Washington Editor

New Phase III data presented at the 2009 ECCO-ESMO European Multidisciplinary Congress in Berlin showed that Amgen Inc.'s Vectibix (panitumumab) plus chemotherapy used as a second-line treatment significantly improved progression-free survival (PFS) in patients with KRAS wild-type metastatic colorectal cancer compared with chemotherapy alone, 5.9 months vs. 3.9 months.

Results of a head-to-head trial also reported at the meeting showed that Amgen's denosumab was superior to Novartis AG's Zometa (zoledronic acid) in delaying time to the first on-study skeletal-related events (SREs) and the first-and-subsequent SREs in patients with advanced breast cancer.

Investors, however, were unimpressed, with Amgen's shares (NASDAQ:AMGN) dipping 2.4 percent Tuesday, or $1.48, to close at $60.83.

In Amgen's global, multicenter, randomized Phase III trial, known as study 181, Vectibix, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), was evaluated in combination with FOLFIRI, an irinotecan-based chemotherapy, in 1,186 patients with mCRC.

Tumor KRAS status was ascertained in 91 percent of study participants - the highest number ever reported for a second-line trial, lead investigator Marc Peeters, coordinator of the digestive oncology unit at the University Hospital Ghent Belgium, told reporters Tuesday during a media briefing.

The study originally was designed to compare the treatment effect in the all randomized population, but was later amended to focus on hypothesis testing in the wild-type KRAS subset, Peeters noted.

The trial was the first large, randomized study prospectively analyzed by KRAS status as a predictive biomarker for EGFR treatment in second-line mCRC, Peeters said. The study's primary objective was to assess the effect of Vectibix on PFS and overall survival by KRAS mutational status, he noted.

Other study endpoints included objective response rate, time to progression, duration of response, safety and patient-reported outcomes.

Results showed that the addition of Vectibix to chemotherapy significantly improved median PFS by two months, 5.9 months vs. 3.9 in the chemotherapy alone group, Peeters said. However, he noted, while improvement in overall survival was greater in the Vectibix arm, 14.5 months vs. 12.5 months in the chemotherapy group, the difference was not statistically significant.

In the wild-type KRAS patients, the objective response rate was 35 percent in the Vectibix plus chemotherapy arm vs. only 10 percent in the chemotherapy alone group, Peeters said.

The overall response rate in the mutated KRAS patients was 13 percent in the Vectibix arm vs. 14 percent in the chemotherapy alone arm. "There was no evidence of benefit in patients in whom tumor KRAS mutations were detected when panitumumab was added to chemotherapy," Peeters said.

He noted that 73 percent of wild-type KRAS patients in the Vectibix arm had adverse events, with 52 percent in the chemotherapy alone arm. Adverse events in the mutated KRAS population was similar, with 64 percent in the Vectibix arm and 50 percent in the chemotherapy alone arm.

Peeters noted that there was a wide range between the Vectibix arms vs. the chemotherapy alone arms with skin toxicity events: 37 percent in the wild-type KRAS patients receiving Vectibix and 2 percent in the chemotherapy arm, and 32 percent in the mutated KRAS Vectibix group and 1 percent in the chemotherapy arm.

Peeters noted that there were only two-infusion related reactions in the study, less than 1 percent, "which is a very, very low number." Both of those reactions were in wild-type KRAS patients who had received Vectibix plus chemotherapy.

Nonetheless, Peeters said, the adverse event profile was as expected for an anti-EGFR antibody combined with chemotherapy.

"It was important we see whether this drug combination was tolerable and convenient for the patients, and we can say that panitumumab was well tolerated, convenient given every two weeks without any premedication, when administrated with FOLFIRI," Peeters said.

In Amgen's 34-month Phase III head-to-head trial, known as study 136, denosumab vs. Zometa, the current standard of care, was evaluated in 2,046 patients with advanced breast cancer, said lead investigator Alison Stopeck, associated professor of medicine at the University of Arizona.

Results showed that denosumab administered subcutaneously demonstrated superiority for both delaying the time to the first on-study SREs, including fracture, radiation to bone, surgery to bone or spinal cord compression, and delaying the time to first-and-subsequent SREs. Both results were statistically significant, Stopeck told reporters.

However, she noted, the median time to first on-study SRE was not reached for denosumab and therefore could not be estimated. The median time to first on-study SRE was 26.5 months for Zometa. Denosumab also delayed the median time to first on-study SRE or hypercalcemia of malignancy compared with Zometa.

In a prespecified exploratory analysis, patients on the denosumab arm reported worsening of pain later than those on the Zometa arm, 88 days vs. 64 days, Stopeck said. Adverse events were similar in the two patient groups, 96 percent for denosumab vs. 97 percent for Zometa.

While Stopeck emphasized that the rate of serious adverse events was lower in the denosumab group, 44 percent vs. 46 percent for Zometa, osteonecrosis of the jaw was slightly higher in the denosumab group, 20 patients, or 2 percent, vs. 14, or 1.4 percent, of Zometa patients.

Increased rates of adverse renal events and acute phase reactions were higher in the Zometa group, while hypocalcemia was higher in the denosumab group, Stopeck noted.

Based on the results of Amgen's study 136, which showed equivalent safety of denosumab and more convenient dosing vs. Zometa, Oppenheimer & Co. Inc. analyst Bret Holley said that, once approved, he expected Amgen's drug to be preferred over Novartis'.

Cowen & Co. analyst Eric Schmidt agreed, adding that the study 136 results supported his view that denosumab would "rapidly dominate and expand" the $1.4 billion worldwide market for bone agents in the oncology setting.