ORLANDO, June 2 — Patients with advanced renal cell carcinoma had significant improvement in progression-free survival when treated with a targeted inhibitor of vascular endothelial growth factor (VEGF), data from a randomized trial demonstrated.

• Explain to patients that an investigational therapy reduced the risk of disease progression in advanced renal cell carcinoma.
• Note that the drug is not yet available.
• Note, too, that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Treatment with tivozanib increased 12-week progression-free survival by almost 60% compared with placebo, Pankaj Bhargava, M.D., of Aveo Pharmaceuticals in Cambridge, Mass., reported here at the American Society of Clinical Oncology meeting.

Independent review showed an overall response rate of 25.4% and a disease control rate of 84.2%.

“The median progression-free survival was 11.8 months in sort of a mixed-bag, real-life patient population that included patients with clear-cell and non-clear cell cancer,” Dr. Bhargava said in an interview. “We think that’s very encouraging for this type of patient population, and we are moving forward with other studies in renal cell carcinoma, including studies of front-line therapy and combination therapy.”

Tivozanib (formerly AV-951) inhibits VEGF receptor 1, 2, and 3 at subnanomolar concentrations and also has activity against cKIT and platelet-derived growth factor ß.

Dr. Bhargava reported updated results from a phase II randomized trial involving 272 patients with advanced renal cell cancer, including 226 patients with clear-cell disease. (See ASCO GU: Targeted Agent Achieves High Control Rate in Renal Cell Carcinoma)

All patients received open-label tivozanib for 16 weeks. Those with tumor shrinkage of ≥25% or more continued tivozanib for an additional 12 weeks. Patients with tumor shrinkage less than 25% were randomized to tivozanib or placebo for 12 weeks. All other patients discontinued treatment.

The primary endpoints were response rate at 16 weeks, progression-free status at the end of randomized therapy, and tivozanib safety.

The patients’ median age was 56, and all had ECOG performance status of 0/1. Three out of four had undergone nephrectomy, and 46% had received one or more prior systemic therapies.

A majority (57.4%) of the patients were classified as intermediate risk.

After 16 weeks of open-label tivozanib, one patient had a complete response, and 68 others had partial responses, for an overall response rate of 25.4%. An additional 58.8% of patients had stable disease, resulting in a clinical benefit rate of 84.2%.

Patients with clear-cell disease had an overall response rate of 27% and a clinical benefit rate of 85%.

Median progression-free survival for the entire cohort was 8.9 months, including 12 months in patients with clear-cell cancer.

Dr. Bhargava reported progression-free survival data for 111 patients who entered the randomized phase of treatment. He said that 34 of 58 (58.6%) tivozanib patients remained progression-free at 12 weeks compared with 20 of 37 (37.7%) placebo-treated patients (P=0.0286).

Tivozanib caused minimal “off-target” toxicity, such as mucositis, stomatitis, fatigue, neutropenia, and hand-foot syndrome, said Dr. Bhargava.

The most common treatment-emergent adverse event was hypertension, which occurred in about half of the patients (all grades) and was controlled with medication in most cases. About 20% of patients had dysphonia. Both conditions are recognized off-target toxicities of VEGF inhibition, he added.

Tivozanib has distinguished itself somewhat from other VEGF inhibitors by its specificity for the VEGF receptor, Robert Motzer, M.D., of Memorial Sloan-Kettering Cancer Center in New York, said in an interview. The specificity accounts for the modest amount of off-target toxicity.

Drugs such as tivozanib are at the center of an ongoing debate in the oncology community, he continued. The debate centers on the issue of whether target specificity or multitargeted activity leads to better results.

“A case can be made for either strategy, and no one really knows at this point whether one strategy will turn out to be better than the other,” said Dr. Motzer. “AV-951 has activity in renal cell carcinoma, and the reduced amount of off-target toxicity is always a good thing. Whether the agent distinguishes itself from other drugs in the class remains to be seen.”

The hypertension associated with the drug appears manageable, he added, but will have to be watched closely as AV-951 moves forward in clinical evaluation.

Dr. Bhargava is an employee of Aveo Pharmaceuticals. None of the co-investigators reported competing interests. Dr. Motzer’s disclosures include relationships with Genentech, Novartis, Pfizer, and Wyeth.

Primary source: Journal of Clinical Oncology

Source reference:
Bhargava P, et al “Updated activity and safety results of a phase II randomized discontinuation trial of tivozanib (AV-951), a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma” J Clin Oncol 2009; 27(15S): Abstract 5032.

Related Article(s):

• ASCO GU: Targeted Agent Achieves High Control Rate in Renal Cell Carcinoma

ORLANDO, June 2 — An investigational agent that targets two growth factors — vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) — increased progression-free survival in patients with advanced non-small cell lung cancer, researchers reported here.

Moreover, the “patients felt better when they were on therapy,” said Roy Herbst, M.D., Ph.D., of M.D. Anderson Cancer Center in Houston.

Dr. Herbst reported the results of the Phase III ZODIAC trial of vandetanib (Zactima) given in combination with docetaxel (Taxotere) at the American Society of Clinical Oncology.

Patients randomized to the drug had a median of 17.3 weeks of progression-free survival compared with a median of 14 weeks for the patients who received docetaxel plus placebo, for a hazard ratio of 0.70 (95% CI 0.70 to 0.90), which was significant, (P<0.001), Dr. Herbst said.

• Explain to interested patients that the drug described in this trial, vandetanib, is not FDA approved and is not available outside a clinical trial setting.
• Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Dr. Herbst said that during vandetanib treatment patients reported less shortness of breath, chest pain, and coughing compared with controls.

The ZODIAC (Zactima in cOmbination with Docetaxel In non-smAll cell lung Cancer) study enrolled 1,391 patients with stage IIIB/IV NSCLC at 198 centers between May 2006 and April 2008. All had previously failed first-line standard chemotherapy.

The median follow-up was 12.8 months.

The secondary endpoint — overall survival — did not reach significance, with median overall survival 10.6 months in the vandetanib arm versus 10.0 in the control arm. But, in an interview Dr. Herbst said he thought there would be a statistically significant overall survival benefit as the data matured.

More toxicities were reported in the vandetanib arm — diarrhea, rash, and neutropenia — but there was not more bleeding, which Dr. Herbst said was encouraging since bleeding, including pulmonary bleeding, is a significant side effect with drugs that target VEGF. “And there was less nausea and vomiting in the vandetanib arm,” he said.

About 22% of patients in the study discontinued vandetanib because of side effects.

In an interview with MedPage Today, Dr. Herbst addressed the issue of cost for targeted therapies such as vandetanib for treatment of lung cancer. While acknowledging that the cost for treatment was likely to be high, he said that “by attacking the cancer at both ends — the blood supply [with VEGFR] and the tumor cells [with EGFR], the net result might be a cost savings, because I think it would be cheaper because it has the potential of avoiding the need for other therapies.”

The trial was supported by AstraZeneca, which is developing vandetanib. Dr. Herbst disclosed that he has a consultant or advisory role with AstraZeneca Oncology and said he received research funding from AstraZeneca Oncology.

Primary source: American Society of Clinical Oncology

Source reference:
Herbst RS, et al “Vandetanib plus docetaxel versus docetaxel as 2nd-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC)” ASCO 2009; Abstract CRA800.

ORLANDO, June 2 — A set of six genes, measured in a blood test, can be used to tell whether a man has prostate cancer, a researcher said here.

• Explain to interested patients that prostate cancer screening is commonly done using one of a variety of tests for prostate specific antigen (PSA).
• Note that this study suggests that a six-gene panel can do better than such tests and that the combination of PSA and the six genes can do even better.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

In a case-control study, the six-gene panel outperformed a standard test — age-adjusted prostate specific antigen — in distinguishing between men with cancer and those without, according to Robert Ross, M.D., of Dana-Farber Cancer Institute in Boston.

When prostate specific antigen (PSA) levels were added to the group of genes, the performance of the test improved even more, Dr. Ross told attendees at the annual meeting of the American Society of Clinical Oncology.

The gold standard for diagnosing prostate cancer is a biopsy, he said, but 60% of biopsies in men thought to be at risk for the disease turn out to be negative.

The goal of this test is to avoid the “pain, discomfort, and anxiety” associated with biopsies, Dr. Ross said, by winnowing out the 60% of men who don’t need the procedure.

Dr. Ross and his colleagues started with a set of 392 genes associated with inflammation, cancer, and the epidermal growth factor receptor, as well as some identified in other genetic studies of cancer.

In a training set of 76 healthy men and 76 with prostate cancer, six genes were significantly associated with disease. Of the six, five are less active in those with the disease and one has greater activity, the researchers found.

The finding was validated in a second cohort of 128 men with cancer and 94 without, he said.

In the second group, the six-gene test correctly detected 85.9% of the men with disease, compared with 69.5% detected by age-adjusted PSA, Dr. Ross said.

The six-gene test had a specificity of 83%, compared with 93.6% for PSA, he said.

When the researchers did both the six-gene test and measured PSA levels, the sensitivity and specificity improved — to 87.5% and 92.6%, respectively.

The results are a “significant improvement” over the predictive value of PSA alone, Dr. Ross said.

“From a clinical hypothesis standpoint, this is great data,” Dr. Ross said. But, he cautioned, “this is a case-control study (and) you’d like to see it validated prospectively.”

He said his institution and several others are collaborating on a 1,000-patient prospective study — dubbed PRECISE — among men who meet the criteria for a biopsy, but have not yet had the test.

The goal will be to see if the test can predict the results of biopsy, he said.

Although the test is still in development, it will not be expensive, especially compared with the $2,000 it costs for a biopsy, said Karl Wassman, of Source MDx, the Boulder, Colo. company that has developed the test.

He said the blood test can be read by standard equipment, using a kit of primers and probes developed by Source MDx, so that the cost will be in the range of “a couple of hundred” dollars.

The various forms of PSA testing are “extremely valuable” in screening for prostate cancer, said Howard Sandler, M.D., of Cedars-Sinai Medical Center in Los Angeles, who was not involved in the study.

But the jury is out on whether screening and early detection have any benefit for patients, he said.

“If screening is beneficial, then better screening is important,” he said, but there’s no high-quality evidence that early detection is useful.

Dr. Sandler said the “weakness of this test” is that it doesn’t answer the most important question about prostate cancer.

“The question is do you have clinically relevant prostate cancer or not?” he said. “Do you have potentially lethal cancer or do you have the cancer that will never kill you?”

Dr. Ross agreed that that question is important and said he and his colleagues have preliminary data that suggests it may be possible to use such a test to distinguish between types of cancer.

The study was supported by Source MDx, Dana Farber and the Harvard Cancer Center, the Gelb Center, and the Bing Sound Wong Fund. Several researchers reported financial links with Source MDx. Dr. Sandler reported financial links with sanofi-aventis, Genentech, Amgen, and AstraZeneca.

Primary source: Journal of Clinical Oncology

Source reference:

Ross RW, et al “Sensitivity and specificity of a whole-blood RNA transcript-based diagnostic test for the diagnosis of prostate cancer (CaP) compared with prostate-specific antigen (PSA) alone” J Clin Oncol 2009; 27(15S): Abstract 5052.