Treatment Advances Bring New Hope in Gastric Cancer

Charles S. Fuchs, MD, MPH

Several new drugs have recently shown promise for the treatment of gastric cancer, including rilotumumab, ramucirumab, and anti-HER2 agents, according to a presentation at the 2013 Chemotherapy Foundation Symposium.

“It is an exciting time in gastric cancer. Hopefully, with these new treatments, we will move the needle forward on survival, said Charles Fuchs, MD, Dana- Farber Cancer Institute, Boston, Massachusetts.

It hasn’t always been this way, he continued. “Gastric cancer has not received enough attention. Worldwide, it is the fourth most common cancer, and it is the second leading cause of cancer-specific death.” In 2012, about 21,000 new cases of gastric cancer are expected in the United States, excluding esophageal cancers.

The standard of care is fluoropyrimidines plus a platinum agent, with survival often in the range of 8 to 10 months. Newer therapies are sorely needed, Fuchs said.

A recent success is the use of trastuzumab (Herceptin) for HER2-positive (HER2+) gastric cancer. In the ToGA trial, 810 HER2+ patients were randomized to capecitabine or 5-FU (physician’s choice) plus cisplatin or the same chemotherapy plus trastuzumab. Overall survival (OS) was 13.8 months with trastuzumab versus 11.1 months for the control arm (P = .0046). This study led to the approval of trastuzumab for frontline treatment of HER2+ gastric cancer.

The next step, according to Fuchs, is to study T-DM1 (Kadcyla), the antibody-drug conjugate that combines trastuzumab with the potent cytotoxic agent emtansine, in HER2+ gastric cancer. A phase III study is comparing T-DM1 every 3 weeks versus T-DM1 weekly versus standard taxane therapy (docetaxel or paclitaxel) in HER2+ advanced gastric cancer (NCT01641939).

More recently, c-MET inhibition has become a research focus in gastric cancer. Combining the c- MET inhibitor rilotumumab with epirubicin/cisplatin/capecitabine (ECX) showed a trend toward improved survival in the overall analysis of a recent phase II study.

Promising Agents in Advanced Gastric Cancer

Agent

Target

Trial

OS advantage versus control (months)

Trastuzumab

HER2

ToGA^a

2.7

Ramucirumab

VEGFR-2

REGARD^b

1.4

Rilotumumab

c-MET

Phase II study^c

5.4

^aPatients were randomized to capecitabine or 5-FU (physician’s choice) plus cisplatin or the same chemotherapy plus trastuzumab.

^bPatients were randomized to ramucirumab versus placebo.

^cOS benefit was observed in subset of patients with high MET expression who received rilotumumab plus ECX versus ECX alone.

ECX indicates epirubicin/cisplatin/capecitabine; OS overall survival.

An exploratory analysis of this phase II trial showed that in patients with high expression of MET, median OS improved from 5.7 months with chemotherapy alone to 11.1 months with the addition of rilotumumab, whereas the addition of rilotumumab to chemotherapy was unfavorable in those with low MET expression.

The ongoing RILOMET-1 study is evaluating rilotumumab plus ECX as first-line therapy in 450 patients with MET-positive gastric or gastroesophageal junction cancer (NCT01697072).

A parallel effort is an ongoing study comparing FOLFOX with or without a MET monoclonal antibody in first-line therapy for advanced gastric or gastroesophageal junction cancer.

With VEGF, studies showed that patients with higher levels of expression in their tumor following gastric cancer resection had worse outcomes. This led to the testing of anti-VEGF therapy with bevacizumab in the AVAGAST study. The addition of bevacizumab appeared to improve survival in this study of 774 patients with gastric cancer (J Clin Oncol. 2011;29[30]:3968-3976).

Interestingly, this was a global trial and outcomes were different according to geographic region. A significant survival benefit for bevacizumab was observed in the Americas and Western Europe, but the benefit was attenuated in Asia.

“The study was not positive, but did support the concept of further study of inhibiting the VEGF pathway in gastric cancer,” Fuchs said.

Subsequently, the REGARD study evaluated the anti-VEGFR-2 monoclonal antibody ramucirumab in 355 patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following progression on first-line therapy. Patients were randomized to ramucirumab versus placebo. Ramucirumab significantly improved OS (5.2 months versus 3.8 months for placebo) and progression-free survival (PFS; median of 2.1 months versus 1.3 months for placebo).

Twelve-week PFS was 40% versus 16% for placebo. Toxicities were comparable between the ramucirumab and placebo groups; adverse events of any grade were reported by 57% of the ramucirumab group and 58% of the placebo group.

As might be expected, more patients treated with the antiangiogenesis drug had hypertension (8% versus 3% in the placebo group for any grade hypertension). No important toxicity signals emerged in this trial.

Ramucirumab achieved similar OS to docetaxel or irinotecan versus best supportive care in other phase III trials, according to Fuchs. “We see a similar benefit with ramucirumab as with other agents, but a better toxicity profile. It is important to look at toxicity when the drug is added to chemotherapy,” Fuchs said.

Based on results of the REGARD study, the FDA granted priority review to ramucirumab.

A combination strategy with ramucirumab is also being explored. The RAINBOW study randomized 663 patients with metastatic gastric cancer who failed on first-line therapy to paclitaxel plus ramucirumab or paclitaxel plus placebo (NCT01170663). A preliminary news release reported significant improvement in PFS and OS in those treated with ramucirumab.

“We will need to see more details on the results,” Fuchs said.

Fuchs, C. Novel agents in gastric cancer. Presented at: 2013 Chemotherapy Foundation Symposium; November 6-8, 2013; New York City.