27 september 2011: toegevoegd onderaan een nieuwe studie die bewijst dat een vergelijkbaar middel everolimus goed werkt bij gevorderde nierkanker.

24/08 Bron: Medscape en verschillende gepubliceerde fase II en fase III studies

Wetenschappers en oncologen pleiten voor een eerstelijns behandeling van uitgezaaide nierkanker met tyrosine kinase inhibitor (TKI) sunitinib voor uitgezaaide niercelkanker (CCRCC) en de mTOR inhibitor, temsirolimus, voor extra risicovolle CCRCC patienten. Dit voorstel wodt gedaan na resultaten uit enkele fase III studies met een behandeling van tyrosine kinase inhibitor (TKI) sunitinib en/of mTOR inhibitor, temsirolimus welke significant een betere overleving geven dan de nu gehanteerde standaard behandeling met interferon (IFN) en/of interleukin (IL)-2, We zullen proberen onderstaand artikel in goed Nederlands te vertalen maar hebben daar even tijd voor nodig.

Nicholas J. Vogelzang, MD

Introduction
The American Society of Clinical Oncology (ASCO) 2006 Annual Meeting was remarkable for featuring 2 phase 3 trials that appear poised to change the standard of care for the treatment of advanced renal cell carcinoma (RCC). Evidence was presented for the use of the tyrosine kinase inhibitor (TKI) sunitinib as first-line therapy for metastatic clear cell cancers (CCRCC) and for the mTOR inhibitor, temsirolimus, for poor-risk CCRCC patients. Indeed, a targeted therapy approach to RCC has become increasingly viable, as promising data also emerged in other studies with these agents, as well as with other TK and mTOR inhibitors.

Background
Metastatic CCRCC has a median survival of 9-15 months, with significant variability depending on a variety of clinical and pathologic features. For almost 20 years, standard off-protocol therapy for metastatic CCRCC was interferon (IFN) or interleukin (IL)-2, but approval by the US Food and Drug Administration (FDA) of the TKIs sorafenib and sunitinib in December 2005 and January 2006, respectively, signaled a change in approach. Sorafenib, which inhibits the vascular endothelial growth factor (VEGF) pathway and c-RAF kinase isoforms, was approved based on substantial improvement in progression-free survival (PFS) seen in a randomized phase 2 trial[1] and in a placebo-controlled phase 3 trial.[2] Both trials were conducted in patients with prior cytokine (or other) therapy. Sunitinib, which inhibits the VEGF and platelet-derived growth factor (PDGF) pathways, was approved based on impressive response rates and prolonged time to progression (using historical controls) in 2 phase 2 trials.[3,4] These trials were also conducted in patients with prior cytokine (or other) therapy. The 2 practice-changing trials presented at ASCO looked at previously untreated patients.

Patients with RCC are classified as good, intermediate, or poor risk, according to a series of factors. The Memorial Sloan-Kettering Cancer Center (MSKCC)[5] risk group categorization defines the 5 poor risk features as a performance status < 80, a serum calcium > 10 (when corrected for albumin), a hemoglobin below normal, absence of a prior nephrectomy, and a lactate dehydrogenase > 1.5 times normal. Other studies[6] from the Cleveland Clinic, the Eastern Cooperative Oncology Group, UCLA, and the Group Francois d'Immunotherapie have used slightly different parameters, but all were able to identify similar prognostic groupings. Risk stratification was particularly important in the temsirolimus trial presented at ASCO

. Targeted Therapy as First-Line Treatment for Renal Cell Cancer: Results From Key Phase 3 Trials Sunitinib
In a plenary session, Motzer and colleagues[7] reported the results of a phase 3 trial of sunitinib vs IFN as first-line therapy in 750 patients with good- and intermediate-risk CCRCC, as assessed by MSKCC risk group categorization. To qualify for the study, patients could have no more than 2 of the poor-risk features.

The primary end point was PFS, with secondary end points of patient-related outcomes, overall survival, response rate, and adverse events/safety. The trial had a 90% power to detect a 35% improvement in median PFS from 20 weeks to 27 weeks. This report was a planned analysis of the PFS end point. Patients with good performance status and who had a good or intermediate prognosis were randomized 1:1 to receive oral sunitinib 50 mg/day for 4 weeks followed by a 2-week off period (6-week cycles) or IFN 9MU subcutaneously 3 times weekly

The treatment arms were well balanced; patients had a median age of 60 years and 90% had undergone prior nephrectomy. Approximately 35% had good-risk disease, 58% had intermediate-risk disease, and 7% had poor-risk disease. The median PFS was 11 months for the sunitinib arm vs 5 months for the IFN arm (hazard ratio 0.415, P < .000001). The objective response rate assessed by the investigators was 37% for sunitinib vs 9% for IFN (P < .000001), while the independent third party review recorded an objective response rate of 31% vs 6% (P < .000001). There was only 1 complete response (in the sunitinib arm).

At the time of the report, 66% of sunitinib patients were remaining on study compared with only 34% of the IFN patients. All subgroups benefited from sunitinib, including the poor-risk patients (HR 0.53). All adverse events were more common in the IFN arm, except diarrhea, hand foot syndrome, and hypertension, which were more common in the sunitinib arm. Adverse events leading to withdrawal from the study occurred in 8% of patients on sunitinib and 13% on IFN. Only 1% of patients on the sunitinib arm withdrew consent while 8% on the IFN arm withdrew consent. Although survival end points were still premature, the HR was 0.65 (P < .02) in favor of sunitinib. The investigators concluded that sunitinib was the new standard of care for first-line treatment of metastatic CCRCC.

Temsirolimus
In the second plenary presentation, Hudes and colleagues[8] assessed the role of temsirolimus, an inhibitor of the protein mTOR, which regulates nutritional needs of the cell. As the controller of the nutritional flow in the cell, mTOR also regulates cell growth and angiogenesis by downregulating or upregulating a variety of proteins, including hypoxia inducible factor (HIF). Upregulated HIF and the proteins it regulates occur frequently in renal cancer cells. Sirolimus (rapamycin) is an FDA-approved mTOR inhibitor used to inhibit allograft rejection, and temsirolimus is one of its analogues. Previous studies[9,10] suggested that temsirolimus was most effective in poor-risk patients (who account for 20% to 30% of patients with metastatic CCRCC) and established recommended doses. As a result, the current trial was designed for CCRCC patients with at least 3 or more of 6 poor-risk features (the 5 from the MSKCC criteria plus having more than 1 metastatic site).

The trial randomized 626 patients in a 1:1:1 ratio to 1 of 3 arms: IFN up to 18MU subcutaneously 3 times weekly, temsirolimus 25 mg/week, or a combination of temsirolimus 15 mg/week plus IFN 6MU 3 times weekly. The trial was powered to compare the temsirolimus arms with the IFN alone arm. It had an 80% power to detect a 40% improvement in median survival times from 4.9 months with IFN to 6.9 months with temsirolimus. This report is based on the second planned interim analysis.

Of the 626 patients enrolled on the temsirolimus study, 442 died. The arms were well balanced, with a slightly lower-risk group of patients than expected (only 74% were poor risk by MSKCC criteria). The survival of patients in the temsirolimus-alone arm was 10.9 months, compared with 7.3 months for the IFN-only arm (HR 0.73, P < .007). The survival of patients in the combined arm (temsirolimus + IFN) was 8.4 months (HR .95, P = .69). Objective responses occurred in 7%, 9%, and 11% of patients in the IFN, temsirolimus, and combination arms, respectively. Any toxicity of greater than or equal to grade 3 was seen in 69% of patients on temsirolimus vs 85% to 87% of patients on the 2 IFN-containing arms. Grade 3 toxicity was primarily asthenia, which occurred less frequently in the temsirolimus arm (12%) than in the 2 IFN arms (27% and 30%, respectively). Grade 3 dyspnea was infrequently (8% to 11%) seen in all 3 arms. Rash was more common on the temsirolimus arm (37%, vs 5% on IFN and 16% on the combination arm). Likewise, adverse events leading to withdrawal from the study occurred in 7%, 14%, and 22% of patients on temsirolimus, IFN, and the combination arms, respectively.

Commentary on the 2 Presentations
Dr. Michael Atkins, of the Beth Israel Hospital and the Dana-Farber Cancer Center in Boston, commented on the 2 plenary presentations. He stated that both sunitinib and temsirolimus are now proven to be better than IFN in the first-line treatment of advanced RCC, and that temsirolimus is the first new agent to improve overall survival in poor-risk patients. He cautioned, however, that while the activity was robust, no complete responses were seen, that survival benefit was not yet proven for sunitinib, and that there were no predictors of response to sunitinib. He mentioned a small study in which detectable levels of phospho S6 kinase (a protein downstream of mTOR) appears to predict for response to temsirolimus in 4 of 10 patients, but he noted that understanding and overcoming the problem of drug resistance or the mechanism of tumor escape from drug control is the next needed step. Other major questions remain, including the role of adjuvant therapy, the role of cytoreductive nephrectomy, the problems of central nervous system metastases, and treatment of patients with tumors of non-clear-cell histologies. Dr. Atkins concluded by encouraging accrual to the many trials open for CCRCC.

Further Evidence for the Role of Targeted Therapies in RCC
Sunitinib
A number of other presentations on sunitinib sought to refine its optimal use, whether through dosing schedule, sequencing, or as combination therapy. For example, Rini and colleagues presented data indicating that sunitinib had substantial activity in metastatic RCC patients who were bevacizumab refractory (defined as disease progression within 3 months of bevacizumab). They treated 60 such patients with sunitinib and found that 74% had some degree of tumor shrinkage (16% partial response and 58% less than 50% regression). The median PFS was 24 weeks, and 57% remained on treatment at the time of the report.

De Mulder and colleagues showed that continuous oral dosing of sunitinib at 37.5 mg/day (in contrast to the usual dosing schedule of 50 mg/day for 4 weeks with a 2-week rest period) was safe and induced tumor shrinkage in 33 of the first 40 evaluable patients (82%). Houk and colleagues used the pharmacokinetic data collected from the 2 large phase 2 trials of sunitinib[3,4] and reported that improved clinical response and longer time to tumor progression were noted in patients with greater drug exposure as measured by AUC (area under the curve). Finally, Ronnen and colleagues combined sunitinib with gefitinib in a phase 1 trial in RCC and determined the recommended phase 2 dose to be 37.5 mg/day of sunitinib and 250 mg/day of gefitinib. Responses were seen in 5 of the 11 patients.

mTOR Inhibitors
Although temsirolimus is not approved, the Hudes study is the first to document the safety, efficacy, and survival advantage of this agent, which is representative of a novel class of agents, the mTOR inhibitors. The role of mTOR inhibitors in metastatic CCRCC is likely to grow, and a number of presentations at the ASCO meeting demonstrated the various approaches to mTOR inhibition currently under study. Amato and colleagues showed that the orally bioavailable mTOR inhibitor everolimus, when given at a dose of 10 mg/day, induced a response in 7 of 25 patients with metastatic CCRCC. More than 86% of patients remained on that study beyond 3 months. This agent also showed activity in advanced endometrial cancer. The original mTOR inhibitor, rapamycin, is being examined for anticancer activity in 2 phase 1 trials.[17,18] Of note, mTOR inhibitors act synergistically with angiogenesis inhibitors, and phase 1 trials of several combinations, including those looking at bevacizumab and everolimus, are underway.

Sorafenib
The second TKI approved for use in metastatic RCC is sorafenib, and a number of studies regarding its use in RCC were discussed.[20-25] Although phase 2 data from a trial by Escudier of sorafenib vs IFN were not yet mature enough to be presented, Eisen and colleagues reported an update of the 900 + patient TARGET study presented at ASCO in 2005 by Escudier and colleagues. That trial now shows a trend for a survival advantage for the sorafenib arm compared with placebo at both the first and second (of 4) planned interim data analyses. Ryan and colleagues presented a phase 2 trial of sorafenib plus IFN conducted by the Southwest Oncology Group showing an objective response rate of 18%.

Sosman and colleagues reported preliminary encouraging results of a phase 1/2 trial of bevacizumab combined with sorafenib. Although neither drug could be given at the recommended phase 2 dose, responses were seen in 8 of the 18 RCC patients. Data concerning the synergistic toxicity and probable efficacy of sorafenib plus bevacizumab were also presented by the National Cancer Institute group, which noted encouraging responses in RCC and ovarian cancer patients.

The question of cross resistance among the TKIs was partially addressed by Tamaskar and colleagues. In a retrospective review, the Cleveland Clinic group showed that of 4 patients progressing after prior TKI therapy, all had tumor shrinkage when switched to an alternative oral TKI antiangiogenic agent: sunitinib to sorafenib (n=1), sorafenib to sunitinib (n=2), and axitinib to sunitinib (n=1).

Conclusions
The results presented at ASCO 2006 are important because they define new standards of care for patients with good-, intermediate-, and poor-risk CCRCC. Sunitinib should now be recommended as first-line therapy for good- and intermediate-risk (and probably poor-risk disease as well) metastatic CCRCC patients. Level 1 evidence continues to support use of sorafenib as second-line therapy after progression on cytokine therapy. It is emerging as an agent to combine with bevacizumab or IFN as first-line therapy, and it may be non-cross-resistant with sunitinib. Both agents are being studied as adjuvant therapy after resection of locally advanced RCC. Temsirolimus (and possibly other mTOR inhibitors) is a promising new agent in metastatic RCC and, when available, should be used in patients with poor-risk disease or combined with angiogenesis inhibitors.

References
Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505-2512. Abstract Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multi-kinase inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Eur J Cancer Suppl. 2005;3:226. Abstract 794.
Motzer RJ, Rini BI, Michaelson MD, et al. Phase 2 trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2005;23:380s. Abstract 4508.
Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16-24. Abstract
Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22:454-463. Abstract
Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie. Ann Oncol. 2002;13:1460-1468. Abstract
Motzer RJ, Huston TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:2s. Abstract LBA3.
Hudes G, Carducci M, Tomczak P, et al. A phase III, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line poor-prognosis patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:2s. Abstract LBA4.
Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918. Abstract
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296. Abstract
Rini BI, George DJ, Michaelson MD, et al. Efficacy and safety of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:222s. Abstract 4522
De Mulder PH, Roigas J, Gillessen S, et al. A phase II study of sunitinib administered in a continuous daily regimen in patients with cytokine-refractory metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:223s. Abstract 4529
. Houk BE, Amantea M, Motzer RJ, et al. Pharmacokinetics and efficacy of sunitinib in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:224s. Abstract 4531.
Ronnen EA, Kondagunta GV, Lau C, et al. A phase I study of sunitinib malate (SU11248) in combination with gefitinib in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:225s. Abstract 4537.
Amato RJ, Misellati A, Khan M, Chiang S. A phase II trial of RAD001 in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:224s. Abstract 4530.
Oza AM, Elit L, Biagi J, et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer -- NCIC IND 160. Proc Am Soc Clin Oncol. 2006;24:121s. Abstract 3003.
Jimeno A, Kulesaza P, Cusatis G, et al. Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adults patients with solid tumors. Proc Am Soc Clin Oncol. 2006;24:125s. Abstract 3020
. Cohen EE, Moshier K, Innocenti F, et al. Phase I study of rapamycin in combination with CYP3A4 modifier, ketoconazole, in patients with advanced malignancies. Proc Am Soc Clin Oncol. 2006;24:136s. Abstract 3061.
Zafar Y, Bendell J, Lager J, et al. Preliminary results of a phase I study of bevacizumab in combination with everolimus in patients with advanced solid tumors. Proc Am Soc Clin Oncol. 2006;24:145s. Abstract 3097.
Sosman JA, Flaherty K, Atkins MB, et al. A phase I/II trial of sorafenib with bevacizumab in metastatic renal cell cancer patients. Proc Am Soc Clin Oncol. 2006;24:128s. Abstract 3031.
Gao X, Reddy P, Dhanda R, et al. Cost-effectiveness of sorafenib versus best supportive care in advanced renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:242s. Abstract 4604.
Escudier B, Szczylik C, Demkow T, et al. Randomized phase II trial of the multi-kinase inhibitor sorafenib versus interferon in treatment-naive patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol. 2006;24:217s. Abstract 4501.
Eisen T, Bukowski RM, Staehler M, et al. Randomized phase III trial of sorafenib in advanced renal cell carcinoma: impact of crossover on survival. Proc Am Soc Clin Oncol. 2006;24:223s. Abstract 4524.
Ryan CW, Goldman BH, Lara Jr PN, Beer TM, Drabkin HA, Crawford E. Sorafenib plus interferon--alpha2b as first-line therapy for advanced renal cell carcinoma: SWOG 0412. Proc Am Soc Clin Oncol. 2006;24:223s. Abstract 4525.
Dhanda R, Gondek K, Song J, Cella D, Bukowski RM, Escudier B. A comparison of quality of life and symptoms in kidney cancer patients receiving sorafenib versus placebo. Proc Am Soc Clin Oncol. 2006;24:225s. Abstract 4534.
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol. 2005;23:380s. Abstract LBA4510.
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Tamaskar I, Shaheen P, Wood L, et al. Antitumor effects of sorafenib and sunitinib in patients with metastatic renal cell carcinoma who had prior therapy with anti-angiogenic agents. Proc Am Soc Clin Oncol. 2006;24:240s. Abstract 4597.

Phase 3 trial of everolimus for metastatic renal cell carcinoma

Source: Cancer

  1. Robert J. Motzer MD1,*,§,
  2. Bernard Escudier MD2,
  3. Stephane Oudard MD, PhD3,
  4. Thomas E. Hutson DO, PharmD4,
  5. Camillo Porta MD5,
  6. Sergio Bracarda MD6,
  7. Viktor Grünwald MD7,
  8. John A. Thompson MD8,
  9. Robert A. Figlin MD9,
  10. Norbert Hollaender PhD10,
  11. Andrea Kay MD11,
  12. Alain Ravaud MD, PhD12,
  13. for the RECORD-1 Study Group

Article first published online: 19 AUG 2010

DOI: 10.1002/cncr.25219

BACKGROUND:

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.

METHODS:

Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus.

RESULTS:

The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio , 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).

CONCLUSIONS:

These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib. Cancer 2010. © 2010 American Cancer Society.


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