With seven targeted therapies approved for metastatic renal cell carcinoma, researchers and drug developers are now focusing on understanding the best way to sequence these therapies and on identifying predictive biomarkers of response.
Jenny J. Kim, MD
Assistant Professor, Oncology
The Sidney Kimmel Comprehensive
Johns Hopkins Medicine
Brian I. Rini, MD
Associate Professor, Medicine
Cleveland Clinic Lerner College of Medicine
Department of Solid Tumor Oncology
Taussig Cancer Institute
Case Western Reserve University
With seven targeted therapies approved for metastatic renal cell carcinoma (RCC), researchers and drug developers are now focusing on understanding the best way to sequence these therapies and on identifying predictive biomarkers of response.
Five of these agents are oral and fall into two categories: multityrosine kinase inhibitors against vascular endothelial growth factor (VEGF) or inhibitors of the mammalian target of rapamycin (mTOR). Based on recent large phase III randomized clinical trials, two VEGF inhibitors are now the standard of care for first-line RCC.
Sunitinib was among the first VEGF inhibitors approved for RCC and is still widely used as a result of strong clinical data showing greater progression-free survival (PFS) and overall survival (OS) in treatment-naïve patients compared with interferon alfa (IFN-α).1 The second widely used oral VEGF inhibitor is pazopanib; studies have demonstrated that pazopanib improved PFS in treatment- naïve metastatic RCC compared with placebo.2 The recent phase II RECORD-3 trial3, comparing first-line everolimus, an mTOR inhibitor, followed by sunitinib to the reverse sequence, showed that treatment with sunitinib first produced longer PFS for patients.
The COMPARZ trial,4 reported at the 2012 annual European Society for Medical Oncology (ESMO) Congress in Vienna, Austria, directly compared the efficacy of pazopanib to sunitinib in patients with metastatic, treatment-naïve RCC. While both drugs demonstrated similar efficacy (31% overall response rate in the pazopanib arm vs 25% in the sunitinib arm; 28.4 months OS in pazopanib arm vs 29.3 months in sunitinib arm), patients perceived pazopanib to have a better side-effect profile compared with sunitinib. Patients on pazopanib had less hematological toxicity, hand-foot syndrome, rash, fatigue, and peripheral edema.
From the experience at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Jenny J. Kim, MD, assistant professor of Oncology, said that both sunitinib and pazopanib are being used in the frontline setting for these patients, although these agents have slightly different side-effect profiles. Kim and her colleagues have noticed that in their experience, patients tend to have more hand-foot syndrome and stomatitis with sunitinib and more liver toxicity with pazopanib. With the approval of pazopanib in 2009, it has been well incorporated along with sunitinib into the gastro-urology practice at Johns Hopkins in the treatment of metastatic RCC.
“There is a trend toward favoring pazopanib recently,” said Kim. “This is most likely due to a lack of hand-foot syndrome, which seems to affect patients’ day-to-day quality of life.” This observation in clinical practice is consistent with what was seen in the COMPARZ trial.
It is important to mention, Kim noted, that discontinuation rates were similar for both sunitinib and pazopanib in the study, although patient subjective toxicity experience was better with pazopanib.
One potential explanation may be that there were higher liver toxicities with pazopanib compared with sunitinib, which led to discontinuation of pazopanib in the trial.
Another small, 168-patient study, the PISCES trial,5 reinforced the COMPARZ trial data, showing that 70% of patients on the trial preferred pazopanib while 22% preferred sunitinib. “While these trials are not perfect, they will likely have an impact on the oncologic community as more ‘tangible’ data comparing the two agents,” said Kim.
Although second-line and subsequent therapies become gradually less effective, axitinib, sorafenib, and everolimus are all options for second-line therapy. “The only drug that has been tested exclusively in a second-line setting is axitinib,” said Brian I. Rini, MD, an associate professor of Medicine at the Cleveland Clinic Lerner College of Medicine and a practicing oncologist at the affiliated Taussig Cancer Institute. Axitinib is a VEGF inhibitor approved for metastatic RCC after failure of one systemic therapy; approval was based on the AXIS trial.6 For patients who had previously failed sunitinib, axitinib significantly delayed PFS for 2.6 months longer compared with sorafenib.
“Clinical trials point to the importance of clinicians to maximize each oral targeted agent and to expose patients to multiple drugs over the course of metastatic disease,” said Rini. When to switch a patient’s therapy in the clinical setting remains a challenge, as the timing of the switch from one therapy to another has not been formally tested. Unfortunately, a specific and potent sequencing regimen probably does not exist with the current drugs we have, said Rini.
According to Kim, all of these agents are being used in the second-line setting because there is a lack of complete cross-resistance among these agents. “At this point, without robust biomarkers of response, exposure to all different agents is probably key for the patients’ best clinical outcome,” said Kim.
The recently announced phase III INTORSECT trial7 compared temsirolimus, an mTOR inhibitor administered as intravenous infusion, with sorafenib, an oral VEGF inhibitor, in patients previously treated with sunitinib. Although there was no difference in PFS, patients on sorafenib had a longer OS compared with those on temsirolimus.
“This result raises a major question,” said Kim. “Is PFS a valid endpoint for these trials, or should we be using OS as a better measure of efficacy?”
The FDA used PFS as a yardstick for approving bevacizumab in combination with IFN-α for metastatic RCC in 2009, based primarily on the results of the BO17705 trial.8 The bevacizumab regimen demonstrated a median PFS of 10.2 months versus 5.4 months for IFN-α2 (HR = 0.60 [95% CI, 0.49-0.72]; P <.0001), but no statistically significant increase in OS. Bevacizumab, a VEGF inhibitor, also is administered via intravenous infusion.
The checkpoint inhibitors currently in development are clearly promising, according to Rini. “These are the next wave of effective kidney cancer therapies,” he said. Rini also said the effectiveness of anti-VEGF therapy may have reached a plateau, and that the development of the immunotherapy checkpoint antibodies are revitalizing kidney cancer research, providing patients with a chance at durable, potentially long-term responses
Results from a phase I trial with the anti-PD-1 antibody nivolumab (BMS-936558) show that the immunotherapy can produce responses in approximately 30% of heavily pretreated patients, and that the responses are durable.9 Nivolumab is now being tested in a phase III trial in pretreated advanced or metastatic RCC.10 Two other immunotherapy checkpoint agents, MPDL3280A and MK-3475 (previously known as lambrolizumab), are currently in phase I trials for solid tumors. “There have been great results so far with nivolumab,” said Kim.
Although most combinations of targeted agents have proved to be disappointing either due to toxicity or lack of improved efficacy, checkpoint inhibitors may provide renewed promise in combinatorial efforts, according to Kim.
“Within the last decade, we have almost tripled the lifespan of metastatic RCC patients,” said Kim. The checkpoint inhibitors now have the potential to turn kidney cancer into a chronic disease, she said.
The next questions for both the newer immunotherapies and oral targeted drugs are how to best identify patients who are most likely to respond. There are no biomarkers yet, but intensive research to identify them is under way.