ORLANDO, June 3 — Patients with metastatic renal cell carcinoma had encouraging progression-free survival with first-line therapy that included an angiogenesis inhibitor and metronomic chemotherapy, a small study showed.

• Explain to interested patients that metastatic renal call carcinoma may respond to a new combination regimen that includes repetitive low doses of chemotherapy and a drug that inhibits tumor blood vessel growth.
• Note, though, that the study included only a small number of patients.
• 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.

A total of 40 patients had a median progression-free survival of 10 months with the combination of standard-dose gemcitabine (Gemzar), metronomic capecitabine (Xeloda), and sorafenib (Nexavar), Joaquim Bellmunt, M.D., reported at the American Society of Clinical Oncology meeting.

Previous studies of standard-dose gemcitabine/capecitabine and first-line sorafenib monotherapy generally resulted in a progression-free survival of five to eight months, said Dr. Bellmunt, of University Hospital del Mar in Barcelona, Spain.

“The study demonstrates there is a synergistic effect from combining chemotherapy plus metronomic therapy plus an antiangiogenic component,” Dr. Bellmunt said. “It is possible to increase the effectiveness without an increase in toxicity.”

The therapeutic strategy evolved in part from the discovery that, under certain circumstances, chemotherapeutic agents can have antiangiogenic activity. The activity is not evident at standard doses because toxicity requires regular rest periods, Dr. Bellmunt explained.

The antiangiogenic effects occur only with metronomic chemotherapy, which employs low doses to achieve continuous exposure of the endothelial cel

ORLANDO, June 3 — An investigational oral angiogenesis inhibitor reduced the risk of tumor progression by 54% in advanced renal cell carcinoma, a researcher said here.

• Explain to interested patients that this study reported promising results from a trial of a new angiogenesis inhibitor for the treatment of kidney cancer.
• Note that this is an interim analysis and that more study is needed. Also explain that the drug has not yet been approved for use.
• 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 an interim analysis of a phase III trial, pazopanib also had a significantly better response rate than placebo, according to Cora Sternberg, M.D., of San Camillo Forlanini Hospital in Rome.

The oral drug — an inhibitor of the vascular endothelial growth factor and platelet derived growth factors receptors, as well as the cytokine receptor c-kit — also appeared to offer an overall survival advantage, Dr. Sternberg said at the annual meeting of the American Society of Clinical Oncology.

The study was conducted in 22 countries at 80 centers, Dr. Sternberg said, and enrolled 435 patients between April 2006 and April 2007. They were randomized in a two-to-one fashion to either 800 milligrams a day of pazopanib or a matching placebo.

Initially, she said, the study was designed to enroll patients pretreated with cytokine therapy, but with the advent of the tyrosine kinase inhibitors, it was redrafted to allow treatment-naive patients to enroll.

The primary endpoint was progression-free survival, Dr. Stenberg said, and overall — as of May 23, 2008 — patients in the pazopanib arm had a median progression-free survival of 9.2 months, compared with 4.2 for placebo.

Those figures yielded a hazard ratio for progression of 0.46 (95% CI 0.34 to 0.62, P<0.0000001), Dr. Sternberg said.

The figures were even better when the analysis was restricted to patients who had not been treated before — a 60% reduction in the risk of progression that was significant at P<0.001.

Pretreated patients also did well, with a 46% reduction in the risk of progression that was significant at P<0.001.

Indeed, Dr. Sternberg said, progression-free survival was significantly better in all prespecified subgroups, regardless of age, sex, performance status, or risk category.

Overall, the tumor response rate was 30% in the pazopanib patients and 3% among those getting placebo. The median duration of response was 59 weeks, she said, at the 2008 cutoff date.

An interim analysis of overall survival showed a 27% reduction in the risk of death that was significant at P=0.02, Dr. Sternberg said.

The drug had a higher toxicity rate than placebo, with 92% of pazopanib patients reporting any adverse event, compared with 74% of placebo patients.

There were 33 grade 3 events among the pazopanib patients, compared with 14 among those getting placebo.

However, Dr. Sternberg said, the “class effects” of the drug — such as proteinuria, hand-foot syndrome, and mucositis — “were extremely low with pazopanib.”

There were no differences between the arms on three different health-related, quality-of-life measures, she added.

The improvement in progression-free survival is “striking,” said Nicholas Vogelzang, M.D., of the Nevada Cancer Institute, who discussed the report during an oral symposium.

Such an improvement has been seen with earlier members of the class, he said, and leaves “no question that these are highly active agents.”

He added that the tumor response rates were also very striking and noted a “good long duration of response of over a year.”

The study was supported by GlaxoSmithKline , which is developing the drug. The researchers reported financial links to the company. Dr. Vogelzang reported financial links with Allos, Ambit, Amgen, Bayer, Celgene (U), Genentech, Keryx (U), Novartis, Onyx, Pfizer, Wilex, Arqule, Clinical Care Options, Cougar, Imedex, Lippincott Williams and Wilkins, Argos, AstraZeneca, Endocyte, GlaxoSmithKline , Keryx, and Medarex.

Primary source: Journal of Clinical Oncology

Source reference:

Sternberg CN, et al “A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC)” J Clin Oncol 2009; 27(15S): Abstract 5021.

ORLANDO, June 3 — A potential survival benefit in colorectal cancer vanished when the bevacizumab (Avastin) component of a chemotherapy regimen ended, data from a large randomized clinical trial showed.

• Explain to patients that adding a biologic agent to standard chemotherapy did not improve survival in patients with early colorectal cancer.
• Patients did appear to get a survival benefit during the time they received the biologic agent.
• 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.

Overall, adding the targeted agent to FOLFOX6 chemotherapy failed to improve disease-free survival (DFS) compared with FOLFOX6 alone.

However, an analysis that highlighted a controversial, six-month extension of bevacizumab treatment revealed a significant improvement in DFS, according to a plenary presentation at the American Society of Clinical Oncology meeting.

“The addition of bevacizumab to modified FOLFOX6 did not result in an overall statistically significant prolongation in disease-free survival,” said Norman Wolmark, M.D., of Allegheny General Hospital in Pittsburgh.

“There was a statistically significant transient benefit in disease-free survival during the one year that bevacizumab was utilized.”

The findings came from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial involving patients with stage II or III colon cancer.

The primary aim of the study was to determine whether the addition of bevacizumab to combination chemotherapy would prolong DFS compared with chemotherapy alone.

The trial involved 2,700 patients, three-fourths of whom had stage III disease. NSABP investigators randomized the patients to a modified FOLFOX6 regimen (oxaliplatin [Eloxitin], leucovorin, 5-fluorouracil) for 12 cycles over six months, or to the same chemotherapy plus bevacizumab, administered every two weeks during chemotherapy and then as monotherapy for an additional six months.

“We received considerable criticism for giving the bevacizumab for the six months beyond the chemotherapy,” Dr. Wolmark said during an ASCO plenary session. “We will see whether it was or was not a wise decision.”

The primary endpoint was DFS, and clinical events comprised first recurrence, second primary cancer, and death. Analysis of DFS was triggered by accrual of 592 events.

After a median follow-up of 35.6 months, the three-year DFS was 77.4% with bevacizumab and 75.5% without, a nonsignificant difference.

However, analysis of survival curves revealed what appeared to be a separation in favor of bevacizumab, ending sometime after the angiogenesis inhibitor was stopped.

To determine whether a transient benefit did occur, investigators calculated cumulative hazard ratios over time. At one year (when a preplanned interim analysis was performed), the bevacizumab group had a 40% reduction in the hazard for clinical events (HR 0.60, P=0.0004).

After the 12-month mark, the benefit increasingly attenuated. At 1.5 years, the hazard ratio was shrunk to 0.74 but remained statistically significant (P=0.004).

The gap between treatment groups narrowed to hazard ratios of 0.81 at two years (P=0.02) and 0.85 at 2.5 years (P=0.05). At the three-year, final analysis, the benefit had disappeared, reflected in a nonsignificant hazard ratio of 0.87.

A test for interaction between bevacizumab and time yielded a highly significant result (P=0.001).

Analysis of the results by disease stage showed no DFS benefit for patients with stage II colon cancer treated with bevacizumab (HR 0.82, P=0.35) or for the larger group of patients with stage III disease (HR 0.90, P=0.25).

“The results lead us to strongly suggest and consider the use of bevacizumab, particularly for adjuvant colorectal trials stage II and III, where bevacizumab would be given for durations well beyond the one year that was utilized in NSABP protocol C-08,” said Dr. Wolmark.

As an invited discussant of the study, Lee M. Ellis, M.D., of the University of Texas M.D. Anderson Cancer Center, said he doubts that the early benefit in the bevacizumab arm was a fluke, but that, instead, a biologic explanation exists for the finding.

Even if additional data support a possible benefit of bevacizumab, the benefit could be as low as 5% and require long-term therapy to maintain the benefit.

Dr. Ellis questioned whether patients would be willing to bear the financial and physical costs when they have a 95% chance of getting no benefit.

“We have to assume that bevacizumab must be continued for a very long period of time to provide benefit,” he continued. “We should not administer a potent drug like bevacizumab forever in a population where approximately 90% to 95% of patients will not benefit.”

Instead, more effort should be directed toward identifying a marker to predict response to bevacizumab, Dr. Ellis added.

One or more investigators in the NSABP C-08 trial disclosed relationships with Genentech, Amgen, Lilly, and Sanofi-Aventis. Dr. Ellis disclosed relationships with Schering-Plough, Amgen, Bayer, Genentech, Genomic Health, Roche, and sanofi-aventis.

Primary source: Journal of Clinical Oncology

Source reference:

Wolmark N, et al “A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon” J Clin Oncol 2009; 27(15S): Abstract LBA4.