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Roche Presents Several Abstracts for New Targeted Cancer Drugs at ASCO

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ORLANDO, Fla. — Roche presented several studies supporting new combination treatments with Herceptin in stomach cancer and in metastatic breast cancer and reported promising data on an investigational pharmacogenomics-guided melanoma treatment at the American Society for Clinical Oncology's annual meeting here this week.

At the meeting, Roche presented data from a pivotal study showing Herceptin (trastuzumab) had a survival benefit in stomach cancer patients; results from a Phase II efficacy trial combining Herceptin and the cell-killing agent DM1 that showed treatment benefit in breast cancer patients who had failed treatment with two or more HER2-targeted treatments; and discussed the potential of developing PLX4032, a drug that targets BRAF-mutated tumors in melanoma, with a companion diagnostic.

Herceptin in Stomach Cancer

Herceptin's indication may extend into gastric cancer, according to the results of a Phase III trial presented by Roche at ASCO.

Results from the first randomized, prospectively-designed, multi-center Phase III study looking at the safety and efficacy of Herceptin in HER2-positive stomach cancer showed that trastuzumab in combination with chemotherapy is "superior" to chemotherapy alone.

"This first randomized trial investigating anti-HER2 therapy in advanced gastric cancer showed that Herceptin plus chemotherapy is superior to chemotherapy alone," Van Cutsem et al. concluded in their abstract. "The overall survival benefit indicates that Herceptin is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer."

The study, called ToGa (for trastuzumab in gastric cancer), randomized 594 patients with HER2-positive gastroesophageal and gastric adenocarcinoma to receive Herceptin plus chemotherapy (5-fluorouracil or capecitabine and cisplatin) or chemotherapy alone for six cycles.

The primary end point for the study was overall survival; secondary end points included overall response rate, progression-free survival, time to progression, duration of response, and safety. An interim analysis was planned at 75 percent of deaths. According to Roche, an independent data monitoring committee recommended releasing the data when the pre-specified boundary was exceeded and median follow-up of patients reached 17.1 months.

Researchers initially tested the tumors from 3,807 patients for HER2 status, and determined that 22 percent were HER2 positive. Then 594 patients were randomized at various sites in Europe, Latin America, and Asia.

The results showed that medial overall survival "significantly improved" for patients on the trastuzumab/chemo combination versus those on just chemo. The objective response rate was 47 percent in the trastuzumab/chemo arm and 35 percent in the chemo arm.

According to researchers, the safety profile was similar in both arms of the study, with "no unexpected adverse events in the trastuzumab/chemo arm." Also, while there was no difference in symptomatic congestive heart failure between arms, researchers noted, asymptomatic left ventricular ejection fraction decreases were reported in 5 percent of the patients receiving the combination treatment versus 1 percent in those receiving chemotherapy.

"Advanced GC is an incurable disease; new and less toxic treatments are needed," the study authors noted in their abstract, adding that HER2 overexpression has been reported in between 6 percent and 35 percent of stomach and gastroesophageal tumors.

Herceptin is developed by Genentech, which operates under Roche. Genentech markets the drug inside the US, while Roche is responsible for marketing in international markets.

Herceptin is currently approved in the US as a single agent and in combination with various chemotherapy regimens for the treatment of adjuvant treatment of HER2-overexpressing breast cancer and for the treatment of metastatic breast cancer.

T-DMI

Roche presented final efficacy results from a Phase II study of a new antibody-drug conjugate, T-DMI (trastuzumab plus DMI), that has shown treatment benefit in metastatic breast cancer patients whose cancer had progressed despite treatment with two or more HER2-targeted therapies.

In the study, by Krop et al., researchers looked at the correlation between patient response to T-DMI and HER2 status in 112 metastatic breast cancer patients. HER2 status was established in patients by fluorescent in situ hybridization, immunohistochemistry, mRNA quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay.

In the trial, 107 patients were evaluable for efficacy at median 4.4 months follow-up. Of these patients 42 or 39 percent had partial responses on T-DM1. Out of 86 patients centrally tested, 64 were HER2 positive and 15 were HER2 negative, as confirmed by FISH and/or IHC. Half of 64 HER2-positive and 13 percent of 15 HER2-negative patients had partial responses.

Among 39 HER2-positive patients who were efficacy-evaluable with qRT-PCR data, 68 percent had partial responses above median levels while 35 percent had partial responses below median levels.

"HER2-positive patients had better responses to T-DM1 than HER2-negative patients, although a small number of partial responses were observed in HER2-negative patients," the study authors reported. "Assessment of HER2 expression by qRT-PCR may identify patients more likely to respond to T-DM1 therapy."

DM1 is developed by ImmunoGen. Genentech and Roche are conducting a broad clinical program with T-DM1 in HER2-positive breast cancer.

According to Roche, a Phase III study evaluating T-DM1 for second-line advanced HER2-positive breast cancer was initiated this year.

New Rx/Dx Product in Melanoma?

Roche is developing a new drug with partner Plexxikon, referred to as PLX4032/R7204. At ASCO's annual meeting, Roche presented data from a Phase I dose-escalation trial that showed the investigational agent was efficacious in a number of cancers linked to expression of mutated BRAF protein.

According to the abstract by Flaherty et al., dose escalation of PLX4032 reached dose-limiting toxicities at 1120 mg BID. The maximum tolerated dose was found to be 720 mg BID. However, researchers suggested future studies should look at how patients tolerate 960 mg BID.

"PLX4032 exhibits anti-tumor activity in V600E BRAF mutant tumors," the authors concluded. "These observations confirm that V600E BRAF is a valid therapeutic target in human cancer."

BRAF-mutated tumors occur in 60 percent of melanomas and are present in 8 percent of solid tumors. Based on the Phase I study results, PLX4032 could enter registration trials for malignant melanoma later this year, Roche said in a statement.

"If successful in treating melanoma, PLX4032 is expected to be launched with a companion diagnostic," according to Roche. The companion diagnostic would also be co-developed by Roche and Plexxikon.

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