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Renal Cell Cancer: Molecularly Targeted Therapies Provide New Avenue for Treatment3 Phase II Studies

Tuma, Rabiya S. PhD

doi: 10.1097/01.COT.0000292284.26881.31

NEW ORLEANS—Renal cell carcinoma (RCC) is known to be largely resistant to chemotherapy, and although some patients have a strong and durable response to immunotherapy, they are the minority.

Now, three Phase II studies presented here at the ASCO Annual Meeting show that a variety of molecularly targeted therapies have significant activity in the disease. In all three trials, more than 50% of the patients remained progression- free at six months.

“Clearly progression-free survival at six months is substantial compared with other second-line trials,” said the Discussant for the two studies, Janice P. Dutcher, MD, Associate Director of Clinical Affairs at Our Lady of Mercy's Comprehensive Cancer Center in Bronx, NY.

The session's Co-Chair, Nicholas J. Vogelzang, MD, the Fred C. Buffet Professor of Medicine and Director of the University of Chicago Cancer Research Center, said, “These studies show us new pathways and new ways forward in the management of a heretofore untreatable or nearly untreatable disease, namely metastatic kidney cancer.”

He added that all three of the abstracts were very highly rated by the program committee.

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The Agents

The trials are similar in that the patients have had some previous treatment, nephrectomy, or systemic therapy or both, but they differ in the molecularly targeted agent used.

Currently, the only FDA-approved therapy for kidney cancer is high-dose interleukin-2 for first-line therapy. Both interleukin-2 and interferon alpha are approved and used in Europe for first-line therapy.

A trial led by Robert J. Motzer, MD, of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center tested SU11248, a tyrosine kinase inhibitor that blocks signaling from a variety of signaling receptors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, which are involved in angiogenesis.

The second trial, led by Mark Ratain, MD, Professor of Medicine and Chief of Clinical Pharmacology at the University of Chicago, tested sorafenib (BAY 43–9006), which also targets several tyrosine kinases, including VEGF and PDGF receptors. It was developed initially as an inhibitor of Raf kinase, which is overexpressed in a variety of cancers including melanoma, colorectal, and pancreatic.

The third trial, led by John D. Hainsworth, MD, Director of Clinical Research at the Sarah Cannon Cancer Center and Tennessee Oncology in Nashville, used a combination of bevacizumab and erlotinib.

Bevacizumab has already shown activity as a single agent in kidney cancer. In the earlier trial progression-free survival was extended from 2.5 months in patients on placebo to 4.8 months (N Engl J Med. 2003;349:427–434).

Erlotinib has not been used previously in kidney cancer, but the investigators reasoned that since it blocks epidermal growth factor (EGFR) signaling it could add therapeutic value to bevacizumab because the EGFR pathway is active in kidney cancer. Thus the combination could work to inhibit tumor growth directly and via an inhibition of the blood vessel development.

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SU11248 in Relapsed RCC

Dr. Motzer's trial enrolled 63 patients with metastatic renal cell carcinoma who had disease progression on prior cytokine therapy in a single-arm multicenter trial to test SU11248's efficacy and safety. The primary endpoint was overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST).



All patients received 50 mg of SU11248 orally a day on a schedule of four weeks on, two weeks off. Treatment was continued until either progression or intolerable side effects occurred.

Fifty-nine patients had clear cell carcinoma. Their median age was 60, with a range of 24 to 87, and 43 patients were male.

Twenty-one patients (33%) had a partial response, and another 23 (37%) had stable disease for longer than three months. Nineteen progressed immediately on therapy. The median time to progression was 8.3 months, with a 95% confidence interval of 6.6 to 10.8 months.

The probability of survival at one year was 65%, and 43 patients are alive with a median follow-up of 10.5 months.

The median duration of therapy was nine months, with a range of less than one month to more than 16 months. The drug dose was reduced in 21 patients (33%), primarily for amylase and lipase elevations without pancreatitis or due to fatigue.

Fatigue, diarrhea, dyspepsia, and nausea were the most common side effects. Dermatitis, which has been seen with the use of other targeted agent therapies, occurred in five patients.

Comparing these results to historic controls of patients treated previously in Phase II trials at Sloan-Kettering, Dr. Motzer said the drug looks significantly better. In the historic group, the median time to progression was just 2.9 months vs 8.3 months for these patients.

“I have been at Sloan-Kettering for almost 20 years, focused on kidney cancer and there is no doubt in my mind that this drug has activity in renal cancer,” said Dr. Motzer. “I think it is the first drug in the last 20 years that I have worked with that has really shown activity.”

A pivotal phase III trial for the use of SU11248 as a second line therapy in kidney cancer is underway and a phase III trial comparing the drug to interferon as a first line therapy is expected to start accrual later this year.

The trial was supported by Pfizer.

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Sorafenib: Relatively New Trial Design

Preclinical studies of sorafenib showed that it inhibited tumor growth but did not, by itself, cause tumor shrinkage. Because of this cytostatic trait, Dr. Ratain and his colleagues used a relatively new clinical trial design to test the efficacy of the drug in a wide variety of solid tumors.

Starting in 2002, the trial, which was sponsored by Bayer Pharmaceuticals and Onxy Pharmaceuticals, enrolled patients with solid tumors who were not responding to other treatments. The patients were treated on study for 12 weeks with sorafenib. If at the end of 12 weeks there was disease progression, (defined as more than 25% tumor growth by WHO bidirectional criteria), the patient was taken off the study.

Patients with stable disease, defined as less than a 25% change in tumor size, were randomized to either sorafenib or placebo. Patients who had more than a 25% reduction in tumor size, an event that was not expected because of the preclinical data, would be left on open-label sorafenib therapy until disease progression.

Patients with disease progression after randomization were unblinded and could be put on drug if they had been on placebo.

Patients were required to have progressive measurable disease and a performance status of zero or one. There were no restrictions on prior therapy with the exception of therapies known to affect Raf kinase. The daily starting dose was 400 mg taken orally, two times a day.

The primary endpoint was the rate of progression in the 12 weeks following randomization. Dr. Ratain emphasized that the trial was not designed to measure tumor shrinkage.

Of 484 patients recruited, 203 had renal cell carcinoma. These patients showed the strongest responses to the drug, although activity was also seen in thyroid cancer and soft tissue sarcoma. Few colorectal cancer patients responded sufficiently to be randomized and thus enrollment was discontinued for this patient group.

Of the renal cell cancer patients enrolled, 106 were evaluable. Of those, 75% were male. The median age was 58. Forty-seven percent had one prior systemic therapy, 39% had two or more, and 87% had a prior nephrectomy.



Seventy-five of the 106 patients continued on study after the initial 12 weeks—37 in the open-label arm of the study and 38 in the randomized section, which is still blinded, Dr. Ratain noted.

The median time to progression in the open-label group is 48 weeks, with 88% of these patients being progression free at 24 weeks. The median time to progression in the randomized group is 23 weeks, with 41% progression free at 24 weeks.

Although the randomized group is still blinded, Dr. Ratain reported that slightly less than half of the randomized patients seem to be responding to the treatment, which would be consistent with those patients being the ones receiving active drug.

Regarding the safety data for all patients, the most common side effects were dermatologic—rash, alopecia, and hand-foot syndrome. Fatigue and anorexia were also common, and some patients also had diarrhea or stomatitis.

Also, as has been seen with other anti-angiogenesis drugs, some patients experienced hypertension, although this was easily controlled with either calcium channel blockers or beta blockers, Dr. Ratain said.

The unusual trial design provides researchers with two chances to be successful, he explained: “You can measure tumor shrinkage [in the open label setting] and also look at randomized patients. In this case we saw shrinkage, but even if we hadn't seen that, if we had seen a marked difference in the stable-disease group, we would have been thrilled.”

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Combined Bevacizumab & Erlotinib

NIH researchers last year reported trial results showing that bevacizumab had activity in renal cell cancer. To build on that success, Dr. Hainsworth and colleagues decided to try combining bevacizumab with erlotinib.

To be eligible for the multicenter Phase II trial, patients had to have clear cell kidney cancer that was either locally advanced and unresectable or metastatic; a good performance status, zero or one; and adequate organ function.

Patients with prior antiangiogenesis therapy, including thalidomide, or active central nervous system metastases were excluded. Unlike the two single-agent trials noted above, most of the patients in this trial did not have prior systemic therapy. All patients had nephrectomy prior to starting on the trial unless it was medically not recommended.

Patients were treated with the same dose of the drugs as has been used in single-agent trials. They received 10 mg/kg of bevacizumab by intravenous infusion every two weeks and 150 mg of erlotinib orally each day.

“Originally we thought to stop treatment at 12 months but we modified that plan because we saw many patients arriving at 12 months and still benefiting from treatment,” Dr. Hainsworth explained. “Now patients are receiving treatment until tumor progression or until failure to respond.”

Sixty-three patients enrolled in the trial, and 58 were evaluable for the ASCO report. When evaluated using RECIST criteria at two months after starting treatment, 12 patients (21%) had a partial response, 38 (66%) had either stable disease or a minor response, and eight patients had disease progression.

Objective responses were detected in numerous different sites of metastatic disease, including those of the lung, liver, bone, lymph node, and adrenal glands.

The median progression-free survival time is longer than 12 months, with 81% of patients still alive at 12 months, Dr. Hainsworth said. The median follow-up is 11 months, with a range of five to 16 months.



The toxicities were generally manageable and similar to those seen in the single-agent trials. The main toxicities were rash and diarrhea. One patient discontinued treatment due to severe rash and another due to rash and purititus.

The relatively mild side effects of these drugs suggest that they may be useful for chronic treatment of patients, Dr. Hainsworth said. Although the targeted therapies are not resulting yet in complete responses many of the patients appear to benefit over many months from such therapy.

“Most patients in this trial and Dr. Ratain's trial have some response to the drug, suggesting that these drugs are active,” Dr. Hainsworth said, noting that even though the drugs aren't meeting the artificial definitions of partial response versus stable disease, there are indications that the majority of patients are benefiting from the therapy.

Furthermore, he said that this type of approach gives credence to the idea of using combined targeted treatments in the future, and using them successfully: “I think further combinations of these drugs in kidney cancer and other cancers—where the targets are rational—are going to be the future of medical oncology.”

Dr. Dutcher expanded on this point, saying that because there are likely to be subtle differences between the individual agents, in terms of their targets, how they inhibit target activity, and their pharmocodynamics, a variety of combinations need to be tested in a systematic way.

“It behooves us to try to do systematic analysis of additions of these agents,” she said. “We don't know what toxicities will arise, or what combinations will be synergistic, additive, or contradict one another.”

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Underlying Pathways

During the session, William G. Kaelin, Jr., MD, Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Center, described the biological pathways that contribute to kidney cancer. Patients with von Hippel-Lindau (VHL) disease are born with only one wild type copy of the VHL tumor-suppressor protein.

These patients develop numerous premalignant cysts in their kidneys and when the cysts are examined carefully, it can be seen that cells within the cysts have lost that intact VHL gene.

Mutations in the VHL gene result in an accumulation of the HIF protein, which normally serves to turn on a large number of genes when the cell is stressed under hypoxic conditions. However, without VHL around to regulate HIF, the protein turns on its downstream targets in a continuous manner, including the VEGF and PDGF receptors. Additionally, accumulation of hypoxia-inducible factor (HIF) turns on the TGF-alpha gene, which is a ligand for the EGFR receptor.

Thus hyperactivation of HIF causes both angiogenesis, via VEGF and PDGF, and cell growth, via EGFR.

With this biology in mind, it makes sense that the drugs tested in these three Phase II studies would have activity, explained Dr. Kaelin, who also suggested that rational combinations should be developed and tested in a systematic manner.

© 2004 Lippincott Williams & Wilkins, Inc.
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