeneous group of patients? a study protocol

Sarcomas comprise 1% of adult tumors and are very heterogeneous. Long-lasting and cumulative treatment side-effects detract from the (progression-free) survival benefit of treatment. Therefore, it is important to assess treatment effectiveness in terms of patient-reported outcomes (PROs), including health-related quality of life (HRQoL) as well. However, questionnaires capturing the unique issues of sarcoma patients are currently lacking. Given the heterogeneity of the disease, the development of such an instrument may be challenging. The study aims to (1) develop an exhaustive list of all HRQoL issues relevant to sarcoma patients and determine content validity; (2) determine a strategy for HRQoL measurement in sarcoma patients. We will conduct an international, multicenter, mixed-methods study (registered at clinicaltrials.gov: NCT04071704) among bone or soft tissue sarcoma patients ≥18 years, using EORTC Quality of Life Group questionnaire development guidelines. First, an exhaustive list of HRQoL issues will be generated, derived from literature and patient (n = 154) and healthcare professional (HCP) interviews (n = 30). Subsequently, another group of sarcoma patients (n = 475) and HCPs (n = 30) will be asked to rate and prioritize the issues. Responses will be analyzed by priority, prevalence and range of responses for each item. The outcome will be a framework for tailored HRQoL measurement in sarcoma patients, taking into account sociodemographic and clinical variables

UPDATED SAFETY OF LENVATINIB plus PEMBROLIZUMAB VS TREATMENT OF PHYSICIAN'S CHOICE IN PATIENTS WITH ADVANCED ENDOMETRIAL CANCER: STUDY 309/KEYNOTE-775

[No Abstract Available

Randomized phase II study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer

Abstract Background Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients. Methods Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m2, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety. Results A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698–1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71–1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6–9.2) and 3.7 months (95% CI 1.9–9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38–1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin. Conclusions The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer. Trial registration ClinicalTrials.gov identifier: NCT00913835; registered June 2, 2009

Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, recurrent, or metastatic endometrial cancer (EC) were randomly assigned to receive lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks (n = 411) or chemotherapy of the treating physician's choice (doxorubicin 60 mg/m(2) intravenously once every 3 weeks or paclitaxel 80 mg/m(2) intravenously once weekly [3 weeks on; 1 week off] [n = 416]). Efficacy was reported for patients with mismatch repair proficient (pMMR) tumors and all-comers, and by subgroups (histology, prior therapy, MMR status). Updated safety was also reported.Lenvatinib plus pembrolizumab showed benefits in OS (pMMR HR, 0.70; 95% CI, 0.58 to 0.83; all-comer HR, 0.65; 95% CI, 0.55 to 0.77), PFS (pMMR HR, 0.60; 95% CI, 0.50 to 0.72; all-comer HR, 0.56; 95% CI, 0.48 to 0.66), and ORR (pMMR patients, 32.4% v 15.1%; all-comers, 33.8% v 14.7%) versus chemotherapy. OS, PFS, and ORR favored lenvatinib plus pembrolizumab in all subgroups of interest. No new safety signals were observed. Lenvatinib plus pembrolizumab continued to show improved efficacy versus chemotherapy and manageable safety in patients with previously treated advanced EC

Lenvatinib (LEN) plus pembrolizumab (PEMBRO) for early-line treatment of advanced/recurrent endometrial cancer (EC).

Background: As part of an ongoing phase Ib/II study (NCT02501096) in patients (pts) with selected solid tumors, LEN (20 mg PO QD) + PEMBRO (200 mg IV Q3W) displayed substantial and durable antitumor activity in advanced EC. In previously treated EC that was not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR; n=94 pts), the objective response rate (ORR) by independent imaging review (IIR) per RECIST 1.1 was 38.3% (95% CI 28.5–48.9). In this post hoc analysis, we assessed 2 subgroups of pts with previously treated, advanced, non MSI-H or dMMR EC who received LEN + PEMBRO in an early-treatment setting. Methods: Pts were examined in 2 subgroups: (1) Pts with only 1 prior line of cytotoxic therapy regardless of surgical stage or setting (adjuvant treatment for local-regional disease or treatment for metastatic disease); and (2) pts from subgroup 1 with local-regional disease at diagnosis who received only adjuvant cytotoxic therapy. There were no restrictions on prior hormonal or chemoradiation therapies in either subgroup. Tumor responses were assessed by IIR per RECIST 1.1. Results: Subgroup 1 included 63 pts and subgroup 2 had 21 pts. ORR (95% CI) was 41.3% (29.0–54.4) for subgroup 1 and 57.1% (34.0–78.2) for subgroup 2. Additional efficacy outcomes are summarized in the table. In subgroup 1, treatment-related adverse events (TRAEs) occurred in 62 (98%) pts (42 [67%] ≥ grade 3). TRAEs led to study-drug interruption of one or both drugs in 43 (68%) pts and dose reductions of LEN in 42 (67%) pts; 12 (19%) pts discontinued one or both drugs due to a TRAE. Serious TRAEs occurred in 18 (29%) pts and 2 (3%) pts died from a TRAE. The safety profile for subgroup 2 was generally similar to the profile for subgroup 1. Conclusions: The efficacy of LEN + PEMBRO for early-line treatment of advanced non MSI-H or dMMR EC appears promising. No new safety signals have emerged. A phase III study of LEN + PEMBRO vs paclitaxel + carboplatin for first-line treatment in advanced or recurrent EC is underway. Clinical trial information: NCT02501096

Randomized controlled phase III trial of weekly paclitaxel ± ofranergene obadenovec (VB-111) for platinum-resistant ovarian cancer (OVAL Study/GOG 3018)

5505 Background: Ofranergene obadenovec (ofra-vec, VB-111) is a nonreplicating adenoviral vector with a murine pro-endothelin 1 (PPE-1-3X) promoter and pro-apoptotic Fas-tumor necrosis factor receptor 1 (TNFR1) chimeric transgene thought to have a dual mechanism of action: vascular disruption and immune activation. Methods: This is a randomized, placebo-controlled, double-blind, multi-center randomized phase III trial (ClinicalTrials.gov identifier: NCT03398655) of ofranergene obadenovec combined with paclitaxel vs paclitaxel with placebo for the treatment of patients with recurrent platinum resistant ovarian cancer (PROC). Patients were randomly assigned 1:1 to receive IV VB-111 1x10 13 viral particles (VPs) every 8 weeks with weekly IV paclitaxel 80 mg/m2 or placebo with paclitaxel until disease progression. The dual primary endpoints were overall survival (OS) and progression free survival (PFS) as assessed by Blinded Independent Central Review (BICR). Results: Between December 2017 and March 2022, 409 patients were randomized at 86 clinical sites in US, Israel, Spain, Poland and Japan. The median PFS was 5.29 months in the VB-111 arm and 5.36 months in the control arm; hazard ratio (HR) 1.03 (CI: 0.83-1.29, p = 0.7823), and median OS with was 13.37 months vs. 13.14 months HR 0.97 (CI: 0.75–1.27 p = 0.8440). Objective response rates (ORR) were similar in both arms: RECIST 1.1 ORR was 28.9% with VB-111 vs. 29.6% with control (CA-125 ORR 41.1% vs 49.4%). In both treatment arms response to CA-125 was a substantial prognostic factor for both PFS and OS. In the VB-111 arm, the HR in CA-125 responders compared to non-responders was for PFS HR 0.2428 (CI: 0.1642-0.3588), and for OS HR 0.3343 (CI: 0.2134-0.5238). Safety profile was consistent with the known safety profile of ofra-vec and was characterized by common transient flu like symptoms such as fever and chills. Conclusions: The addition of ofranergene obadenovec to paclitaxel did not improve PFS or OS. Clinical trial information: NCT03398655