Newly developed targeted agents in the management of advanced renal cell carcinoma have given us treatment options in this disease not imagined a decade ago.
Newly developed targeted agents in the management of advanced renal cell carcinoma have given us treatment options in this disease not imagined a decade ago. Our work in the laboratory and in clinical trials in RCC is fostering a new era of individualized therapy based on the molecular biology of the patient's underlying tumor. The advent of these new agents has clearly resulted in improved progression-free survival rates, but these advances have been met with continuing challenges. At this year's ASCO meeting, several interesting presentations and abstracts illustrated the progress and the depth of ongoing scientific research being done in metastatic RCC.
D. F. McDermott, MD, presented for his co-investigators on the results of the SELECT trial, pointing out that aldesleukin (HD IL-2) was approved in 1992 for treating patients with metastatic renal cell carcinoma (RCC) when a series of phase II trials showed a 14% response rate with durable responses in a small percentage of select patients. However, over the years the significant toxicity, the rising costs, and the limited availability of this approach have narrowed its application to only a handful of patients at a few select centers.
The fundamental question in the SELECT trial was: Can we pick likely responders before we begin IL-2 therapy? Dr. McDermott noted that several retrospective analyses suggested that clinical characteristics and tumor features could predict for benefit, which include: UCLA SANI Score; clear cell histology, and carbonic anhydrase 9 (CA-9). The current trial was initiated to improve the therapeutic index of HD IL-2.
Dr. McDermott said that the primary endpoint of the trial was to prospectively determine if the response rate to HD IL-2 in metastatic RCC patients with good pathological predictive features was significantly higher than a historical, unselected population. Dr. McDermott listed the secondary endpoints of the trial as: to prospectively determine the response rate in patients with poor pathologic features, to determine if other predictive and prognostic models could help define the optimal patient population for HD IL-2 therapy, and to confirm the predictive value of factors associated with response to immunotherapy in other retrospective trials.
In this multicenter, prospective study, patients with histologically confirmed RCC metastatic or unresectable, measurable disease, age ? 18 years, ECOG PS 0-1 and adequate organ function received HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 (maximum 28 doses) every 12 weeks.
Dr. McDermott reported that the response rate to HD IL-2 in the SELECT trial was higher than the historical experience. Moreover, clear cell histology may select patients who respond to IL-2. And analysis of tumor (central pathology review and staining for CAIX) failed to show predictive capability for CAIX staining or further improve the selection criteria for HD IL-2 in patients with metastatic RCC.
In the analysis of renal cell carcinoma (RCC), Brian I. Rini, MD, provided preliminary data that may support the use of gene expression to predict recurrence-free interval (RFI) for patients with localized clear cell RCC. In a prospectively defined, observational investigation, Dr. Rini reported on a genomic study that considered whether genomic markers in RCC might be able to accurately predict RFI, much like the 70-gene or 21-gene signature used in clinical practice for breast cancer.
This study from the Cleveland Clinic examined archived paraffin-embedded tissue samples from 931 patients with clinical and pathologic data. Looking at the RNA expression for 732 candidate genes that represented major pathways implicated in cancer progression, Dr. Rini and colleagues narrowed the prognostic gene number first to 448 genes and then to 300 genes.
Finally, in a multivariate model, 29 genes remained associated with RFI after adjustment for false discovery and clinical/pathologic variables. Tumors of patients with a low risk of recurrence are characterized by an increased expression of angiogenesis and hypoxia-associated genes (as compared with high-risk tumors) and increased expression of cell-mediated cytotoxic response genes. Tumors with a high risk of recurrence are characterized by high expression of interleukin (IL)-6 and IL-8, high expression of cell cycle genes and invasion genes (as compared with tumors with a low risk of recurrence).
According to Dr. Rini, this study shows that molecular information can be added to clinical information in determining RFI for patients with RCC. These data can ultimately be used to more precisely estimate an individual patient's recurrence risk, risk stratify for adjuvant therapy trials, and ultimately predict treatment benefit in the adjuvant and/or metastatic setting.
The session led by Christopher W. Ryan, MD was an overview of the clinical management opportunities we have for the treatment of advanced renal cell carcinoma (mRCC) according to 2010 data. He pointed out that prior to 2005 the only FDA-approved drug for the treatment for mRCC was Interleukin-2, and in the past 5 years FDA has approved six new agents (VEGF and mTOR inhibitors), including three in 2009 alone.
Of the seven FDA-approved agents for the treatment of mRCC, six have received a general indication either for "advanced" or metastatic disease, without reference to line of therapy or a specific patient population. Only everolimus has been approved for use in a specifically defined population. According to Dr. Ryan, this leaves the clinician with the daunting challenge of picking the "right" therapy for any particular patient. He noted that the rapid development of these therapies has outpaced our knowledge on how to best use them in the clinic.
Dr. Ryan broke the seven agents approved for mRCC into their respective groups: Immune modulators (Aldesleukin [IL-2]); VEGF-receptor tyrosine kinase inhibiting agents (sorafenib, sunitinib, pazopanib), Anti-VEGF agents (bevacizumab), and mTOR inhibitors (temsirolimus, everolimus). He noted that all seven agents were studied in phase III trials, compared with either placebo or interferon, and that across the board all of the agents showed progression-free survival benefit. On the other hand, proving overall survival benefit has been more elusive, with only one agent, temsirolimus, technically meeting its statistically significant goal, with a P value of .008.
Dr. Ryan added that all of the agents; however, showed a trend toward improving overall survival. He posited that the failure of these agents in meeting overall survival criteria might be due to the fact that most of the studies had built-in cross-over, allowing these patients to cross from the control to the experimental arm upon progression.
After reviewing the data on the seven agents approved for mRCC and several treatment decision algorithms, Dr. Ryan concluded that there are no inherently ‘wrong' therapeutic choices for clinicians. For now, the choice of first-line therapy needs to be based on existing data, and physicians should chose a therapy that best addresses a combination of the patient's clinical conditions, any medical co-morbidities, and the patient's attitude toward risk.
Dr. Ryan also stressed that randomized trials currently underway will provide important comparative data to aid in treatment decisions moving forward. Further study of host and tumor biology may yield molecular phenotypes associated with response to specific molecularly targeted agents. This evolution will undoubtedly lead to more rational use of the many targeted therapies currently being administered in an untargeted manner in patients with mRCC.