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SAN FRANCISCO -- Questions about statistical versus clinical significance -- as well as cost -- emerged from a study showing a small improvement in progression-free survival (PFS) in metastatic gastric cancer with the addition of a targeted agent to chemotherapy.

Results of a randomized trial showed a median PFS of 5.7 months with chemotherapy plus the angiogenesis inhibitor ramucirumab (Cyramza) versus 5.4 months with chemotherapy alone in patients with previously untreated gastric or gastroesophageal junction cancer. The difference translated into a 25% reduction in the risk of disease progression or death with ramucirumab.

Overall survival did not differ significantly between patients who received chemotherapy alone or with ramucirumab, Charles S. Fuchs, MD, of Yale Cancer Center in New Haven, Connecticut, reported here at the .

In the formal discussion that followed Fuchs' presentation, Steven Leong, MD, of the University of Colorado Cancer Center in Aurora, said the 0.3-month improvement in PFS represented a difference of 9 days.

"If you focus on the median PFS, it doesn't look that impressive," said Leong. "Median PFS looks at a very simple, specific point, and that's where the two [survival] curves come very close together. The hazard ratio (0.75) takes into account all the different time points, and that's probably a more reliable result."

The between-group difference did not match the hazard ratios of previous phase III studies of ramucirumab in the second-line setting, he added.

Turning to cost as a consideration in evaluating the results, Leong noted that patients assigned to ramucirumab received the antibody twice during every 21-day cycle, and the median duration of treatment was 19 weeks. Using the average wholesale price for the drug, he said a single treatment for a 70-kg (154-lb) man would cost $7,456.96, excluding infusion costs. The total drug cost for nine treatments would be $67,112,64.

Leong offered an educated guess that ramucirumab would not win FDA approval as first-line therapy for metastatic gastric/GEJ cancer, adding that Lilly previously announced that it wouldn't seek one. He further predicted that ramucirumab combinations would not replace the current first-line standard of care. Whether the National Comprehensive Cancer Network includes the drug as a first-line option in its guidelines remains to be seen, Leong said.

Ramucirumab won FDA approval as second-line therapy for metastatic gastric/GEJ cancer on the basis of two phase III trials that showed both a PFS and overall survival benefit. Fuchs reported findings from the international multicenter , which evaluated the addition of ramucirumab to standard chemotherapy in patients with newly diagnosed metastatic gastric/GEJ cancer.

The trial involved 645 patients, who were randomized to receive cisplatin and capecitabine or 5-FU, with or without ramucirumab. The primary endpoint was investigator-assessed PFS, and overall survival was the key secondary endpoint.

The primary-endpoint analysis showed a statistically significant benefit with the addition of ramucirumab to chemotherapy (95% CI 0.61-0.94, P=0.011). The advantage held up in the final intention-to-treat analysis, as the ramucirumab group had a median PFS of 5.85 months versus 5.55 months for the control arm (HR 0.75, 95% CI 0.63-0.91, P=0.0024).

Median overall survival was 11.17 months with ramucirumab and 10.74 months without it, a nonsignificant difference (HR 0.96, 95% CI 0.80-1.16).

A subgroup analysis showed a consistent PFS benefit in favor of treatment with ramucirumab. A similar analysis of overall survival did not identify groups that clearly benefited from the addition of the angiogenesis inhibitor.

The overall response rate was 41% with ramucirumab and 36% with chemotherapy alone, and the disease control rate (response plus stable disease) was 82% and 77%, neither of which achieved statistical significance.

The addition of ramucirumab to chemotherapy did not add appreciably to toxicity, Fuchs reported. Only adverse events associated with angiogenesis inhibition (hypertension, hand-foot syndrome, thrombocytopenia) occurred more often in the ramucirumab arm.

About half of patients in each group received additional therapy after progression on randomized therapy. In the ramucirumab arm, 12% of patients continued to receive ramucirumab after progression, and 17% of patients in the control arm received ramucirumab at progression. An exploratory analysis provided a suggestion of improved survival with second-line ramucirumab: median survival of 16.2 months and 14.9 months for patients originally randomized to ramucirumab or placebo respectively, versus 13.2 and 13.0 months for patients in the two arms who received other agents at progression.

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