Viktor Grünwald

Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial

BACKGROUND Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124. FINDINGS All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity. INTERPRETATION Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.

Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors.

A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor–tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.

Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial

BACKGROUND An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. METHODS In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. FINDINGS 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). INTERPRETATION Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. FUNDING Novartis Pharmaceuticals Corporation.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

BACKGROUND Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. METHODS In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. FINDINGS Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). INTERPRETATION The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease.

Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes

BACKGROUND Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. METHODS In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m(2) over 2-5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192. FINDINGS Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3-4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]). INTERPRETATION Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma. FUNDING Eisai Limited, Hatfield, UK.

Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

Phase II trial with S-1 in chemotherapy-naı̈ve patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG)

S-1 is a new oral fluorinated pyrimidine derivate, in which the oral 5-fluorouracil (5-FU) prodrug, tegafur, was combined with two 5-FU-modulating substances, 5-chloro-2,4-dihydroxypyridine (gimeracil), and potassium oxonate (oteracil), at a molar ratio of 1:0.4:1. The final mechanism of action is exerted by 5-FU. The present study is the first European phase II trial of S-1 in gastric cancer. The primary study objectives were the safety, toxicity and activity of S-1 in non-pretreated patients with gastric cancer. The secondary objective was the duration of response. Patients had to have histologically- or cytologically-verified metastatic or locally advanced, unresectable gastric cancer; S-1 was administered orally twice daily at 40, then 35 mg/m(2) for 28 days every 5 weeks. The starting dose of 40 mg/m(2) was found to be intolerable due to significant non-haematological toxicity, and this dose was rapidly reduced to 35 mg/m(2) twice daily. Of the 7 patients enrolled at the 40 mg/m(2) level, only 3 were evaluable. At 35 mg/m(2), a response rate of 26.1% (95% Confidence Interval (CI) 12.0-45.1%) in 23 enrolled patients, and 31.6% (C.I. 14.7-53.0%) in 19 evaluable patients according to an independent radiology review, was found. The median duration of response at 35 mg/m(2) (6 patients) was 223 days (range, 108-828 days), and of stable disease was 111 days (range 68-411 days). S-1 can be administered with an acceptable safety and toxicity in European patients at a dose of 35 mg/m(2) days 1 - 28 every 5 weeks and is associated with a moderate response rate similar to the results achieved with other fluoropyrimidines.

Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study

INTRODUCTION In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs. PATIENTS AND METHODS Median PFS was estimated using the Kaplan-Meier method, and Cox proportional hazards model was used to analyse differences in PFS. RESULTS All patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24-0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19-0.54; P<.001). The everolimus safety profile was similar for both groups. CONCLUSIONS Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.

Can Tyrosine Kinase Inhibitors be Discontinued in Patients with Metastatic Renal Cell Carcinoma and a Complete Response to Treatment? A Multicentre, Retrospective Analysis

BACKGROUND Discontinuation of treatment with tyrosine kinase inhibitors (TKIs) and readministration in case of recurrence could improve quality of life (QoL) and reduce treatment costs for patients with metastatic renal cell carcinoma (mRCC) in which a complete remission (CR) is achieved by medical treatment alone or with additional resection of residual metastases. OBJECTIVE To evaluate whether TKIs can be discontinued in these selected patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with TKIs (n=266) in five institutions. Patients with a CR under TKI treatment alone or with additional metastasectomy of residual disease following a partial response (PR), in which TKIs were discontinued, were included in the analysis. Outcome criteria analysed were time to recurrence of previous metastases, occurrence of new metastases, symptomatic progression, improvement of adverse events, and response to reexposure to TKIs. INTERVENTIONS Sunitinib 50mg/day for 4 wk on and 2 wk off, sorafenib 800mg/day. MEASUREMENTS Response according to Response Evaluation Criteria in Solid Tumours (RECIST). RESULTS AND LIMITATIONS We identified 12 cases: 5 CRs with sunitinib, 1 CR with sorafenib, and 6 surgical CRs with sunitinib followed by residual metastasectomy. Side-effects subsided in all patients off treatment. At a median follow-up of 8.5 mo (range: 4-25) from TKI discontinuation, 7 of 12 patients remained without recurrence and 5 had recurrent disease, with new metastases in 3 cases. Median time to progression was 6 mo (range: 3-8). Readministration of TKI was effective in all cases. The study is limited by small numbers and retrospective design. CONCLUSIONS Discontinuation of TKI in patients with mRCC and CR carries the risk of progression with new metastases and potential complications. Further investigation in a larger cohort of patients is warranted before such an approach can be regarded as safe.

Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial.

BACKGROUND In the phase 3 CheckMate 025 study, previously treated patients with advanced renal cell carcinoma who were randomly assigned to nivolumab had an overall survival benefit compared with those assigned to everolimus. We aimed to compare health-related quality of life (HRQoL) between treatment groups in this trial. METHODS CheckMate 025 was an open-label study done at 146 oncology centres in 24 countries. Patients were randomly assigned to treatment between Oct 22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or everolimus once per day. The study was stopped early at the planned interim analysis in July, 2015, because the study met its primary endpoint. A protocol amendment permitted patients in the everolimus group to cross over to nivolumab treatment. All patients not on active study therapy are being followed up for survival. At the interim analysis, HRQoL was assessed with the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaires. Prespecified endpoints were to assess, in each treatment group, disease-related symptom progression rate based on the FKSI-DRS and changes in reported global health outcomes based on the EQ-5D. Other endpoints were post hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the number of patients with non-missing data at baseline and at least one post-baseline visit. We defined FKSI-DRS completion as completion of five or more of the nine items in the questionnaire; otherwise data were treated as missing. FKSI-DRS symptom index score was prorated for missing items. We made no adjustments for missing EQ-5D data. We used descriptive statistics and multivariate analyses, including mixed-effects model repeated-measures, for between group comparisons. Analyses were powered according to the original study protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent randomisation and had a baseline assessment and at least one post-baseline assessment. CheckMate 025 is registered with ClinicalTrials.gov, number NCT01668784. FINDINGS HRQoL data were collected at baseline for 362 (88%) of 410 patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus group. The mean difference in FKSI-DRS scores between the nivolumab and everolimus groups was 1·6 (95% CI 1·4-1·9; p<0·0001) with descriptive statistics and 1·7 (1·2-2·1; p<0·0001) with mixed-effects model repeated-measures analysis. In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an increase of at least 2 points from baseline) HRQoL improvement with nivolumab (200 [55%] of 361 patients) versus everolimus (126 [37%] of 343 patients; p<0·0001). Median time to HRQoL improvement was shorter in patients given nivolumab (4·7 months, 95% CI 3·7-7·5) than in patients given everolimus (median not reached, NE-NE). INTERPRETATION Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma. FUNDING Bristol-Myers Squibb.