Combination therapy using targeted agents is a promising yet elusive target in renal cell carcinoma, but questions about toxicity and benefits versus monotherapy have been raised in other studies.
Multiple targeted agents have been approved by the FDA in recent years, including sorafenib (Nexavar), sunitinib (Sutent), and temsirolimus (Torisel).
"There have been multiple drugs with targeted activity that have moved the standard of care in the last four years," Dr. Motzer told the 2008 Genitourinary Cancers Symposium here. "There are more agents on the way."
The use of multiple agents is a common strategy used to target other cancers, Dr. Motzer said. Typical strategies combine different classes of agents, agents that target multiple pathways, or agents that target different steps in the same pathway. Potential classes of agents include VEGF inhibitors, epidermal growth factor receptor inhibitors, mTOR/akt inhibitors, and inhibitors of angiogenic escape mechanisms.
A number of agents show potential activity in advanced clear-cell RCC. Several compounds inhibit VEGF or VEGF receptor, including axitinib, paxopanib, cediranib (AZD2171), VEGF-Trap, and IMC-1121B.
A randomized phase III trial recently found that the combination of bevacizumab (Avastin; not approved for this indication) plus interferon-alpha offers superior progression-free survival compared with interferon-alpha alone (Proc Am Soc Clin Oncol 2007; 25:2s [abs. 3]). But toxicity for the combination appears to be greater than for bevacizumab monotherapy when comparing results across multiple studies, Dr. Motzer cautioned.
Most other trials using multiple agents in RCC have been disappointing, he added.
A phase III trial of temsirolimus plus interferon found inferior survival compared to temsirolimus monotherapy with increased toxicity and decreased dose delivery. A phase I trial of sunitinib plus interferon found an unfavorable toxicity profile. A phase II trial of sorafenib plus interferon showed a higher response rate than monotherapy but greater toxicity for the combination.
"We clearly have to be cautious," Dr. Motzer said, particularly when combining targeted agents with each other.
A promising combination of bevacizumab and erlotinib showed higher toxicity than either agent when used as monotherapy. Bevacizumab plus sunitinib resulted in hypertension that prevented long-term use, Dr. Motzer said, although bevacizumab plus temsirolimus appears to be well tolerated.
One reason these targeted agents may not work well together is redundant mechanisms of action and overlapping adverse event profiles. Hand-foot syndrome, hypertension, cytopenia, and gastrointestinal upset are common adverse events that may have an additive effect when agents are used in combination.
"There have been many promises from targeted agents and little delivery," Dr. Motzer said. "But at least the promise of these combinations has focused even more attention on RCC biology."
Increased research has produced novel pathways that offer targets for another generation of new agents, he said. New pathways and new agents offer renewed promise of superior efficacy and tolerability. But experience with targeted agent combinations to date suggests that early promise must be tempered with a large dose of doubt.
"It is clear that phase II and phase III trials are essential," Dr. Motzer said.
Until data show conclusively that combination therapy offers clear benefits to monotherapy, it should be restricted to clinical trial settings, he said.
Dr. Motzer has received research funding from Pfizer.