Summary Background The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no ...continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. Methods In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov , number NCT00973609. Findings Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5–25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1–8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3–7·4) for the bevacizumab alone group, and 6·4 months (4·8–7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio HR 1·08 95% CI 0·85–1·37; p=0·53; upper limit of the one-sided 98·8% CI 1·42), whereas no treatment was not (HR 1·26 0·99–1·60; p=0·056; upper limit of the one-sided 98·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 19% patients in the fluoropyrimidine plus bevacizumab group, 67 43% in the bevacizumab monotherapy group, and 73 46% in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 13% of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 14% of 156 patients in the bevacizumab alone group, and 12 8% of 158 patients in the no treatment group). Interpretation Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies. Funding RochePharma AG and AIO Studien gGmbH.
Summary Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic ...colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov , number NCT00433927. Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months 95% CI 24·5–39·4 vs 25·0 months 23·0–28·1; hazard ratio 0·70 0·54–0·90; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% 95% CI 64·3–78·8 vs 97 of 173, 56·1% 48·3–63·6; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% 60·3–75·4 vs 85 of 173, 49·1% 41·5–56·8; p=0·0005), and median depth of response (–48·9% –54·3 to −42·0 vs −32·3% –38·2 to −29·2; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Funding Merck KGaA and Pfizer.
The major prognostic relevance of primary tumour location (LPT) in advanced colorectal cancer was shown in large retrospective studies, but quantitative estimates are highly heterogeneous, and there ...is still limited information about its impact within the framework of biomarker-guided treatment strategies. Therefore, we analysed LPT in relation to other clinical and molecular parameters, based on mature survival data from the recent randomised AIO KRK0207 trial.
Patients uniformly received first-line induction treatment with a combination of bevacizumab, oxaliplatin and fluoropyrimidine. LPT was retrospectively determined using surgical reports, pathology reports and endoscopy reports. The prognostic analyses were performed using Kaplan–Meier estimations and log-rank tests, while hazard ratios (HRs) and multivariable results were derived from Cox models.
Among 754 patients with unequivocal information on LPT, patients with left-sided tumours showed a median overall survival of 24.8 months compared with the right-sided cohort with 18.4 months (HR: 1.54, 95% confidence interval: 1.30–1.81, P < 0.0001). In a multivariable model, LPT proved to be the strongest prognosticator (HR 1.60), with performance status, number of metastatic sites, baseline carcinoembryonic antigen (CEA) and platelets independently retaining prognostic significance. In the subgroup of patients with known RAS/BRAF status (n = 567, 75%), a BRAF mutation showed the greatest unfavourable impact (HR 3.16). Although BRAF is strongly correlated to LPT, the latter remained a significant prognosticator in the BRAF wild-type subgroup. In contrast, no major impact of LPT was seen on tumours carrying RAS mutations.
Within the framework of a uniform treatment strategy according to the current standards, LPT proved to have an important, although not solely dominating, relevance for survival prognosis. Its impact seems to be low in tumours with a RAS mutation.
ClinicalTrials.govNCT00973609.
•Primary tumour location was a major prognostic factor in patients receiving triple combinations including bevacizumab.•A right-sided tumour location retained its unfavourable prognostic impact on survival in multivariable analysis.•Performance status, number of metastatic sites, baseline CEA and platelets were additional factors of independent impact.•When incorporating molecular data, right-sided tumours were also associated with shorter survival in the BRAF-mutant subgroup.•In contrast, no prognostic impact of the location of the primary tumour could be shown in case of RAS mutations.
We explored the association of early tumor shrinkage (ETS) and non‐ETS with efficacy of first‐line and consecutive second‐line treatment in patients with KRAS wild‐type metastatic colorectal cancer ...treated in FIRE‐3. Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions, evaluated after 6 weeks of treatment. Shrinkage was classified as ETS (shrinkage by ≥ 20%), mETS (shrinkage by 0 to <20%), mPD (minor progression >0 to <20%) and PD (progression ≥20%). Overall survival (OS) was 33.2 (95% CI 28.0–38.4) months in ETS patients, while non‐ETS was associated with less favorable outcome (mETS 24.0 (95% CI 21.2–26.9) months, mPD 19.0 (95% CI 13.0–25.0) months, PD 12.8 (95% CI 11.1–14.5) months). Differences in PFS of first‐line therapy were less pronounced. ETS subgroups defined in first‐line therapy also correlated with efficacy of second‐line therapy. Progression‐free survival in second‐line (PFS2nd) was 6.5 months (5.8–7.2) for ETS, and was 5.6 (95% CI 4.7–6.5) months for mETS, 4.9 (95% CI 3.7–6.1) months for mPD and 3.3 (95% CI 2.3–4.3) months for PD. PFS of first‐line and PFS2nd showed a linear correlation (Bravais–Pearson coefficient: 0.16, p = 0.006). While ETS is associated with the most favorable outcome, non‐ETS represents a heterogeneous subgroup with distinct characteristics of less favorable initial tumor response to treatment. This is the first analysis to demonstrate that early tumor response observed during first‐line FOLFIRI‐based therapy may also relate to efficacy of second‐line treatment. Early response parameters may serve as stratification factors in trials recruiting pretreated patients.
What's new?
Early tumor shrinkage (ETS) is linked to favorable survival in metastatic colorectal cancer (mCRC). However, ETS occurs in only some patients, for reasons that remain unknown while non‐ETS patients represent a heterogeneous subgroup. Here, ETS and non‐ETS subgroups were examined in KRAS wild‐type mCRC patients enrolled in FIRE‐3, a trial comparing first‐line FOLFIRI (5‐fluorouracil, leucovorin, and irinotecan) plus cetuximab with FOLFIRI plus bevacizumab. Efficacy of first‐line FOLFIRI‐based therapy differed in ETS and non‐ETS subgroups, with the latter generally experiencing less‐favorable initial tumor responses. Patients who benefited from first‐line therapy tended to also benefit from second‐line therapy, supporting a role for efficacy parameters in mCRC patient stratification.
Abstract 4606
The treatment of patients with Chronic Lymphocytic Leukemia (CLL) has changed significantly over the last years. To select an appropriate treatment, multiple factors have to be ...considered. In particular, the stage of disease, patient's age, comorbidities and personal preferences, respectively, influence decision making. The clinical tumor registry on lymphoid neoplasms (TLN Registry) conducted by the iOMEDICO AG in collaboration with the Arbeitskreis Klinische Studien (AKS) and the Kompetenznetz Maligne Lymphome (KML) was established to collect data on the daily practice treatment of 3000 non-selected patients with lymphoid neoplasms. Here, we present data regarding treatment and sequences of regimes in patients (pts) with CLL treated by office-based hematologists in Germany.
While targeting 500 CLL pts, the registry prospectively collects data on pts characteristics, tumor history, treatment, response rates and sequences of regimes. In addition data on adverse drug reactions and concomitant diseases are documented. CLL pts older than 18 years receiving a first- or second line therapy which has started no longer than 4 weeks before patient enrolment can be recruited into the registry if informed written consent is present. All pts are followed for 5 years. Currently, 116 sites across Germany are participating.
The TLN Registry started in May 2009. Currently, 492 pts with CLL have been recruited. The mean age at the start of first line therapy is 69 years. The majority of pts (63%) are male. About 20% of the pts in first line therapy are treated within clinical trials. Median time between diagnosis and start of first line therapy is 22 months (range 0 – 285 months). Most of the pts receive Bendamustine/Rituximab (BR, 34%) or Fludarabin/Cyclophosphamide/Rituximab (FCR, 21%) in first line therapy. Overall, 97% of the first line therapies were successful (91% CR/PR, 6% SD). In particular, 99% of BR (98% CR/PR, 1% SD) and 100% of FCR (98% CR/PR, 2% SD) therapies were successful. Over time, a change in treatment selection becomes apparent. 50% of the pts started first line therapy before October 2009. They mainly received BR (19%), Bendamustine (16%), FCR (16%) or Chlorambucil (15%), respectively. Pts starting first line therapy after October 2009 mainly received BR (43%) or FCR (24%). Bendamustine-containing regimens are more often used as first line therapy in pts older than 75 years as compared to younger ones (62% vs. 42%). Fludarabine-containing regimens are more often used in pts younger than 75 years (37% vs. 6%). Similar to the first line therapy, BR is the most often used second line therapy (52%). About 41% of the pts have completed first line therapy and have not yet started second line therapy. The median treatment-free interval since the end of the first line therapy is 10 months. Data on second line therapy are available in 24% of the pts. The majority of these pts (73%) were recruited at the start of second line therapy. Most of them receive BR as second line therapy after first line therapy either with Chlorambucil (17%) or Bendamustine (13%). The median treatment-free interval between the end of first line therapy and the start of second line therapy is 16 months (range 1 – 49 months).
The registry provides an overview on particularities and changes in routine treatment of pts with CLL treated by office-based hematologists in Germany. Implementation of new standards affecting treatment preferences are currently under evaluation. BR and FCR are widely accepted and very effective as first line therapies. Our data indicate that age is an important factor for selecting the appropriate treatment. Further analyses will investigate additional variables influencing the choice of treatment. With more data becoming available the sequences of regimes and their effectiveness can be analyzed.
No relevant conflicts of interest to declare.
The German study groups, the German Low‐Grade Lymphoma Study Group (GLSG) and Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO), initiated in 2007 a double randomized trial to investigate ...efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment in the first‐line follicular lymphoma. Previously untreated patients with stage II–IV follicular lymphoma in need of therapy were randomized to receive 6 cycles of R‐CHOP, R‐MCP, or R‐FCM. Responding patients were subsequently randomized to 2 years rituximab maintenance or observation, stratified by type of immunochemotherapy, quality of remission, and Follicular Lymphoma International Prognostic Index (FLIPI). Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24–86), and (FLIPI) was low in 13%, intermediate in 28%, and high in 60%. High and comparable overall response rates were observed after R‐CHOP (88%), R‐MCP (89%), and R‐FCM (91%). Rituximab maintenance substantially prolonged progression‐free survival (PFS) in comparison to observation in remission (hazard ratio 0.39, P = 0.0064). In the rituximab maintenance group, the 3‐year PFS was 89% compared with 69% in the observation group. No differences in overall survival were observed for maintenance vs. observation (hazard ratio 1.04, 95% confidence interval 0.32–3.43, P = 0.95). In this randomized trial, 2 years of rituximab maintenance was associated with significantly prolonged PFS in comparison to observation after response to first‐line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the PRIMA trial results.
(Clinical Trial EudraCT Number: 2005‐005473‐29, 2006‐09‐26)
Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative ...effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov , number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio HR 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 25% of 297 patients in the cetuximab group vs 62 21% of 295 patients in the bevacizumab group), skin reactions (77 26% vs six 2%), and diarrhoea (34 11% vs 40 14%). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.
We investigated choice and efficacy of subsequent treatment, with special focus on second-line therapy, in the FIRE-3 trial (FOLFIRI plus cetuximab arm A or bevacizumab arm B) for patients with KRAS ...wild-type metastatic colorectal cancer.
Start of subsequent-line (second or third) therapy was defined as use of an antitumor drug that was not part of the previous regimen. We evaluated choice, duration, and efficacy of subsequent therapy and determined the impact of subsequent-line treatment on outcome of patients in FIRE-3.
Of 592 patients in the intent-to-treat population, 414 (69.9%) received second-line and 256 (43.2%) received third-line therapy. In subsequent treatment lines, 47.1% of patients originally assigned to arm A received bevacizumab, and 52.2% originally assigned to arm B received either cetuximab or panitumumab. Oxaliplatin was subsequently used in 55.9% (arm A) and 53.2% (arm B) of patients. Second-line therapy was administered for a median duration of 5.0 versus 3.2 months (P < .001) in study arm A versus B. Progression-free (6.5 v 4.7 months; hazard ratio, 0.68; 95% CI, 0.54 to 0.85; P < .001) and overall survival (16.3 v 13.2 months; hazard ratio, 0.70; 95% CI, 0.55 to 0.88; P = .0021) from start of second-line therapy were longer in patients in arm A compared with arm B.
Our data suggest that the sequence of drug application might be more important than exposure to single agents. In patients with RAS wild-type tumors, first-line application of anti-epidermal growth factor receptor-directed therapy may represent a favorable condition for promoting effective subsequent therapy including antiangiogenic agents.
Abstract There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head‐to‐head phase III randomised trials are missing. We assess real‐world ...effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX ( n = 613) or gemcitabine/nab‐paclitaxel (GEMNAB; n = 938) as palliative first‐line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health‐related quality of life (HRQoL) between three common first‐ to second‐line treatment sequences, adjusting for time‐varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5‐fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 8.9, 11.9 and 6.4 4.8, 7.7 months for FOLFIRINOX→GEMNAB, 8.4 7.4, 9.7 and 5.8 4.6, 7.1 months for GEMNAB→FOLFOX/OFF and 8.9 7.8, 10.4 and 4.6 4.1, 6.1 months for GEMNAB→NALIRI+5‐fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor‐risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 1.47, 2.98; TTD: HR 1.97 1.19, 3.27) and those with GEMNAB→NALIRI+5‐fluorouracil (OS: HR 1.35, 0.76, 2.39; TTD: HR 2.62 1.56, 4.42). Brackets denote 95%‐confidence intervals. The estimated real‐world effectiveness of the three treatment sequences evaluated were largely comparable. Poor‐risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient‐reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.
Abstract Background Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. Objectives To prospectively evaluate ...sequential use of the multikinase inhibitors sorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. Design, setting, and participants The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). Intervention Patients were randomised to sorafenib 400 mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50 mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). Outcome measurements and statistical analysis The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. Results and limitations In total, 365 patients were randomised (So-Su, n = 182; Su-So, n = 183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio HR 1.01; 90% confidence interval CI 0.81–1.27; p = 0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77–1.30; p = 0.5 for superiority). More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. Conclusions Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC. Patient summary We investigated if total progression-free survival (PFS) is improved in patients with advanced/metastatic kidney cancer who are treated with sorafenib and then with sunitinib (So-Su), compared with sunitinib and then sorafenib (Su-So). We found that total PFS was not improved with So-Su compared with Su-So, but both treatment options were similarly effective in patients with advanced/metastatic kidney cancer. Trial registration ClinicalTrials.gov identifier NCT00732914 , www.clinicaltrials.gov
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