CHICAGO—The choices in second-line therapy for advanced renal-cell carcinoma have improved. In a Phase III trial comparing axitinib with sorafenib in previously treated patients, axitinib was associated with a two-month improvement in progression-free survival.
The randomized, international Phase III AXIS 1032 study reported at the ASCO Annual Meeting (Abstract 4503) included 723 patients with clear-cell advanced renal cell carcinoma.
The researchers, led by Brian Rini, MD, of the Department of Solid Tumor Oncology at Cleveland Clinic Taussig Cancer Center. said that this is the first trial to directly compare axitinib, a selective inhibitor of VEGF receptors 1, 2, and 3, and sorafenib, a tyrosine kinase inhibitor, against each other in relapsed or refractory renal cell carcinoma patients.
Patients were previously treated with one prior first-line systemic regimen of sunitinib (54% in each arm), cytokines (35% in each arm), bevacizumab with interferon-alpha (8% each), or temsirolimus (3% each); and 91% of the 361 axitinib and of the 362 sorafenib patients had a prior nephrectomy.
Dr. Rini reported progression-free survival of 6.7 months with axitinib and 4.7 months for sorafenib. Response was influenced by the previous treatment. Progression-free survival favored axitinib in both the prior cytokine subgroup (12.1 vs 6.5 months) and the prior sunitinib subgroup (4.8 vs 3.4 months).
Objective response rates were 19.4% for axitinib vs 9.4% for sorafenib.
Common adverse events more frequent with axitinib compared with sorafenib were hypertension (40% vs 29%, all grades), fatigue (39% vs 32%), dysphonia (31% vs 14%), and hypothyroidism (19% vs 8%).
Adverse events more frequent with sorafenib were hand-foot syndrome (27% vs 51%), rash (13% vs 32%), alopecia (4% vs 32%), and anemia (4% vs 12%).
“These data support the hypothesis that the more potent biochemical targeting of the VEGF receptor is associated with superior clinical activity in renal cell carcinoma,” Dr. Rini concluded.
A head-to-head first-line trial of axitinib and sorafenib in both previously treated and previously untreated patients with advanced renal cell carcinoma, has now begun, he added. “We expect axitinib to be much more active as a first-line therapy since it has shown such good results as a second-line therapy.”
A secondary objective of AXIS 1032 was to evaluate the effect of axitinib versus sorafenib on kidney cancer specific symptoms and functioning in patients with renal cell carcinoma. These outcomes were presented in a separate report (Abstract 4504) by principal investigator David Cella, PhD, Professor and Chair of the Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine.
He said patient-reported health–related quality-of life test scores were similar in both treatment arms, but axitinib showed a 16 to 17 percent risk reduction in a _composite endpoint of time to deterioration (TTD), defined as the time to death, disease progression, or a decrease in FKSI (Functional Assessment of Cancer Therapy–Kidney Symptom Index) scores, whichever occurred first.
Dr. Cella concluded that axitinib was associated with improved progression-free survival compared with sorafenib while generally maintaining health-related quality of life, and that the TTD composite endpoint results support the primary efficacy analysis, and indicate the value of progression-free survival in renal cell carcinoma.
Discussant Questions Need for More Tyrosine Kinase Inhibitors
The Discussant for these two papers, Bruce G. Redman, DO, Clinical Professor in the Department of Internal Medicine and Associate Program Director for Tumor Immunology at the University of Michigan Health System, said that from the data, axitinib is a reasonable option for these patients.
But more broadly, he asked, “Do we need another TKI?”
The primary objective in the axitinib-versus-sorafenib trial was progression-free survival in patients with metastatic renal cell carcinoma. He said that in this trial it is important to note that patients received just one prior systemic treatment, with more than half receiving sunitinib and one-third a cytokine.
The authors concluded that axitinib therapy led to a statistically significant improvement in progression-free survival compared with sorafenib, and Dr. Redman said these conclusions were well supported by the data: “They say this data supports the hypothesis that a more potent—meaning direct TKI targeting the VEGF receptor—is associated with superior clinical activity. I have an alternate conclusion, that axitinib should be considered a reference standard for second-line therapy of advanced renal cell carcinoma, other than for the obvious fact that it is still an investigational agent,” he said.
Dr. Redman said that axitinib does appear to be well tolerated for metastatic renal cell carcinoma and that he considers axitinib to be a valid treatment option after IL-2, but added that he didn't think that anybody in the US is still using interferon as front line therapy.
“I say axitinib is a ‘reasonable’ option after prior TKI therapy,” Dr. Redman said. But questions remain:
- After progression on a “good” TKI, what is the role of a second “good” TKI?
- Does it matter if there was clinical benefit to the first TKI in deciding to treat with a second TKI?
- Do we need more TKIs or mTOR inhibitors or do we want a new target?
Dr. Rini, interviewed after his presentation, responded to Dr. Redman's comment about prior therapy with a TKI or a cytokine, and said that he agreed that because of the biology of the disease, the type of prior therapy has an impact on subsequent therapies.
“We know that sequential VEGF agents have activity, yet the activity goes down with each agent, as opposed to [patients treated with] prior cytokines, who don't have VEGF therapy exposure, who clearly had the most robust response.”
Dr. Rini said he also agreed that it is still unanswered whether or not to switch mechanisms — going to an mTOR inhibitor such as everolimus or staying with a VEGF inhibitor for second-line therapy.
He also agreed with Dr. Redman's suggestion that there might not be a need for more TKIs, but rather for different therapeutic targets, and speculated that axitinib will be the last VEGF TKI developed.
“I don't think we need to search for even more potent TKIs,” Dr. Rini said. “I think we've probably maxed out the clinical benefit of that approach, at least as monotherapy.”
Dr. Redman had asked about the role of a second TKI after progression on a TKI that produced “good” responses, and Dr. Rini said he interpreted “good” to mean a drug that produces superior outcomes, but then said the question hasn't been answered.
“We haven't really looked at our data to say whether the response to a frontline TKI had an impact on response to either one of the second-line TKIs,” he said. “Clinically we have that sense, that a patient who does really well on frontline sunitinib will do really well on their second-line TKI, but there's no data to support that — it's just a clinical sense.”
In fact, he said, he and colleagues presented retrospective data at the ASCO meeting that suggests that that is not the case. “To me, it means we have a lot to learn about giving these drugs, especially how to choose a subsequent therapy,” Dr. Rini said.
In his discussion of the two axitinib presentations, Dr. Redman said the important question is whether a delay of progression can be achieved with minimal or acceptable toxicity, and Dr. Rini said he also agreed with that. “If all axitinib did was give people two more months of toxic living, then I'd be the first to argue that that's not a benefit,” he said. “Dave Cella's presentation showed that in fact it was the opposite, that the time-to-progression advantage actually delayed the time– to-symptom variation.
“To me, that really reinforces the real-world clinical advantage of what we see when we look at a median PFS.”
Higher Score Better
Dr. Brian Rini corrected one point that Dr. Bruce Redman had made in his Discussant comments, where he had interpreted one graph to mean that patients felt better and symptoms improved after they discontinued a TKI. But that was a misinterpretation, Dr. Rini said: “On the slide, a higher score on those scales is better. Those scales showed the scores creeping up over time, because when patients get sick and drop out, their scores are not included.
“It's the good patients who stay on, so their scores go up. If you look at the scores 28 days after therapy, they were dramatically reduced. Patients who come off therapy, largely for disease progression, feel worse because their disease is worse!”
“Unfortunately, Dr. Redman misinterpreted that slide, and came to the opposite conclusion,” he said, adding that he talked with Dr. Redman about this after the session. “Patients don't feel better when their disease is worse. The overriding thing that makes people feel bad is their disease—if they have worse disease, they feel worse, period.”