Renal Cell Cancer Care in the Age of Targeted Therapies: Level 1 Evidence Supports Sequencing

CHICAGO--Sunitinib (Sutent)  doubles overall survival for newly diagnosed patients with metastatic renal cell carcinoma, and everolimus (Certican) significantly extends progression-free survival in patients whose disease has progressed on sunitinib or sorafenib (Nexavar) or both, researchers reported here at the ASCO Annual Meeting.

These Phase III trial data provide Level 1 evidence for how to start sequencing targeted therapies in patients with advanced renal cell cancer, but researchers are still working out how to optimize care, balance the costs and benefits of care, and evaluate second- and third-generation agents.

There is no question about it-there has been a fundamental transition in the way we treat the disease, said Brian Rini, MD, a staff member in the Department of Solid Tumor Oncology at the Cleveland Clinic Taussig Cancer Center and Associate Professor at the Lerner College of Medicine in Ohio, who discussed the sunitinib and everolimus trials.

It is not so much about one arm versus the other; it is about 2008 versus 2001. All of the survival numbers are high. We had never seen median survivals of 26 months on a trial, not even close, he said, referring to the median overall survival seen in sunitinib-treated patients.

Several experts noted that having numerous active drugs, such as everolimus (previously called Rad001), that work when a patient has progressed on another targeted agent, is critically important. Using these agents in sequence, some physicians expect that overall survival for patients diagnosed with metastatic disease will likely extend to two and a half to three years.

This prolongation in survival resembles what has happened in colorectal cancer care, a setting where patients can get multiple lines of therapy, which together significantly increase survival, noted Nicholas Petrelli, MD, Medical Director of the Helen F. Graham Cancer Center in Newark, Delaware, who moderated a news conference at the meeting in which the everolimus trial data were featured.

With first, second-, third-, fourth-line therapies, we've gone over the last two or three decades from a median survival of nine months to over 20 months for patients with advanced colorectal cancer. We are beginning to see the same with kidney cancer.

To test the efficacy of a vascular endothelial growth factor (VEGF) inhibitor in previously untreated metastatic clear cell renal cancer, researchers enrolled 750 patients in a randomized controlled study between August 2004 and October 2005. Patients received either 50 mg sunitinib daily or 9 MU given subcutaneously three times weekly.

Results of a planned interim analysis demonstrated that progression-free survival, which was the primary endpoint, increased significantly from five to 11 months. Based on that analysis, the data safety monitoring board recommended in February 2006 that patients be allowed to cross over to sunitinib upon disease progression on interferon.

In the current analysis, Robert Figlin, MD, Chair of the Division of Medical Oncology and Experimental Therapeutics and Associate Director for Clinical Research at City of Hope, presented the final overall survival data from the trial (Abstract 5024).

Patients assigned to the sunitinib arm had a median survival of 26 months compared with a median survival of 22 months for the patients initially treated with interferon. The difference was borderline statistically significant with a p-value of 0.051 and a hazard ratio of 0.821.

If the 25 patients who chose to cross over from interferon to sunitinib were not included, the median overall survival is 26 months in the sunitinib arm and 20 months in the interferon arm, which is statistically significant.

Although sequential therapy is now the common treatment pattern for patients with advanced kidney cancer, 162 patients in the control arm and 193 patients in the experimental arm did not receive any post-study therapy.

This is perhaps the most pure look at the data given the constraints of the emergence of multiple active agents, Dr. Rini said. In this subgroup, the median overall survival was 14.1 months on interferon, which is exactly what you would expect, he said, and 28.1 months on sunitinib.

Many experts, including Dr. Rini, expected the overall survival data to show significant improvement for the targeted therapy over interferon and thus were not surprised by the final numbers. Nonetheless the data are important, he said. There are reimbursement issues worldwide, and also I think they will help in convincing the non-kidney cancer folks about the benefits of these therapies.

Dr. Figlin took a more strident view of the value of the results: I think sunitinib is the reference standard for future treatment, he said during an interview. It is the thing that has demonstrated a paradigm shift based upon Phase III data, and it is the drug against which all future improvements will have to be judged.

Although sunitinib and other drugs that block the VEGF receptor, such as sorafenib, prolong survival, patients eventually relapse. To determine whether everolimus, which blocks the mTOR signaling protein, is effective in patients who have relapsed on an anti-VEGF tyrosine kinase inhibitor, investigators enrolled 410 patients who had been treated with sunitinib, sorafenib, or both in a trial comparing everolimus with placebo (Abstract LBA5026). Patients were randomized in a 2:1 fashion to active drug and placebo.

Following a planned interim analysis in which progression-free survival, which was the primary endpoint, was significantly extended in the active drug arm, the data safety monitoring committee recommended stopping the trial and offering everolimus to patients initially assigned to placebo.

The 272 patients assigned to everolimus had a median progression-free survival of 4.0 compared with 1.9 months for the 138 patients on placebo. Overall survival was also extended, with the median not yet reached in the active drug arm and 8.8 months in the placebo group.

Everolimus is the first and only agent with established clinical benefit with renal cell carcinoma after VEGF-tyrosine kinase inhibitor therapy, said the lead author, Robert Motzer, MD, an Attending Physician in the Genitourinary Service at Memorial Sloan-Kettering Cancer Center. It is a setting of unmet need that has now been filled. Everolimus should be standard of care in this setting pending approval by regulatory authorities.

Importantly, when the researchers looked at patient subsets, including stratifying by previous therapy, all subgroups appeared to benefit equally. Fifty percent of the patients had had prior sunitinib, 25% had prior sorafenib, and 25% had had both drugs.

The hazard ratio for relapse for each of these three subgroups was between 0.28 and 0.30. It was noteworthy, Dr. Rini said, that a substantial fraction of the patients had had other prior therapies in addition to the targeted therapies-So this was not a pure second-line study, but more likely third-line or later for most patients, he said.

Additionally, the investigators included patients from all three MSKCC risk groups, favorable, intermediate, and poor. Again, there was no difference in the hazard ratio for relapse on everolimus for these subgroups. By contrast, a previous study showing that the other mTOR inhibitor, temsirolimus, is effective in renal cancer patients tested the drug only in those who had poor prognosis at initial diagnosis.

Both Dr. Rini and Keith Flaherty, MD, Assistant Professor of Medicine at the Abramson Cancer Center at the University of Pennsylvania, caution that not too much should be made of this difference, though, because the patients in the temsirolimus arm had poor-risk disease at diagnosis, while the patients in the everolimus trial had been treated by several agents already before their risk assessment. Thus, it is not clear whether the risk stratification is still as meaningful.

Despite this cautionary note and the fact that the drug was tested against placebo, which might not reflect current clinical practice, Dr. Flaherty called this study a monumental event for the field. This is the first randomized trial to be conducted in patients whose disease has progressed on a targeted therapy, he said. It is a more resounding positive result than we have seen previously. The magnitude of increase in median and reduction by hazard ratio was bigger than we have seen in any other study.

Finally, he noted, that because a full quarter of the patients had progressed on both sunitinib and sorafenib, oncologists who currently treat their patients with those two drugs in sequence can continue doing so and add everolimus on as a third-line agent in the series, while still practicing evidence-based medicine.

Two studies compared the safety and efficacy of anti-angiogenesis therapy in patients over age 65 and their younger counterparts. Neither study found a significant difference in outcomes or adverse events.

In a subset analysis from the Advanced Renal Cell Carcinoma Sorafenib Expanded Access Program, Ronald M. Bukowski, MD, Director of the Experimental Therapeutics Program at Taussig Cancer Center, reported that the median progression-free survival in 775 patients over the age of 65 was 38 weeks compared with 35 weeks in the 1,112 patients 65 or younger (Abstract 5044).

Safety data from 1135 elderly patients and 1361 patients 65 years or younger showed no substantial differences in Grade 2/3 toxicities including hand-foot syndrome, rash, fatigue, hypertension, diarrhea, nausea, or anorexia.

Similarly, the rate of cardiac-related events were similar in the two groups, with 5% of each group having Grade 3 or 4 hypertension, 1% having Grade 3/4 cardiac ischemia, and 1% or less hypotension or cardiac arrhythmia.

At least for a cut-point of age 65, there does not seem to be any selection for greater toxicity in the older population, said Daniel George, MD, Associate Professor of Medicine at Duke University Medical Center, during a poster discussion session.

In a subset analysis of patients 65 or older who participated in the AVOREN trial, which tested bevacizumab plus interferon versus interferon alone, modest increases were seen in adverse events (Abstract 5095). In 121 elderly patients treated with the combination, 18% had Grade 3/4 fatigue compared with 9% of the 206 younger patients on the same regimen.

Elderly patients also experienced more Grade 3/4 asthenia than their younger counterparts (14% vs 7%), neutropenia (6% vs 3%), pneumonia (4% vs 0%), anorexia (5% vs 2%), and depression (5% vs 2%). The investigators have reported previously, however, that the adverse events associated with interferon can be lessened by reducing the dose of the cytokine without compromising the efficacy of the regimen.

Kidney cancer experts agree they are in a fortunate position with so many active agents, but a key question facing the field now is how to use the agents in a way that maximizes their value.

For example, should the drugs be used in a sequence of monotherapy regimens as is done now? If so, does it matter which agent precedes another? Or could physicians increase the number of complete responses or extend the median duration of response by using combination regimens?

No clear answers to these questions are yet available, but several presentations at the meeting did start to address these issues.

With respect to the possibility of combination therapy, early evidence suggests that combining anti-angiogenesis drugs is not easy. In general, the combinations increase toxicities seen with the single agents and the doses of each drug need to be reduced substantially relative to the standard monotherapy doses.

Jeffrey Sosman, MD, Professor of Medicine and Medical Oncologist at Vanderbilt-Ingram Cancer Center, presented the final data from a Phase I trial that tested the combination of sorafenib and bevacizumab (Abstract 5011).

With a total of 48 patients enrolled, Dr. Sosman reported that the maximally tolerated dose was half of the standard dose of each agent-5 mg/kg bevacizumab every two weeks and 200 mg sorafenib once daily. The investigators were unable to raise the dose of either agent beyond that level, despite multiple attempts.

When they increased the bevacizumab dose, extreme hypertension and proteinuria became problems. When they raised the dose of sorafenib, hand-foot syndrome, anorexia, and hypertension became problems. They did not see any evidence of microangiopathic hemolytic anemia as has been reported with the combination of bevacizumab and sunitinib, Dr. Sosman said (OT, 6/10/08 issue).

The bevacizumab-sorafenib combination appears to have significant activity, however. A waterfall plot showed that of the 48 patients who participated in the trial, 41 had some degree of tumor shrinkage. The median progression-free survival was approximately 14 months, with 11 patients continuing on therapy and some remaining progression-free for longer than 32 weeks.

Despite these promising efficacy data, Dr. Flaherty, who was a coauthor with Dr. Sosman, emphasized that this combination and other combinations of anti-angiogenesis inhibitors should not be used off study.

Five to seven years ago I would have said we have a long way to go in terms of perfecting anti-angiogenesis therapy, and that there was no end in sight how good it could get, Dr. Flaherty said in an interview. Now I have very much changed my tune on that topic. Bevacizumab plus sorafenib is very promising in terms of anti-tumor activity, but it is definitely a major challenge to co-administer these drugs and I absolutely believe these are on-target effects.

It is not a matter of getting cleaner and cleaner drugs to use in combination. It is that angiogenesis is part of normal homeostasis. You just can't poison that process and get away with it completely.

Meanwhile, John Hainsworth, MD, Chief Scientific Officer at the Sarah Cannon Research Institute in Nashville, presented data from a Phase II trial showing that patients can tolerate a combination of bevacizumab and everolimus at full doses (Abstract 5010).

The combination led to few hematologic toxicities, and the most common Grade 3/4 non-hematologic toxicities were proteinuria (20% of patients), fatigue (9%), diarrhea (8%), mucositis or stomatitis (7%), hyperlipidemia (3%), and hypertension (2%).

Nine patients (15%) withdrew from the trial because of side effects, including five due to proteinuria, two to pulmonary embolism, and one each to stomatitis and diarrhea. The mucositis and stomatitis were particularly bothersome for patients, Dr. Hainsworth reported. Additionally, the frequency of Grade 3/4 proteinuria suggests that the problem may be more common with the combination than with bevacizumab alone, and should be carefully watched in future trials.

Fifty-nine patients with advanced clear cell renal cancer enrolled in the trial, 30 of whom had had no prior targeted therapy and 29 who had received sunitinib or sorafenib previously. All of the patients received 10 mg/kg of bevacizumab every two weeks and 10 mg everolimus daily. The median duration of treatment was six months, with 24% of patients remaining on therapy at the time of the presentation. Forty-five patients had discontinued therapy, including 24 who stopped therapy due to disease progression and nine because of toxicity.

Overall 20% of patients showed a partial response by Response Evaluation Criteria in Solid Tumors, including 23% of the previously untreated patients and 17% of the patients who had previous targeted therapy. A waterfall plot showed that 51 of the patients had some amount of tumor shrinkage. The median progression-free survival was 12 months in patients who had not had previous targeted therapy and 11 months for those who had had prior targeted therapy.

We did not see a lot of difference between the patients who had previous treatment and those who had not, Dr. Hainsworth said.

It is an active regimen in both untreated patients and those who had previously received sunitinib or sorafenib. Unlike most other combos of active targeted agents in renal cell carcinoma, this combination can be given at full doses and is tolerable by most patients.

Although the trial demonstrates that the combination has activity, it does not shed any light on whether the combination is better than using bevacizumab and everolimus in sequence. In fact, thus far there have been only a few trials that have examined different sequences.

In one series of 42 patients, researchers from the Cleveland Clinic reported that nearly one-third of patients previously treated with bevacizumab or sunitinib showed a reduction in tumor burden when treated with sorafenib (Abstract 5123). The median progression-free survival was 2.9 months for the 18 patients previously treated with bevacizumab and 3.8 months for the 24 who had had prior sunitinib.

Similarly, Janice Dutcher, MD, Associate Director for Clinical Affairs at Our Lady of Mercy's Cancer Center and Professor of Medicine at New York Medical College, and colleagues reported that a substantial fraction of patients who had been previously treated with sorafenib, sunitinib, or both responded to axitinib, which is an oral anti-VEGF inhibitor (Abstract 5127).

Specifically, 62 patients enrolled in the Phase II study. Of the 50 patients who had a post-treatment scan, 13 (26%) had a partial response. The median progression-free survival for patients previously treated with sunitinib and sorafenib was 7.1 months-9.1 months for patients previously treated with sorafenib plus cytokines, and 7.8 months for those treated with sorafenib alone.

Again, neither of these trials indicates whether one order is better than another, but they do suggest that patients whose disease progresses on one targeted agent have a good chance of responding on another one.

The goal now, experts agree, is to find a way to expand the number of patients who have long-term responses and survival. Exactly how to do that remains unclear, but the hope is that carefully designed combinations and better patient selection will continue to shift the curve in the right direction and start to raise the tail of the curve.

The researchers interviewed for this article all reported various potential conflicts of interest, and the trials discussed were supported by the manufacturers of the drugs being tested.