Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti-PD-L1, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679/ECHO-302).

BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .

Patterns of initial ovarian cancer recurrence on niraparib maintenance monotherapy in patients with no baseline evidence of disease after first-line chemotherapy: An ad hoc subgroup analysis of PRIMA/ENGOT-OV26/GOG-3012.

OBJECTIVES: Patterns of disease recurrence on poly(ADP-ribose) polymerase inhibitor maintenance therapy are unclear and may affect subsequent treatment. This ad hoc subgroup analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study evaluated patterns of initial recurrence in patients with advanced ovarian cancer (AOC). METHODS: PRIMA included participants at high risk for disease progression. This ad hoc analysis only evaluated participants randomized to niraparib maintenance without evidence of disease at baseline. The number and site(s) of initial recurrent lesions at investigator-assessed progressive disease (PD) were evaluated. RESULTS: Of the 314 niraparib-treated patients analyzed, 190 developed ≥1 new lesion (median number of new lesions, 1.0; interquartile range, 1-2). In total, 93.2% (177/190) of patients developed 1-3 lesions at first disease progression. The most common sites of recurrence were the peritoneum (30.0% [57/190]), lymph nodes (26.3% [50/190]), and liver (20.5% [39/190]). Similar results were observed when patients with PD were stratified by biomarker status, disease stage at diagnosis, and type of debulking surgery. Patients with homologous recombination-proficient tumors, stage III disease, or a history of primary debulking developed a median of 2.0 new lesions at first progression; patients with homologous recombination-deficient tumors, stage IV disease, or a history of interval debulking developed a median of 1.0 new lesion. CONCLUSIONS: Many patients with AOC without lesions at first-line maintenance treatment initiation develop oligometastatic disease at first recurrence. Prospective evaluation is required to determine whether these patients have improved outcomes when local therapies are combined with continuous, systemic, targeted maintenance therapy.

Real world data of niraparib in platinum sensitive relapsed ovarian cancer: A multicenter experience of the MITO group.

OBJECTIVE: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC). METHODS: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively. RESULTS: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively. CONCLUSION: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.

Efficacy and safety of niraparib in patients aged 65 years and older with advanced ovarian cancer: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD). RESULTS: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups. CONCLUSION: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age.

Health-related quality of life in patients with newly diagnosed advanced ovarian cancer treated with niraparib vs placebo: Results from the phase 3 randomized PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.

The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. METHODS: A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. RESULT: The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). CONCLUSION: Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.

An Emulated Target Trial Case Study of Real-World Overall Survival With Second-Line Maintenance Niraparib Versus Active Surveillance in Patients With Recurrent Ovarian Cancer.

PURPOSE: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. METHODS: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. RESULTS: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). CONCLUSIONS: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.

Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients.

OBJECTIVES: Despite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction. METHODS: Patients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups. RESULTS: Of 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1-3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction. CONCLUSIONS: Niraparib dose reduction occurs in almost half of patients within cycles 1-3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

QbD Enabled Development and Evaluation of Pazopanib Loaded Nanoliposomes for PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800 mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7 nm and 182.0 nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.

Pazopanib with 5-FU and oxaliplatin as first line therapy in advanced gastric cancer: A randomized phase-II study-The PaFLO trial. A study of the Arbeitsgemeinschaft Internistische Onkologie AIO-STO-0510.

VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P = .882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.

Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study.

BACKGROUND: Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer. METHODS: We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing. FINDINGS: Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1]). INTERPRETATION: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection. FUNDING: Eli Lilly and Company.

The impact of a 1-hour time interval between pazopanib and subsequent intake of gastric acid suppressants on pazopanib exposure.

Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (Cmin ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy.

Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma: Final results of cohorts A, G, H and I of IVY Phase I study.

Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

First-line pazopanib in intermediate- and poor-risk patients with metastatic renal cell carcinoma: Final results of the FLIPPER trial.

Temsirolimus has long been the only approved first-line standard of care (SOC) with overall survival (OS) benefit in poor-risk patients with advanced or metastatic renal cell cancer (mRCC). However, tyrosine kinase inhibitors are also commonly used in clinical practice. Pazopanib is an SOC for first-line mRCC treatment, but for poor-risk patients data are scarce. The FLIPPER (First-Line Pazopanib in Poor-Risk Patients with Metastatic Renal Cell Carcinoma) study aimed to assess efficacy and safety of first-line pazopanib in poor-risk mRCC patients. FLIPPER was a single-arm, multicenter, Phase IV trial. Key inclusion criteria were treatment-naive clear cell, inoperable advanced or mRCC, poor-risk according to MSKCC with slight modification, Karnofsky performance status (KPS) ≥60% and adequate organ function. Oral pazopanib 800 mg was given daily. Primary endpoint was the 6-month progression-free survival rate (PFS6). Secondary endpoints included PFS, OS, overall response rate (ORR), duration of response (DOR) and safety. For analysis, descriptive statistics were used. Between 2012 and 2016, 60 patients had been included. Forty-three patients qualified for safety analyses, 34 for efficacy. Median age was 66 years, 64.7% of patients were poor-risk, 82.4% had a KPS ≤70%. PFS6 was 35.3% (95% CI, 19.7-53.5). Median PFS and OS were 4.5 months (95% CI, 3.6-7.8) and 9.3 months (95% CI, 6.6-22.2), respectively. ORR was 32.4% (95% CI, 17.4-50.5), median DOR 9.7 months (95% CI, 1.8-12.4). The most common treatment-related grade 3/4 adverse event reported in 4.7% of patients was hypertension. No treatment-related death occurred. Since pazopanib is active and well tolerated in poor-risk patients with clear cell mRCC, our results support its use as first-line treatment in this setting.

A randomized, open-label, phase 2, multicenter trial of gemcitabine with pazopanib or gemcitabine with docetaxel in patients with advanced soft-tissue sarcoma.

BACKGROUND: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. METHODS: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). RESULTS: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). CONCLUSIONS: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.

SARC025 arms 1 and 2: A phase 1 study of the poly(ADP-ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma.

BACKGROUND: In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES. METHODS: Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2-6 [D2-6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re-escalation in cohort C. In arm 2, patients were assigned to NIR (days 1-7 [D1-7]) and escalating doses of IRN (D2-6). RESULTS: From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose-limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1-7 plus TMZ at 30 mg/m2 every day on D2-6 (arm 1) or NIR at 100 mg every day on D1-7 plus IRN at 20 mg/m2 every day on D2-6 (arm 2). One confirmed partial response was observed in arm 2; the median progression-free survival was 9.0 weeks (95% CI, 7.0-10.1 weeks) and 16.3 weeks (95% CI, 5.1-69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP-ribose) activity was 89% (range, 83%-98%). CONCLUSIONS: The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple-combination study of NIR, IRN, and TMZ has commenced.