original articles - Oxford Academic - Oxford University Press

original articles 13. Socinski MA, Bondarenko I, Karaseva NA et al Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 2012; 30: 2055–2062. 14. de Marinis F, Pereira JR, Fossella F et al Lung cancer symptom scale outcomes in relation to standard efficacy measures: an analysis of the phase III study of pemetrexed versus docetaxel in advanced non-small cell lung cancer. J Thorac Oncol 2008; 3: 30–36. 15. Bezjak A, Tu D, Seymour L et al Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2006; 24: 3831–3837. 16. Kris MG, Natale RB, Herbst RS et al Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290: 2149–2158. 17. Langer CJ, Besse B, Gualberto A et al The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 5311–5320. 18. Scagliotti G, Novello S, von Pawel J et al Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 1835–1842. 19. Johnson DH, Fehrenbacher L, Novotny WF et al Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-smallcell lung cancer. J Clin Oncol 2004; 22: 2184–2191.

Annals of Oncology 20. Scagliotti GV, Parikh P, von Pawel J et al Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543–3551. 21. Sandler A, Gray R, Perry MC et al Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542–2550. 22. Pirker R, Pereira JR, Szczesna A et al Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009; 373: 1525–1531. 23. Wistuba II, Gazdar AF. Pathology of lung cancer. In: Syrigos K, Nutting CM, Roussos C (eds), Tumors of the Chest: Biology, Diagnosis and Management. Germany: Springer; 2006: 93–105. 24. Sparreboom A, van Zuylen L, Brouwer E et al Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 1999; 59: 1454–1457. 25. Belani CP, Ramalingam S, Perry MC et al Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 2008; 26: 468–473. 26. Socinski MA, Ivanova A, Bakri K et al A randomized phase II trial comparing every 3-weeks carboplatin/paclitaxel with every 3-weeks carboplatin and weekly paclitaxel in advanced non-small cell lung cancer. Ann Oncol 2006; 17: 104–109.

Annals of Oncology 24: 2396–2402, 2013 doi:10.1093/annonc/mdt228 Published online 26 June 2013

A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN B. Melichar1*, S. Bracarda2, V. Matveev3, B. Alekseev4, S. Ivanov5, A. Zyryanov6, R. Janciauskiene7, E. Fernebro8, P. Mulders9, S. Osborne10, S. Jethwa10, G. Mickisch11, M. Gore12, R. J. A. van Moorselaar13, M. Staehler14, N. Magne15 & J. Bellmunt16,17 on behalf of BEVLiN Investigators 1 Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic; 2Department of Oncology, Ospedali San Donato, Arezzo, Italy; 3NN Blokhin Cancer Research Center, Moscow; 4Research Oncology Institute, Moscow; 5Department of Chemotherapy Profsouznaya Str 86, Russian Research Center of Roentgenoradiology, Moscow; 6Region Hospital #1 Oncology, Ekaterinburg, Russia; 7Institute of Oncology, Lithuanian University of Health Sciences, Kaunas, Lithuania; 8Department of Oncology, Växjö Hospital, Växjö, Sweden; 9Radbound University Nijmegen Medical Centre, Nijmegen, The Netherlands; 10F Hoffmann-La Roche, Basel, Switzerland; 11Center of Operative Urology, Bremen, Germany; 12The Royal Marsden, London, UK; 13Department of Urology, VU University Medical Centre, Amsterdam, The Netherlands; 14Klinikum der Universität München, Germany; 15Department of Radiotherapy, Institut de Cancérologie de la Loire, St Priest en Jarez cedex, France; 16Dana Farber Cancer Institute, Harvard Medical School, Boston, USA;; 17Medical Oncology Service Hospital del Mar, Barcelona, Spain

Received 21 December 2012; revised 3 May 2013; accepted 13 May 2013

Background: Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-α2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with lowdose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity. Methods: BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatmentnaive, clear cell mRCC and favourable/intermediate Memorial Sloan-Kettering Cancer Center scores received

*Correspondence to: Prof. Bohuslav Melichar, Department of Oncology, Palacký University Medical School and Teaching Hospital, IP Pavlova 6, 775 20 Olomouc, Czech Republic. Tel: +420-588-444-288; Fax: +420-588-442-522; E-mail: bohuslav.melichar@ fnol.cz

© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]. Downloaded from https://academic.oup.com/annonc/article-abstract/24/9/2396/202731/A-multinational-phase-II-trial-of-bevacizumab-with by PPD Development LP user on 17 September 2017

original articles

Annals of Oncology

bevacizumab (10 mg/kg every 2 weeks) and IFN (3 MIU thrice weekly) until disease progression. Descriptive comparisons with AVOREN patients having favourable/intermediate MSKCC scores treated with bevacizumab plus IFN (9 MIU) were made. Primary end points were grade ≥3 IFN-associated adverse events (AEs) and progression-free survival (PFS). All grade ≥3 AEs and bevacizumab/IFN-related grade 1–2 AEs occurring from first administration until 28 days after last treatment were reported. Results: A total of 146 patients were treated; the median follow-up was 29.4 months. Any-grade and grade ≥3 IFNassociated AEs occurred in 53.4% and 10.3% of patients, respectively. The median PFS and overall survival were 15.3 [95% confidence interval (CI): 11.7–18.0] and 30.7 months (95% CI: 25.7–not reached), respectively. The ORR was 28.8%. Conclusions: Compared with a historical control AVOREN subgroup, low-dose IFN with bevacizumab resulted in a reduction in incidence rates of IFN-related AEs, without compromising efficacy [NCT00796757]. Key words: renal cell carcinoma, angiogenesis, bevacizumab, immunotherapy, interferon, VEGF

introduction Most patients with metastatic renal cell carcinoma (mRCC) present with metastases that are not amenable to surgical removal and for which chemotherapy provides, at best, modest benefits [1–3 ]. Cytokines, in particular interferon-α (IFN), prolong progression-free survival (PFS) and overall survival (OS) in mRCC patients [4, 5]; however, the use of IFN is often limited by toxicity, most commonly fatigue and asthenia [6–9 ]. Lower-dose IFN (from 5 MU/day to 0.5 MU b.i.d.) is an option for some patients, improving tolerability and quality of life while maintaining efficacy [10, 11]. Bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF)-A, is the only targeted agent that has been safely combined with other active agents in mRCC and significantly improves PFS when combined with IFN in patients with previously untreated mRCC [6, 12]. In the double-blind Avastin and Roferon in Renal Cell Carcinoma (AVOREN) trial, the combination of bevacizumab with IFN [9 MIU three times a week (tiw)] improved PFS [median of 10.2 versus 5.4 months; hazard ratio (HR) 0.63; P = 0.0001] and the objective response rate (ORR, 30.6% versus 12.4%; P = 0.0001) compared with IFN plus placebo [12]. In the Cancer and Leukemia Group B (CALGB) 90 206 study, an open-label mRCC trial, the addition of bevacizumab to IFN (9 MIU tiw) significantly improved both PFS (median of 8.5 versus 5.2 months; HR 0.71; P < 0.0001) and ORR (25.5% versus 13.1%; P < 0.0001) [6]. A trend towards OS improvement in both trials’ combination arms was not statistically significant, possibly due to the availability of subsequent-line treatments unavailable when these studies were designed [6, 12–14 ]. The most commonly reported grade ≥3 adverse events (AEs) in the bevacizumab plus IFN treatment arms in these studies were IFN-related, including fatigue, asthenia, anorexia, and neutropenia [6, 15]. IFN dose reduction was permitted in both trials and was associated with a reduction in grade 3/4 AEs in a retrospective analysis of AVOREN data, with improved efficacy in the bevacizumab plus IFN arm being maintained relative to IFN plus placebo (HR 0.63, P = 0.0026) [16]. The Bevacizumab and Low-Dose Interferon (BEVLiN) trial prospectively evaluated the safety and efficacy of bevacizumab plus low-dose IFN (3 MIU tiw) in patients with previously untreated mRCC. The design allowed for a descriptive

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comparison with a historical control group of AVOREN patients with favourable or intermediate Memorial SloanKettering Cancer Center (MSKCC) scores receiving bevacizumab plus IFN (9 MIU).

methods patients and treatment BEVLiN (NCT00796757) is a prospective, multicentre, open-label, singlearm, multinational, phase II trial. Patients ≥18 years with previously untreated, histologically, and/or cytologically verified mRCC (>50% clearcell mRCC), prior nephrectomy, ≥1 measurable or non-measurable lesion [according to Response Evaluation Criteria in Solid Tumors (RECIST)], an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2 (Karnofsky performance status ≥70), favourable or intermediate MSKCC score, life expectancy ≥12 weeks, and international normalized ratio (in absence of anti-coagulation treatment) ≤1.5 within 7 days before enrolment were eligible. This trial was approved by local institutional review boards or ethic committees and conducted in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practice. All patients gave written informed consent before enrolment.

procedures Patients received intravenous bevacizumab at 10 mg/kg every 2 weeks (q2w) and subcutaneous IFN at 3 MIU tiw until disease progression, unacceptable toxicity, or consent withdrawal. Patients were followed until death or for 2 years after the enrolment of the last patient, whichever occurred first. The co-primary end points were PFS and safety, specifically grade ≥3 IFN-associated AEs (fatigue, asthenia, depression, anorexia, influenza-like illness, pyrexia, nausea, vomiting, chills, and malaise) evaluated using the National Cancer Institute Common Terminology Criteria for AEs v 3.0. All grade ≥3 AEs and bevacizumab/IFN-related grade 1–2 AEs occurring from first administration until 28 days after last treatment were reported. Secondary end points were OS, investigator-assessed ORR (according to RECIST), grade 3–5 AEs, overall AEs, and serious AEs (SAE). Patients were assessed for safety end points at treatment start, q2w thereafter until disease progression, and every 3 months during the followup. AEs of special interest were those associated with VEGF-A-targeted therapy, including hypertension, proteinuria, wound-healing complications, gastrointestinal perforation, haemorrhage, arterial and venous thromboembolic events, congestive heart failure, and reversible posterior leukoencephalopathy syndrome. Tumour assessments were conducted at baseline, every 8 weeks until week 32, and every 12 weeks thereafter until disease progression. A data monitoring committee reviewed safety data

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original articles collected during the trial on an ongoing basis. One planned interim efficacy analysis was carried out once baseline assessments of the entire study population were completed. The AVOREN design was described previously [12].

analyses Cross-study comparisons of efficacy end points between the BEVLiN trial and the AVOREN trial were based on intention-to-treat (ITT) populations. The BEVLiN ITT population included all enrolled patients with a valid baseline assessment and ≥1 post-baseline visit. The AVOREN ITT (efficacy) subgroup population included patients with favourable or intermediate MSKCC scores randomized to receive bevacizumab plus high-dose IFN. Across-study comparisons of safety end points were based on all enrolled patients who received ≥1 dose of either study drug in BEVLiN and patients with favourable or intermediate MSKCC scores who received bevacizumab and intended to receive 9 MIU IFN in AVOREN. To ensure similar definitions across studies, PFS was defined as the interval from date of the first post-baseline visit to the date of disease progression or death from any cause, whichever occurred first. OS was defined as the interval from the date of the first post-baseline visit until the date of death from any cause. Patients without an event were censored at the date of the last follow-up or date of last study drug administration. The median PFS and OS values and 95% confidence intervals (CIs) were calculated using the Kaplan–Meier methods. A sample size of 140 patients was based on the assumptions of a 30% reduction in the incidence of specific IFN-related AEs (grade ≥3) and a similar median PFS compared with AVOREN, on an exploratory basis. A historical, solely descriptive comparison with the AVOREN trial was made without formal statistical comparisons between study results using P-values or HRs.

results Bevacizumab and Low-Dose Interferon Between December 2008 and February 2010, 147 patients were enrolled at 39 sites in 12 countries; 146 received study treatment. At the data cutoff date, 5 February 2012, the median follow-up was 29.4 months (range, 1.5–35.4 months). Sixty patients were alive, 61 had died, 4 were not followed until the cutoff date, 7 were lost to follow-up, and 15 had withdrawn from the trial. Baseline characteristics for BEVLiN patients are shown (Table 1). Patients received a median of 22.5 cycles of bevacizumab and 132 doses of IFN (supplementary Table S1, available at Annals of Oncology online); the median duration of treatment was10.0 months (range 2.8–20.7 months). The overall incidence rates of any-grade AEs, grade ≥3 AEs, and SAEs were 84.2%, 42.5%, and 17.8%, respectively (Table 2). Any-grade IFN-associated AEs and grade ≥3 IFN-associated AEs were reported in 53.4% and 10.3% of patients, respectively. AEs contributed to temporary IFN interruption in 24.0% of patients. The ORR among patients with measurable disease (n = 139) at baseline was 28.8% (95% Pearson–Clopper CI 21.4–37.1). The median PFS in the ITT population was 15.3 months (95% CI: 11.7–18.0), with an estimated PFS rate of 58.2% and 28.9% at 12 and 24 months, respectively (Table 3, Figure 1). The median OS was 30.7 months (95% CI: 25.7–not reached). A total of 32.9% of patients received anti-neoplastic therapy after disease progression (supplementary Table S1, available at Annals of Oncology online).

 | Melichar et al.

Annals of Oncology Table 1. Baseline characteristics of patients in the BEVLiN and AVOREN subgroup ITT populations Patients

BEVLiNa (n = 146)

Age Median, years (range) 62 (22–47) 2 60 (41.1) Number of lesions per patientf, n (%) 1 14 (9.6) 2 16 (11.0) 3 14 (9.6) 4 16 (11.0) ≥5 86 (58.9) Location of metastasesf,g, n (%) Lung 107 (73.3) Lymph nodes 85 (58.2) Adrenal 27 (18.5) Bone 26 (17.8) Liver 23 (15.8) Prior therapiesf,g, n (%) Radiation therapy 12 (8.2) Surgery 146 (100.0) Other therapy 5 (3.4)

AVORENb,c (n = 272) 61 (30–42) 169 (62.1) 103 (37.9) 261 (96.0) 2 (0.7) 1 (0.4) 8 (2.9) 183 (67.3) 89 (32.7) 131 (48.2) 137 (50.4) 4 (1.5) 235 (86.4) 37 (13.6) 64 (23.5) 105 (38.6) 103 (37.9)

205 (75.4)

49 (18.0) 47 (17.3)

a

Demographic characteristics were collected at screening in the BEVLiN trial. Demographic characteristics were collected at randomization in the AVOREN trial. c The AVOREN subgroup ITT population includes patients who had favourable or intermediate MSKCC score at baseline (inclusion criterion for BEVLiN patients) and who were randomized to receive bevacizumab plus IFN 9 MIU. d KPS was converted to ECOG PS for AVOREN subgroup patients. A KPS score of 100 was converted to an ECOG PS of 0, a KPS score of 80 or 90 was converted to an ECOG PS of 1, and a KPS score of 70 was converted to an ECOG PS of 2. e Based on patients with at least one target or non-target lesion. f Data not available for the AVOREN subgroup. g Multiple categories were possible for a single patient. BEVLiN, Bevacizumab and Low-Dose Interferon; ECOG PS, Eastern Cooperative Oncology Group performance status; IFN, interferon-α2a; ITT, intention-to-treat; KPS, Karnofsky performance status; SD, standard deviation. b



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Annals of Oncology Table 2. Overall and IFN-associated AEs in the BEVLiN and AVOREN subgroup safety populations Any grade BEVLiN (n = 146)

Patients c

AEs, % (95% CI) 84.2 (77.3–89.7) SAEs, % (95% CI) 17.8 (12.0–25.0) AEs leading to death, % (95% CI) — IFN-associated AEs, % (95% CI) 53.4 (45.0–61.7) Specific IFN-associated AE by type, % (95% CI) Fatigue or asthaenia 37.0 (29.2–45.4) Influenza-like illness 4.1 (1.5–8.7) Pyrexia 19.2 (13.1–26.5) Chills 8.9 (4.8–14.7) Malaise 0.0 (0.0–2.5) Depression 3.4 (1.1–7.8) Anorexia 0.0 (0.0–2.5) Nausea 8.9 (4.8–14.7) Vomiting 6.8 (3.3–12.2) AE resulting in IFN treatment change, n (%) Temporary interruption 35 (24.0) Permanent discontinuation 22 (15.1)

AVOREN (n = 283)

Grades 3–5a BEVLiN (n = 146)

AVORENb (n = 283)

98.2 (95.9–99.4) 30.0 (24.8–35.7) — 89.0 (84.8–92.4)

42.5 (34.3–50.9) — 1.4 (0.2–4.9)d 10.3 (5.9–16.4)

60.4 (54.5–66.2) — 1.8 (0.6–4.1)e 26.9 (21.8–32.4)

62.5 (56.6–68.2) 26.5 (21.5–32.1) 44.5 (38.6–50.5) 16.6 (12.5–21.5) 2.8 (1.2–5.5) 12.4 (8.8–16.8) 35.7 (30.1–41.6) 28.6 (23.4–34.3) 13.1 (9.38–17.6)

9.6 (5.3–15.6) 0.0 (0.0–2.5) 0.0 (0.0–2.5) 0.7 (0.0–3.8) 0.0 (0.0–2.5) 0.0 (0.0–2.5) 0.0 (0.0–2.5) 0.7 (0.0–3.8) 0.0 (0.0–2.5)

20.8 (16.3–26.1) 2.1 (0.8–4.6) 1.8 (0.6–4.1) 0.4 (0.0–2.0) 0.4 (0.0–2.0) 2.8 (1.2–5.5) 2.5 (1.0–5.0) 0.7 (0.1–2.5) 0.7 (0.1–2.5)

134 (47.3) 63 (22.3)

22 (15.1) 12 (8.2)

†

92 (32.5) 39 (13.8)

Occurring from first bevacizumab administration up to 28 days post-last dose of bevacizumab and/or IFN. The AVOREN subgroup safety population consists of patients who had favourable or intermediate Memorial Sloan-Kettering Cancer Center scores at baseline (inclusion criterion for BEVLiN patients) and who actually received bevacizumab and intended to receive IFN 9 MIU. In AVOREN, IFN treatment was given for ≤1 year. c For BEVLiN, include all grade 1–2 treatment-related AEs and all grade ≥3 AEs, regardless of the relationship with treatment. For AVOREN, include all AEs of any grade. d AEs leading to death in BEVLiN patients were cardiac arrest and cerebral haemorrhage. e AEs leading to death in the AVOREN subgroup were atrial fibrillation, gastrointestinal perforation, hepatic failure, haemotypsis, and rupture aneurysm. AE, adverse event; BEVLiN, Bevacizumab and Low-Dose Interferon; CI, confidence interval. IFN, interferon-α2a; SAE, serious adverse event. a

b

AVOREN historical control group Patients in the AVOREN efficacy and safety subgroup had been randomized to receive bevacizumab plus IFN between June 2004 and October 2005 [12]. The AVOREN efficacy and safety population subgroup consisted of 272 and 283 patients, respectively. The median follow-up for the AVOREN subgroup was 38.9 months (range, 0.9–45.6 months). The overall incidence rates of any-grade AEs, grade ≥3 AEs, and SAEs were 98.2%, 60.4%, and 30.0%, respectively (Table 2). Any-grade IFN-associated AEs and grade ≥3 IFN-associated AEs were reported in 89.0% and 26.9% of patients, respectively. AEs contributed to temporary IFN interruption in 47.3% of patients. The ORR (n = 256) was 35.9% (95% Pearson–Clopper CI: 30.1–42.2). At the time of analysis, 101 (69.2%) patients in the BEVLiN ITT population had experienced a PFS event. The median PFS was 10.5 months (95% CI: 10.1–12.9), and 12and 24-month PFS rates were 47.6% and 11.0%, respectively (Table 3). The median OS was 25.8 months (95% CI: 22.7–29.4).

discussion The modified combination regimen in the BEVLiN trial appeared to allow for increased exposure to both bevacizumab and IFN. The median number of bevacizumab cycles (22.5


versus 18.0) and IFN doses (132 versus 109) was higher in BEVLiN than in the AVOREN trial. Furthermore, the BEVLiN regimen was associated with fewer temporary interruptions and permanent discontinuations due to AEs. The use of IFN is often limited by toxicity, most commonly fatigue and asthenia [6–9 ], and IFN-associated AEs may be increased with the concomitant administration of bevacizumab [12]. In BEVLiN patients, the incidence rates of grade ≥3 overall and IFN-associated AEs were lower by ∼18% and 17%, respectively, compared with the AVOREN subgroup. Incidence rates of SAEs were also markedly lower in BEVLiN, with 95% CIs mostly not overlapping. Moreover, despite the longer duration of IFN treatment, the incidence of any-grade fatigue/ asthenia, pyrexia, influenza-like illness, depression, anorexia, and nausea was also lower in BEVLiN. These observations support previous reports that IFN-associated toxic effects are dose-related [17, 18] and prospectively demonstrate that reducing the IFN dose substantially improves the safety profile of the bevacizumab plus IFN regimen. Approximately 60% of patients in both studies reported a ≥1 bevacizumab (VEGF-A)–blockade-related AE of any grade, hypertension, proteinuria, and bleeding being the most common. The overall incidence of grade ≥3 VEGF-A-blockadeassociated AEs was similar between the two populations, although a higher frequency of grade ≥3 hypertension (15.8% versus 6.4%) was observed in BEVLiN patients. The longer

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Table 3. Efficacy end points in the BEVLiN and AVOREN subgroup ITT populations BEVLiN (n = 146) BORa,b, n (%) Complete response Partial response Stable disease Progressive disease PFS Patients with an event, n (%) Median PFS, months (95% CI) PFS rate, % (95% CI) At 6 months At 12 months At 18 months At 24 months At 30 months OS Patients with an event, n (%) Median OS, months (95% CI) OS rate, % (95% CI) At 6 months At 12 month At 18 months At 24 months At 30 months

AVOREN (n = 272)

3 (2.2) 37 (26.6) 71 (51.1) 23 (16.5)

5 (2.0) 87 (34.0) 117 (45.7) 40 (15.6)

101 (69.2)

250 (91.9)

15.3 (11.7–18.0)

10·5 (10.1–12.9)

71.4 (63.9–78.9) 58.2 (49.9–66.6) 41.9 (33.4–50.5) 28.9 (20.8–36.9) 21.8 (13.9–29.7)

65.4 (59.7–71.0) 47.6 (41.7–53.6) 24.6 (19.3–29.8) 11.0 (7.1–14.9) 7.5 (4.2–10.8)

61 (41.8)

177 (62.5)

30.7 (25.7–not reached)

25.8 (22.7–29.4)

91.5 (86.9–96.1) 84.1 (78.0–90.2) 71.4 (63.7–79.1) 59.6 (51.0–68.2) 50.9 (41.7–60.2)

90.1 (86.5–93.6) 79.7 (74.9–84.5) 65.5 (59.8–71.2) 53.6 (47.6–59.6) 43.4 (37.5–49.3)

There was insufficient post-baseline information to assess BOR for five patients in BEVLiN (3.6%) and seven patients in the AVOREN subgroup (2.7%). b There were 139 patients with measurable disease in BEVLiN and 256 patients with measurable disease in the AVOREN subgroup. BEVLiN, Bevacizumab and Low-Dose Interferon; BOR, best objective response; CI, confidence interval; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival. a

duration of bevacizumab treatment may have contributed to the higher occurrence of some AEs, including grade ≥3 hypertension and any-grade proteinuria [19, 20]. Importantly, there was no indication that either PFS or OS outcomes in BEVLiN patients were inferior to those observed in the comparative AVOREN subgroup. The median PFS (15.3 months) and OS (30.7 months) in BEVLiN patients compared well with other targeted agents used in the first-line setting of mRCC patients with MSKCC favourable/ intermediate scores [7, 21, 22]. The observation that nearly 30% of patients were alive and progression-free at 2 years demonstrated that a substantial subset of patients experienced long-term clinical benefit from the modified regimen. Potential factors contributing to treatment efficacy in the BEVLiN study include the longer exposure to both bevacizumab and IFN, taking the advantage of the possible synergistic anti-angiogenic effect of low-dose IFN [8, 16]. A

 | Melichar et al.

complete response rate of 2% is remarkably similar in BEVLiN, AVOREN, and earlier trials of IFN [10]. The anecdotal experience with these rare patients indicates that complete response is durable on prolonged IFN therapy. The potential contribution of bevacizumab and the optimal duration of bevacizumab therapy in patients experiencing complete response remain speculative. A lower proportion of patients who received subsequent therapies (32.9% in BEVLiN compared with 46.0% in the bevacizumab plus IFN comparator subgroup in AVOREN) reflects the fact that 30.8% of patients did not progress at the time of analysis as well as the limited availability of targeted agents in some participating countries. Inherent in the BEVLiN trial design were limitations based primarily on using a historical control population as the safety and efficacy comparator. Descriptive analyses were conducted among BEVLiN patients and those in the AVOREN subgroup. Although baseline characteristics and were generally similar in both studies, since AVOREN preceded BEVLiN by ∼5 years, incremental experience with the administration of bevacizumab and management of complications, differences in the availability and use of treatment modalities, best supportive care upon progressive disease, and potentially unobserved latent variables (‘trial effects’) [23] may explain an improvement in outcomes. In fact, the results of the BEVLiN trial are remarkably similar to the efficacy of bevacizumab plus IFN recently reported in the Torisel and Avastin (TORAVA) trial [24]. In conclusion, data from the present, multinational, phase II trial further support the hypothesis that, in patients with previously untreated mRCC, the use of bevacizumab in combination with low-dose IFN results in a more favourable safety profile, with similar efficacy, compared with bevacizumab plus high-dose IFN. These results suggest that the regimen of bevacizumab plus low-dose IFN (3 MIU) is a viable option for the first-line treatment of patients with clear-cell mRCC who have favourable or intermediate MSKCC scores.

acknowledgements Support for third-party writing assistance for this manuscript, furnished by Melita Dvorak-Ewell, PhD (medical writing), and Andrea Michels (copyediting) was provided by F. Hoffmann-La Roche Ltd.

funding This work was supported by F. Hoffmann-La Roche Ltd. The trial was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The study sponsor was involved in trial design, coordination of data collection, data analysis and interpretation, the writing of the report, and supplied bevacizumab. After data lock, the sponsor, investigators, and all authors had full access to the data. All authors gave their permission to submit for publication.

disclosure Consultancy: BM, SB, GM, RJAM, MS, NM, JB. Honoraria: BM, SB, RJ, GM, MG, MS, NM, JB. Travel grants: BM, RJ, GM, NM.



Annals of Oncology

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Figure 1. Kaplan–Meier estimates of survival in the BEVLiN ITT population: (A) PFS and (B) overall survival. BEVLiN, Bevacizumab and Low-Dose Interferon; ITT, intention-to-treat.

Employment (Roche): SO, SJ. Stock ownership (Roche): SJ. All remaining authors have declared no conflicts of interest.

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Annals of Oncology 24: 2402–2408, 2013 doi:10.1093/annonc/mdt194 Published online 30 May 2013

Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial A. Bahl1,†, S. Oudard2,†, B. Tombal3, M. Özgürog^ lu4, S. Hansen5, I. Kocak6, G. Gravis7, J. Devin8, L. Shen8, J. S. de Bono9* & A. O. Sartor;10 for the TROPIC Investigators‡ 1 Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; 2Department of Medical Oncology, Hôpital Européen Georges Pompidou, René Descartes University, Paris, France; 3Division of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; 4Department of Medical Oncology, Cerrahpas¸ a Medical Faculty, Istanbul University, Istanbul, Turkey; 5Department of Oncology, Odense University Hospital, Odense, Denmark; 6Clinic of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 7Department of Medical Oncology, Institut Paoli Calmette, Hôpital de Jour, Marseille, France; 8 Department of Biostatistics and Programming, Sanofi, Bridgewater, USA; 9Department of Drug Development, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK; 10Departments of Medicine and Urology, Tulane Cancer Center, Tulane University, New Orleans, USA

Received 17 December 2012; revised 5 April 2013 & 12 April 2013; accepted 15 April 2013

Background: Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone. *Correspondence to: Professor Johann Sebastian de Bono, Department of Drug Development, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-722-4028; Fax: +44-208-642-7979; E-mail: [email protected] †

Joint lead authors/authors contributed equally. Investigators listed in web appendix.

‡

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