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Mixed Results from Targeted Therapy in Colorectal, Lung Cancers

Carlson, Robert H.

doi: 10.1097/01.COT.0000294349.08020.fe

ORLANDO, FL—Targeted anticancer therapies offer the potential of improved patient outcome and fewer side effects compared with conventional treatments, but these promises don't always pan out in clinical trials. Data from two such trials were discussed here in late-breaker oral presentations during the first of the three plenary sessions at the ASCO Annual Meeting.

The Eastern Cooperative Oncology Group (ECOG) 4599 trial of bevacizumab with paclitaxel-carboplatin showed the drug significantly extended survival when compared with chemotherapy alone for patients with previously untreated advanced non-small cell lung cancer (NSCLC).

But results of the CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) trial of the anti-vascular endothelial growth factor receptor (VEGFR) agent PTK/ZK found that adding it to the FOLFOX 4 regimen did not achieve a statistically significant increase in progression-free survival or response rates in patients with advanced colorectal cancer. (FOLFOX-4 is a specific combination of fluorouracil, leucovorin, and oxaliplatin.)

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Bevacizumab in NSCLC

ECOG 4599 is a randomized Phase II/III trial testing paclitaxel plus carboplatin with or without bevacizumab in 878 patients with advanced, non-squamous NSCLC.

Principal investigator Alan B. Sandler, MD, Associate Professor of Medicine at Vanderbilt University Medical Center, noted that a bevacizumab-chemotherapy regimen had already shown a survival advantage in metastatic colorectal carcinoma.



And a small, randomized Phase II trial of paclitaxel-carboplatin with or without bevacizumab showed an improved median time to progression with bevacizumab of 7.4 vs 4.2 months in previously untreated NSCLC patients.

Dr. Sandler reported a median time to progression of 6.4 months on the bevacizumab-chemotherapy arm of E4599, and 4.5 months on the chemotherapy-alone arm, representing a hazard ratio of 0.62.

The response rate was also dramatically improved in the bevacizumab arm—27.2% vs 10.0% with chemotherapy alone.

Most importantly, median overall survival was 12.5 months with bevacizumab vs 10.2 months with chemotherapy alone, representing a hazard ratio of 0.77.

“Also note that 51.9% of patients were alive at one year on the bevacizumab arm, while 43.7% were alive at one year on the chemotherapy-alone arm,” he said. “And at two years, 22% of the bevacizumab-arm patients were alive vs 17% on the chemotherapy-alone arm.”

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Bevacizumab Safety

Neutropenia and thrombocytopenia were seen more in the bevacizumab-chemotherapy patients than in the chemotherapy-alone patients, but the difference between the two arms was not felt to be clinically relevant, Dr. Sandler said.

The incidence of febrile neutropenia was low in both arms, and not statistically different between the two.

Hemorrhage was one of the more common toxicities, occurring in 4.5% of patients receiving bevacizumab-chemotherapy and 0.7% with chemotherapy alone. Although the difference was statistically significant, the incidence with bevacizumab was considered relatively low compared with a higher hemorrhage rate in an earlier, Phase II bevacizumab study.

In the E4599 trial, hemoptysis of Grades 3 to 5 occurred in 1.9% of patients in the bevacizumab-chemotherapy arm and 0.2% in the chemotherapy-alone arm, while Grade 3 to 5 hypertension was seen in 6% and 0.7% of patients, respectively. Dr. Sandler said this was easily managed clinically by adjusting antihypertensive medications.

There were 10 treatment-related deaths on study—two on the chemotherapy-alone arm and eight on the bevacizumab-chemotherapy arm, five of which were related to hemoptysis.

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Gender Difference

A survival benefit was seen in the E4599 trial across all treatment subgroups, Dr. Sandler said, except in gender—a hazard ratio for overall survival of 0.69 for males and 0.96 for females.

“Please note, however, that there still remains a strong treatment effect for females with respect to response rate and progression-free survival,” Dr. Sandler said, noting a response rate of 31.7% with bevacizumab-chemotherapy vs 7.4% for chemotherapy alone.

In the CONFIRM-1 trial, adding PTK/ZK to the FOLFOX4 regimen did not achieve a statistically significant increase in progression-free survival or response rates in patients with advanced colorectal cancer.

He speculated that the survival difference by gender might be due to second- and third-line treatment with EGFR-TK inhibitors, known to have robust activity in women with non-squamous cell histology.



In response to a question from the audience about whether this trial sets a new standard of treatment, Dr. Sandler said, “Yes, I think that with the strict requirements for eligibility [in E4599], the combination of paclitaxel, carboplatin, and bevacizumab is now certainly the new standard for ECOG, and will serve as a control arm for future studies. I also feel it appropriate to be considered as such in the community, when appropriate bodies, such as the FDA, perform their reviews.”

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PTK/ZK in Colorectal Cancer

Another trial presented here did not show a significant improvement in progression-free survival when an anti-VEGF drug was added to chemotherapy.

The placebo-controlled, Phase-III CONFIRM-1 trial randomized 1,168 patients with metastatic adenocarcinoma of the colon or rectum to first-line chemotherapy with the FOLFOX-4 regimen with or without PTK/ZK in a double-blind fashion.

PTK/ZK is a potent, small-molecule tyrosine kinase inhibitor of all known VEGF receptors.

Lead author Joel Randolph Hecht, MD, Clinical Professor of Medicine and Director of the Gastrointestinal Oncology Program at UCLA Jonsson Comprehensive Cancer Center, reported very similar tumor responses in both trial arms of 40% to 45%.

In addition, he reported, approximately 15% of patients in each arm had progressive disease in the first analysis.

The hazard ratio for disease progression by central assessment was 0.88, or a 12% reduction in risk, for the PTK/ZK group, not statistically significant.

But a pre-planned investigator analysis showed a 17% reduction in the risk of progression, with a hazard ratio of 0.83, which was statistically significant, Dr. Hecht said.

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Safety in CONFIRM-1

The PTK/ZK-FOLFOX4 combination was generally well tolerated although more patients in the FOLFOX4-PTK/ZK arm discontinued due to adverse events or withdrawal of consent. In the FOLFOX4-placebo arm, more patients discontinued due to progressive disease.

“Safety results were consistent with that seen with FOLFOX4 therapy, with few differences between the arms, and none of these differences reached statistical significance,” Dr. Hecht said.

There was an increase in hypertension with PTK/ZK that was easily managed, as well as increases in dizziness and venous thrombosis, and a single case of fatal pulmonary embolism.

But unlike in other anti-VEGF pathway trials, there was no significant increase in bleeding, arterial thrombosis, bowel perforation, or posterior reversible encephalopathy.

Overall, the number of deaths from any cause within 28 days of the last study drug administration was the same in both arms.

The trial was sponsored by Novartis and Schering AG Germany, and funded in part by the National Colorectal Research Alliance.

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Speculation on CONFIRM-1 Results

The Discussant for the study, Lee M. Ellis, MD, Professor of Surgical Oncology and Cancer Biology at the University of Texas M. D. Anderson Cancer Center, reviewed the biology of VEGF and the effects of anti-VEGF therapy, distinguishing it from anti-angiogenic therapy.

“Anti-angiogenic therapy is not as far along in development and is meant to target endothelial cells,” Dr. Ellis said. “We don't know the effects on permeability—it may increase permeability, or decrease it.

“And we don't know if it will inhibit blood vessel growth, or how it will affect blood flow or vessel function within tumors.”

In contrast, he said, anti-VEGF therapy inhibits the activity of both endothelial cells and some—-but not all—tumor cells.

“And we definitely cannot show for sure that [anti-VEGF therapy] inhibits new blood vessel growth,” he said. “This is very difficult to do in the clinic.”

Dr. Ellis speculated on what might have happened in the CONFIRM-1 trial.

“After administration of chemotherapy and PTK/ZK, you may get an increase in VEGF expression, although PTK/ZK is there to inhibit activity of the receptor,” he explained. “However, at 23 hours after washout of PTK/ZK you have an increase in VEGF secretion from tumor cells and endothelial cells.

In the ECOG 4599 trial of bevacizumab with paclitaxel-carboplatin, the addition of bevacizumab significantly extended survival when compared with chemotherapy alone for patients with previously untreated advanced NSCLC.

“This is unopposed because of the washout of the tyrosine kinase inhibitor, so it's possible that any effect or benefit gained early on was lost at later time points.”



But not achieving a primary trial endpoint does not mean a drug is not active, Dr. Ellis said.

“We have to remember that in the Phase III trial of capecitabine plus or minus bevacizumab in refractory breast cancer [reported at the most recent San Antonio Breast Cancer Symposium] there was no additional benefit to adding bevacizumab to capecitabine.

“That trial did not meet its primary endpoint, but obviously with persistence and trust in the biology of the system, and trust in the drug, there have been many successes, including some reported here.”

© 2005 Lippincott Williams & Wilkins, Inc.
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