MSKCC Risk Group Research Articles

Targeted Therapy in Metastatic Renal Cell Carcinoma

Purpose: To evaluate the efficacy and safety of targeted therapy in patients with metastatic renal cell carcinoma. Materials and Methods: In this retrospective analysis, 43 consecutive patients with metastatic renal cell carcinoma received targeted therapy between December 2005 and December 2007. All patients underwent radical nephrectomy. Twenty-two patients received targeted therapy as a first-line treatment and 21 as a second-line treatment. Results: The median follow-up duration after radical nephrectomy and after the initiation of targeted therapy was 87 and 14 months, respectively. The initial response rate was 74.4% (partial response 37.2%, stable disease 37.2%) and the last response rate was 34.9% (partial response 4.7%, stable disease 30.2%). The median survival was 17 months (95% confidence interval (CI), 11.6-22.4) and the median progression-free survival was 10 months (95% CI, 7.5-12.5). Eleven patients (50%) with synchronous metastasis and 3 (14.3%) with metachronous metastasis died from renal cell carcinoma (p=0.023), but there was no significant difference in terms of median survival (15 months vs. longer than 14 months, p=0.210). Also, there was a significant difference in the overall mortality of the MSKCC risk groups (13.3% vs. 44.4%, p=0.049), but no significant difference in median survival (longer than 14 months vs. 15 months, p=0.236). Conclusions: Targeted therapy shows promising clinical activity in patients with metastatic renal cell carcinoma. Time to metastasis and MSKCC risk group may be associated with overall survival, and the prognostic implications of those factors should be analyzed in further prospective studies. (Korean J Urol 2009;50:1-5)

Pre-treatment global quality of health predicts progression free survival in metastatic kidney cancer patients treated with sorafenib or sunitinib

Our goal was to prospectively evaluate self-reported quality-of-life (QoL) during second-line therapy in 51 consecutive patients with cytokine-refractory kidney cancer treated with sorafenib or sunitinib. QoL was assessed by the EORTC QoL questionnaire QLQ-C30 at baseline and at weeks 4, 6, 10, 12 and 16. Global QoL deteriorated significantly during the first 4 weeks of treatment (P < 0.0001). Patients experienced a reduction of their role, cognitive, and social function (all P < 0.0001). In addition, fatigue (P < 0.0001), nausea/vomiting (P = 0.003), and pain (P < 0.0001) as well as dyspnoea (P < 0.0001), insomnia (P = 0.026), appetite loss (P = 0.013), and diarrhoea (P < 0.0001) increased significantly. After 16 weeks, fatigue (P < 0.0001), pain (P = 0.015), appetite loss (P = 0.002) and diarrhoea (P = 0.038) were still influenced by the therapy, while all functional scales recovered. Global QoL at baseline was predictive of overall response (P = 0.006) and progression free survival (PFS) (P < 0.0001). A better physical function at baseline, a better ECOG performance status, and a low risk profile according to MSKCC risk groups correlated with a longer PFS (all P < 0.0001). No significant differences regarding QoL were found between sorafenib and sunitinib during the study period. Second-line therapy with sorafenib or sunitinib does not adversely affect patients global QoL after 16 weeks of treatment. Evaluation of baseline QoL can help to further stratify patients into risk groups predicting overall response and PFS.

Then and now: The effect of tyrosine kinase inhibitors on survival in patients with metastatic renal cell carcinoma in Alberta, Canada

16033 Background: Tyrosine kinase inhibitors (TKIs) improve progression free survival in both first line (sunitinib) and second line (sorafenib) treatment of metastatic renal cell carcinoma (mRCC). We performed a Retrospective Population based study to assess the impact of TKIs on overall survival (OS) in patients (pts) treated for mRCC in Alberta, Canada. Methods: 130 pts were identified who commenced either sorafenib, or sunitinib between December 2003 and June 2007 for mRCC at one of two referral cancer centres in Alberta. Survival was compared to that of an earlier cohort of 141 pts treated with Interferon α (IFN) at the same centres between May 1995 and March 2003. Data was collected enabling stratification into risk categories according to the MSKCC prognostic model. The primary endpoint was OS measured from date of commencement of TKI in the recent cohort, and IFN in the earlier cohort. The Kaplan Meier method was used to determine OS, with Cox Regression analysis used to determine hazard ratios (HR) and confidence intervals (CI). Results: Of the 130 pts treated with a TKI, 78 received treatment in the first line setting, whereas 52 received treatment after prior IFN therapy. All 141 pts from the IFN cohort received treatment in the 1st line setting. Patients treated on TKIs had an improved OS compared with the earlier IFN cohort with a HR of 0.621 (95% CI .45–.857, p=0.004). Median OS was 16.5 months and 10.2 months, respectively. There was no significant impact on OS based on whether the TKI was received after prior IFN therapy or in first line (HR .774, 95% CI .451–1.327, p=.351). Survival according to MSKCC risk groups is outlined in Table 1. Factors associated with improved survival on multivariate analysis were treatment with a TKI, time between diagnosis and treatment greater than 12 months, LDH ≤ 1.5 ULN, normal Hb, normal corr. Ca++ and Karnofsky PS ≥80%. Conclusions: TKIs improve OS compared with IFN in mRCC with significant benefits in favourable and intermediate risk groups. Risk Group No. pts TKI/IFN HR 95% CI P value Favourable 46/21 .311 .115-.84 .021 Intermediate 45/66 .559 .332-.94 .028 Poor 28/25 .814 .46-1.442 .559 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Pfizer Oncology Pfizer Oncology

Sunitinib malate (SU) plus interferon (IFN) in first line metastatic renal cell cancer (mRCC): Results of a dose-finding study

5101 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs with anti-tumor activity in mRCC patients previously treated with cytokines (JAMA, 2006;295:2516). A phase 3 randomized trial showed superiority for SU over IFN in first-line mRCC (PROC ASCO 24,18S, 2006). Dose and safety for SU combined with IFN was investigated in this phase I trial. Methods: Patients (pts) with previously untreated clear-cell mRCC received SU in repeated 6-week cycles of 50 or 37.5 mg/day orally for 4 weeks, followed by 2 weeks off treatment. IFN was given continuously, starting at 3 MU SC 3x/week with intrapatient dose escalation weekly as tolerated, to a maximum of 9 MU. Pts not tolerating a dose combination received lower doses of SU or IFN, or had dose interruptions. Doses of SU plus IFN were considered tolerable if = 4/6 pts completed 2 cycles without dose reduction or interruption. Results: 25 pts were enrolled; 19 are evaluable for safety/response. 6 pts who started treatment at 37.5 SU and 3 MU IFN are too early. The median age of the 19 pts (16 M: 3 F) was 63 years (range 45–77). MSKCC risk group (JCO 20:289–96, 2002) was 37% good and 63% intermediate. 12 pts started treatment with SU 50 mg and dose escalated IFN to 6 or 9 MU TIW. 13 pts started treatment with SU 37.5 mg and dose escalated IFN at 3 MU or to 6 MU TIW. 4 of 19 pts tolerated two cycles. 68% of pts had dose interruptions of SU; 90% of pts had dose interruptions of IFN. 15/19 pts had grade 3 toxicity, 1 pt had grade 4 hypertension and 1 pt grade 5 toxicity (myocardial infarction). Most common grade 3 toxicities were neutropenia (26%), fatigue (26%), and hand-foot syndrome (16%). Although response was not a primary endpoint, at a median of 3 cycles, there were 2 PR, 14 SD, 2 PD and 1 pt was not evaluable. Conclusions: The adverse events seen with combination SU and IFN in mRCC, neutropenia and fatigue, were similar to those seen with single agent SU and IFN, and resulted in frequent dose modifications and interruptions. The safety and efficacy of 37.5 mg sunitinib and 3 MU IFN is being evaluated. No significant financial relationships to disclose.

Sequential use of sorafenib and sunitinib in renal cancer: Retrospective analysis in 90 patients

5038 Background: Sorafenib (So) and sunitinib (Su) have been recently approved for the treatment of advanced renal cell carcinoma (RCC). Following this approval, sequential use of both drugs is often proposed, although very few data are available to support it. Material and Methods: We reviewed all patients (pts) who received sequentially So-Su or Su-So in the last 3 years from 4 sites in France. All pts had been enrolled in clinical studies or in the extended access programs. In all patients demography, prognostic factors (MSKCC score), number of metastatic sites, best response (BR) and PFS with each treatment were recorded. Some patients are still too early for response and PFS assessment under the second treatment. Results: 68 pts first received So while 22 pts received Su first (continuous dosing in 12, intermittent in 10). Results under the first treatments were as follows: median PFS 26.1 wks, mean duration of treatment 33.2 wks; and median PFS was 22 wks, mean duration of treatment 26.9 wks for So and Su respectively. BR in terms of partial response (PR), stable disease (SD), progressive disease (PD) is given in the table . 2 pts stopped So because of toxicity and response is not available (NA), and 22 pts (NE) are too early in the course of the second treatment. Overall, PR rate was 17.6% for So and 22.7% for Su. PR or SD was observed as best response in the second treatment in both sequences. Only 6 pts had PD with both drugs: all of them had 3 or more metastatic sites and were in intermediate or poor MSKCC risk groups. Conversely, 4 pts had PR with both drugs, and were in good (n=2) or intermediate (n=2) risk groups. 11 pts only have died so far. Conclusions: these results suggest the lack of cross resistance between So and Su, and support the sequential use of So and Su in RCC. Updated data will be presented at ASCO. [Table: see text] No significant financial relationships to disclose.

Pegylated interferon alpha-2B (PEG-Intron) for metastatic renal cell cancer (mRCC): Results of a phase II clinical trial and biologic correlates of response

4528 Background: PEG-Intron (PEG-I) is a pegylated derivative of interferon alpha-2b (IFN), recombinant, with a single molecule of mono methoxy polyethylene glycol which increases serum half-life. Methods: A single arm, one-stage phase II trial was conducted between 6/02 and 6/04 in 32 previously untreated patients (pts) with mRCC to assess time to progression and biologic correlates (primary and secondary endpoints). Eligibility included measurable disease and fresh tumor procured at surgery for genetic and immunohistochemical (vascular endothelial growth factor [VEGF] and carbonic anhydrase IX [CAIX]) studies. PEG-I was given SC at a weekly dose of 4.5 μg/kg until progression or intolerability. Quality of life (QOL) was assessed using the FACT-BRM. Results: All 32 were evaluable, 91% had prior nephrectomy, and MSKCC risk group (JCO 20:289–96, 2002) was: 41% good, 53% intermediate, 6% poor. 10 pts (31%; 95% CI: 16%-50%) achieved a partial response (PR). Median time to progression was 5.0 mos (95% C.I. [3, 7]); median survival was 31 mos (95% C.I. [18, not reached]). There were no grade IV toxicities; primary grade III toxicities were hematologic (6/32 pts; 19%) and fatigue (4/32 pts; 13%). FACT-BRM scores showed an initial decrease in QOL at 2 weeks followed by partial recovery. Genomic profiling of tumor samples identified four novel genes that correlated with IFN resistance: ABCD3, Hs.76704, Hs.11325, and Hs.94122. Change in serum VEGF levels did not correlate with response. Tumor tissue samples are being immunohistochemically stained for CAIX. Conclusions: PEG-I treatment results in a 31% response rate and similar median time to progression as standard IFN (JCO 18:2972–80, 2000) in this population with predominantly good and intermediate risk pts. Once weekly dosing was generally well tolerated. Future investigation of PEG-I in combination with novel targeted agents in mRCC is warranted. Further study of the four identified genes may provide insight into IFN resistance. Supported by Schering-Plough, Inc. [Table: see text]