Update on the Management of Genitourinary Malignancies: A Report from the 2007 Annual Meeting of the American Society of Clinical Oncology (ASCO)
Kidney cancer, the orphan disease that had only one approved therapy for 15 years, once again this year stole the genitourinary(GU) limelight. Interferon, the drug that although not approved for kidney cancer was the most prescribed therapy for this disease prior to the recent approval of several targeted therapies, had been virtually abandoned. It now appears to be a retread. Of particular note, although, no longer headline news, longer follow-up on previously presented trials in metastatic renal cell carcinoma (mRCC) and results of expanded access programs for sunitinib and sorafenib provided very useful clinical information for the practicing oncologist.
At this year’s Plenary Session, Dr. Escudier presented the initial results of the AVOREN trial, an international randomized, double-blind Phase III study of bevacizumab/interferon-alpha-2a versus placebo/interferon-alpha-2a as first line therapy in mRCC. In this trial, 649 patients with untreated clear cell RCC were treated with either interferon at a dose of 9 MU TIW or the same dose of interferon plus bevacizumab 10mg/kg given intravenously every 2 weeks. Response rates were more than doubled (31% vs. 13%) and progression free survival (PFS) was significantly prolonged (5.4 vs. 10.2 months) for the combination compared to interferon alone. There was also a trend favoring improved survival in the combination arm; however, the median overall survival has not yet been reached for the combination. Good and intermediate risk patients, based on the Memorial Sloan Kettering Cancer Center (MSKCC) criteria, had improved PFS with the combination, however, there was no increased benefit in poor-risk patients.
The updated results of sunitinib versus interferon in untreated patients with good and intermediate risk renal cell carcinoma were also updated and allow an interesting comparative assessment of effectiveness., The PFS with interferon in both trials was similar for the interferon arm (4.1 and 5.4 months, respectively). On the other hand, the PFS was also similar in the alternate arm. The PFS for the sunitinib arm was 10.8 months and for the interferon plus bevacizumab arm it was 10.2 months. This puts the clinician equipoised between using either interferon plus bevacizumab or sunitinib as first-line therapy for untreated good or intermediate risk patients with mRCC with equally anticipated benefit. It also sets the background for a clinical trial in mRCC comparing sunitinib versus sunitinib plus bevacizumab versus bevacizumab plus interferon. These drugs have very different toxicities as well as route of administration and in the interim will require the treating physician to consider all of these issues prior to recommending a particular therapy.
Longer Follow-up Confirms Earlier Results But with Some New Twists
The final results from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) were presented and again confirmed a survival benefit for sorafenib compared to placebo in low and intermediate risk patients with clear cell renal cell carcinoma failing front-line therapy. The overall survival benefit of 3.5 months (17.8 versus 14.3 months) remained significant (p=.027) when patients who received placebo and crossed over to sorafenib (48% of patients on the control arm) were censored at time of crossover. The only new information to emerge was from the correlative science. High serum vascular endothelial growth factor (VEGF) levels are an independent predictor of poorer survival. However, patients with both high or low levels of VEGF responded equally to sorafenib.
A Little More May Get You a Little Longer and a Little Better
Several papers presented emphasized the potential benefit of dose escalation of sorafenib or sunitinib. In a randomized Phase II trial of sorafenib versus interferon in previously untreated patients, patients progressing on the usual dose of 400 mg twice a day had their dose increased to 600 mg twice a day.For these 44 patients, tumor shrinkage was documented in 44% and stable disease in 46% with a delay in progression of 4.1 months and improved quality of life. In a second trial of intra-patient dose escalation, sorafenib doses were step wise increased from 800 mg daily to 1200 mg and then 1600 mg daily.Ninety-three percent of patients were able to tolerate dose escalation with early toxicity predicting an inability to dose escalate. With longer time on treatment, patients became more tolerant with less toxicity. The complete and partial response rate of 55% is higher than what has been reported with standard dose sorafenib. Among the patients with prior cytokine therapy, the response rate was 43%. Similarly, in a presentation on sunitinib pharmacokinetics, the probability of a complete or partial response increased with the higher daily sunitinib exposure such that a 4-fold increase in the area under the curve (AUC) resulted in a 4-fold increase in response and both improved time to progression and overall survival. These studies emphasize the need to maintain the highest possible dose. Patient awareness that a lower dose may be less effective may encourage them to be more tolerant of toxicity.
Lessons Learned from the Expanded Access Programs
Table 1: Sorafenib and Sunitinib: Expand Access Program Trial Results:
These expanded access programs provide very useful information in terms of the patients encountered in clinical practice. Patients with brain metastases achieved similar benefit and there were no CNS-related bleeding events. Responses were similar in patients with chromophobe and papillary histology. In the sorafenib program, of the 118 patients with papillary carcinoma treated, there were 4 partial responses and 91 patients with stable disease for an overall clinical benefit rate of 80%. Similarly for the 18 patients with chromophobe histology, there was 1 partial response and 16 patients with stable disease for a clinical benefit rate of 95%. Response rates to sunitinib were similar for clear cell and non clear cell, but are lower than reported in earlier clinical trials. Patients over age 65 and with poor performance also had similar benefit. The toxicities were as previously reported with these drugs, primarily consisting of hypertension, fatigue and diarrhea.
Choosing the Right Treatment Based on the Setting and Prior Therapy
Dr. Ronald Bukowski, in his discussion of the AVOREN trial at the Plenary Session as well as in an earlier educational session on targeted therapy for mRCC provided a mRCC, presented a treatment algorithm for 2007, shown in the table below. Recommendations are based on prior therapy and risk category based on the previously published MSKCC criteria. The original five risk factors included in this predictive model were hypercalcemia, Karnofsky performance status <80, no prior nephrectomy, anemia, and an elevated LDH level. Good risk was defined as no risk factors, intermediate risk as 1 or 2 risk factors and poor risk as 3 or more risk factors. An updated nomogram for predicting PFS was presented by Dr. Motzer using data generated from the sunitinib versus interferon trial.[(http://news.cancerconnect.com/update-on-the-management-of-genitourinary-malignancies/#_ftn14 "_ftnref14")] The risk factors identified are hypercalcemia, number of sites of metastatic disease, ECOG performance status __>__1, no prior nephrectomy, time from diagnosis less than 1 year, elevated LDH level and thrombocytosis.
Table 2: mRCC treatment algorithem
Several abstracts presented at ASCO demonstrate that responses can be seen to targeted agents given before or after other targeted agents, but the ideal sequence is not known. This renders support for a current sequencing trial known as START, where the sequence of the 3 drugs (sunitinib, bevacizumab and temsorilimus) changes to determine if there is an impact on PFS and overall survival. Also presented at this meeting were several targeted therapy combination studies, with no clear winner emerging in terms of response, but as expected more toxicity. This again supports the BEST intergroup study, which is a randomized Four arm trial of bevacizumab vs. temsorilimus/bevacizumab vs. sorafenib/bevacizumab vs. sorafenib/temsorilimus. Patients may have had one prior cytokine.
Emerging Therapeutic Approaches for Kidney Cancer
Other promising new drugs for advanced kidney cancer reported at this meeting included pazopanib (GW786034) and axitinib (AG013736), both tyrosine kinase inhibitors (TKIs) of the VEGF and platelet derived growth factor (PDGF) receptors. In the preliminary analysis of a Phase II trial of pazopanib, the independently reviewed response rate at week 12 was 27% with a disease control rate (partial response plus stable disease) of 73%. One-third of the patients had failed a prior therapy. The most common drug related adverse events were diarrhea, hair color changes, hypertension, nausea and fatigue. A Phase III trial of pazopanib in advanced renal cell carcinoma has completed enrollment.
Axitinib was assessed in 62 patients with mRCC who had failed a sorafenib-based therapy. Multiple prior regimens were allowed. Partial response and stable disease were achieved in 21% and 34% of patients, respectively. The toxicity profile was typical of a VEGF receptor TKI.
A third new drug in advanced stage of development is the oral mammalian target of Rapamycin (mTOR) inhibitor, everolimus (RAD001). In a Phase II trial allowing up to two prior therapies, 12 of 37 (32%) patients achieved a partial response and 14 patients (38%) had stable disease as best response. This drug is in Phase III trials of everolimus vs. placebo in patients who have progressed on either sorafenib or sunitinib. It is a 2:1 randomization with crossover to active drug. Temsorilimus, a weekly administered intravenous mTOR inhibitor, was FDA approved just days prior to ASCO for the treatment of advanced renal cell carcinoma.
Bladder Cancer, Very Little to Crow about
There was only one oral presentation on bladder cancer, the EORTC/Intergroup Study 30987. This randomized Phase IIII trial demonstrated a greater response rate when paclitaxel was added to the standard doublet of gemcitabine/cisplatin (57% vs. 46% p = 0.02). However, the difference in overall median survival, 15 months with triple therapy and 12.8 months with the combination, was not significantly different (p = 0.10). On subset analysis, there was a survival benefit when the bladder was the primary tumor site, suggesting a potential benefit for triple therapy in patients subsequently treated with surgery. Compared to gemcitabine/cisplatin, triple therapy was associated with more febrile neutropenia (13% vs. 4%) and less thrombocytopenia and bleeding (7% vs. 11%).
Shorter Course Hormonal Therapy not Supported in Localized Prostate Cancer
Dr. Bolla presented the initial results of the randomized EORTC Phase III trial of 6 months versus 3 years of androgen deprivation therapy in combination with external beam radiation for locally advanced prostate cancer. This trial of 970 men with predominantly stage T3 disease was designed to be an equivalency trial. On an ad hoc interim analysis, biochemical PFS was 59% in the 6 month arm compared to 78% in the 36 month arm (p<.0001, HR 2.29). Median overall survival at 5 years was 80.6% for the shorter duration group and 85.3% for the 36 month arm (HR 1.43). There was no difference in quality of life. The authors concluded appropriately that the longer duration androgen deprivation therapy should remain the standard of care.
Effective Second-Line Therapy for Hormone Refractory Prostate Cancer Emerges
To date, docetaxel is the only chemotherapy with a demonstrated survival benefit in hormone refractory prostate cancer (HRPC). Second-line chemotherapy for this disease state remains an unmet medical need. Satraplatin is an oral platinum compound which is currently under priority review at the FDA for this indication. Dr. Cora Sternberg presented the second Phase III trial of prednisone plus satraplatin or placebo. This randomized double-blind trial known as SPARC (Satraplatin and Prednisone Against Refractory Cancer) accrued 950 patients globally, half of whom had prior docetaxel. Compared to the placebo group, there was a highly significant 33% improvement in independently-assessed PFS (p <.0000003), the primary study endpoint. Improvement actually increased over time, such that at 6 months, 30% of patients taking satraplatin had no disease progression compared to 17% taking the placebo. At 12 months, 16% in the satraplatin arm had not progressed compared to 7% in the placebo arm. In addition to delay in PFS, the satraplatin-treated group had a 36% longer time to pain progression (39 vs. 24 weeks), a higher pain response rate (24% vs. 14%; p=0.005), a higher tumor response (6.5% vs. 0.6%; p=0.001), and higher prostate specific antigen (PSA) response rate (25% vs. 12%; p<0.001). Analysis of overall survival will require further follow-up. Satraplatin is well tolerated with the primary toxicity being myelosuppression. All patients received prophylactic antiemetics to avoid the anticipated nausea and vomiting. Unlike cisplatin, satraplatin is not associated with significant renal or neurologic toxicity.
A New Test to Predict Early Response in Hormone Refractory Prostate Cancer May be on the Horizon
Dr. Moreno presented an interesting study using circulating tumor cells (CTCs) to predict survival in men being treated for hormone refractory prostate cancer(HRPC). CTCs were measured using an automated sample processor at baseline, 2-5 weeks after start of treatment and then monthly for up to 18 months. Patients with baseline CTC counts > 5 versus < 5 had median overall survivals of 10.7 months and 21.4 months, respectively. For samples analyzed at 2-5 weeks after starting therapy, the median survival was 20.6 months if the CTC count was < 5 and 9.5 months if > 5. If the CTC count dropped to 0 with treatment, the median overall survival was 20+ months compared to 10 months if it remained > 1. CTC count predicted survival at all points in time. Compared to the predictive value of a decline in PSA level, CTC levels were more predictive and provided information much earlier in the patient’s treatment course. Although currently not recommended as an indicator for early treatment change decisions, the future potential use of CTC to direct care seems promising.
On the Horizon: Immunotherapy and HRPC
In a poster session, Dr. Gerritsen presented updated data on the Phase I trial evaluating dose-escalation of the combination of GVAX and ipilimumab. GVAX is an immunotherapeutic agent comprising whole tumor cells that include the two genetically modified, non patient-specific prostate cancer cell lines LNCap and PC-3. These cell lines contain many common antigens found in metastatic prostate cancer. The cells have been modified to secrete granulocyte macrophage colony stimulating factor (GM-CSF) to stimulate a systemic immune response to the antigens used in the cell lines. Ipilimumab is a fully human antibody that is targeted against the CTLA-4. CTLA-4 is a molecule present on T-cells that is thought to play a role in suppressing the body’s immune response.
This trial included 12 patients with HRPC and six of these patients were treated at the doses that proved to provide optimal results (3 and 5 mg) and are being used in the Phase III trials evaluating each agent separately. Of the 6 patients receiving optimal doses of therapy, 5 patients achieved at least a 50% reduction in prostate specific antigen (PSA) levels that lasted at least 2 months; 2 of these patients had a 95% reduction in PSA levels. Two responses are still ongoing with a median 18 month follow-up. Importantly, 3 of the 5 PSA responders demonstrated antitumor activity through improvement of multiple bone lesions as determined by bone scan, improvement of pain cause by bone metastases, and resolution of abdominal lymph node disease as determined by computed tomography (CT) scan. One patient had complete resolution of disease by CT scan. Sixty-six percent of the remaining patients who received GVAX plus lower doses of ipilimumab achieved disease stabilization as determined through PSA levels for at least two months. The main new finding in this study was that 5 of the 6 patients at the higher dose developed adrenal insufficiency and/or hypothyroidism requiring treatment. Other side effects occurring in more than 50% included fever, fatigue and anorexia.
The researchers concluded that the treatment combination including GVAX and ipilimumab appears promising in the treatment of HRPC. Future larger trials evaluating this combination and comparing it to other treatment options will help determine its true clinical utility for men with HRPC. GVAX is currently being evaluated in two Phase III trials, VITAL-1 and VITAL-2, and has recently received fast-track designation by the United States Food and Drug Administration (FDA).
ASCO 2007, for the most part, would be described as an interim year for genitourinary malignancies. At the end of this year’s conference there was elation over what seems like an abundance of current and future drugs for the treatment of advanced kidney cancer. There was also the sense of more questions than answers in terms of “best” combinations and “best” sequencing of these drugs. In the arena of prostate cancer, the clear headline story is satraplatin. Effective chemotherapy for HRPC has been very slow in coming. If improvement of PFS translates to improvement in overall survival, we will have a new standard of care for docetaxel-refractory patients.
1 Escudier B, Koralewski P, Pluznaska A, et al. Arandomized , controlled double-blinded phase III study of bevacizumab/interferon-alpha 2a versus placebo/interferon-alpha-2a as first line therapy in metastatic renal cell carcinoma. Journal of Clinical Oncology.2007; 25: 18S Part I of II, 3
4 Motzer RJ, Figlin RA, Hutson TE, et al. Sunitinib versus interferon-alpha (INF-a) as first-line treatment of metastatic renal cell carcinoma (mRCC): Updated results and analysis of prognostic factors. Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5024.
6. Bukowski RM, Eisen T, Szczylik C, et al. Final results of the randomized Phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis. Journal of Clinical Oncology.2007; 25: No.18S: Part I of II, 5024.
7 Szczylik C, Demkow T, Staehler M, et al. Randomized Phase II trial of fist-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results. Journal of Clinical Oncology.2007; 25: No. 18S Part I of II, 5025.
8. Amato RJ, Harris P, Dalton M, et al. A phase II trial of intra-patient dose-escalated sorafenib in patients with metastatic renal cell cancer. Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5026.
- Houk BE, Bello CL, Michaelson MD, et al. Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach. Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5027.
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12 Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, multitargeted inhibitor of vascular endothelia growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology. 2006; 24:16-24.
13. Sablin MP, Bouaita L, Balleyguier C, et al. Sequential use of sorafenib and sunitinib in renal cell carcinoma: Retrospective analysis in 90 patients. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Vol 25, No. 18S Part I of II, 2007:5038.
15Hutson TE, Davis ID, Machiels JP, et al. Pazopanib (GW786034) is active in metastatic renal cell carcinoma: interim results of a phase II randomized discontinuation trial. Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5031.
16. Rini BI, Wilding G, Hudes G, et al. Axitinib (AG-013736) in patients with metastatic renal cell carcinoma refractory to sorafenib. Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5032.
18. Belmunt H, von der Masse, Mead GM, et al. Randomized Phase III study comparing paclitaxel/cisplatin/gemcitabine (PCG) and gemcitabine/cisplatin (GC) in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy (EORTC30987/Intergroup study. Proceedings from American Society of Clinical Oncology Conference. Chicago, IL. 2007. LBA #5030.
19.Bolla M, van Tienhoven G, de Reijke TM, et al. Concomitant and adjuvant androgen deprivation therapy (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT-Results of the randomized EORTC phase III trial 22961. Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5014.
20.Sternberg CN, Petrylak D, Witjes F, et al. Satraplatin demonstrates significant clinical benefit for the treatment of patients with HRPC: Results of a randomized phase III trial. Journal of Clinical Oncology.2007; 25: No. 18S Part I of II, 5019.
21Moreno J, DeBono JS, Shaffer B, et al. Multi-center study evaluating circulating tumor cells (CTCs) as a surrogate for survival in men treated for castration refractory prostate cancer (CRPC). Journal of Clinical Oncology. 2007; 25: No. 18S Part I of II, 5015.
22 Gerritsen W, Van Den Eertwegh A, De Gruijl T, et al. Biochemical and immunologic correlates of clinical responses in a combination trial of the GM-CAS-gene transduced allogeneic prostate cancer immunotherapy and ipilimumab in patients with metastatic hormone-refractory prostate cancer (MHRPC). Proceedings from the 43rd annual meeting of the American Society of Clinical Oncology. Chicago, IL. 2007. Abstract #5120.