Ramucirumab and the Evolving Role of Targeted Therapy in Advanced Gastric Cancer

Adel Aref

Gastric cancer is the second leading cause of cancer mortality worldwide. For many years, the only option of first-line treatment of metastatic gastric cancer was fluoropyrimidine and cisplatin. The ToGA trial revealed a new era in the management of advanced gastric cancer (1), in which around 20% of patients who have overexpression of HER2 receptor the addition of trastuzumab to fluorouracil and cisplatin had led to improvement in overall survival.

VEGF and VEGFR represent an important target in the management of advanced gastric cancer. Bevacizumab was tested in the management of metastatic gastric cancer in the AVAGAST trial, where the addition of bevacizumab to chemotherapy was associated with significantly increased progression-free survival and overall response rate in the first-line treatment of advanced gastric cancer but not the overall survival (2). In another trial, EXPAND, addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial (3).

Options for treatment in second-line setting are not clear and more limited. When reviewing the NCCN guidelines and the ESMO guidelines we don’t find a category I of recommendations regarding the best option. Till recently, there was no data for the use of targeted therapy in the second-line setting. In the NCCN guidelines (version 3, 2013) the options for second-line are mainly taxanes and irinotecan, either as single agents or in combinations.
In the recently published phase III trial, REGARD trial (4), 355 patients at 119 centres in 29 countries,  aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1),  to receive best supportive care plus either ramucirumab or placebo, intravenously once every 2 weeks. Ramucirumab is a monoclonal antibody, VEGFR-2 antagonist. The results of this trial showed that the median overall survival was 5.2 months (IQR 2.3-9.9) in patients in the ramucirumab group and 3.8 months (1.7-7.1) in those in the placebo group (hazard ratio [HR] 0.776, 95% CI 0.603-0.998; p=0.047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0.774, 0.605-0.991; p=0.042).

Median time to deterioration in ECOG performance status to a score of 2 or worse was 5.1 months (IQR 1.9–16.8) in the ramucirumab group and 2.4months (1.3 to not reached) in the placebo group. The survival benefit associated with ramucirumab was similar between Asian patients and those from America, Europe, and Australia, although relatively few Asian patients were enrolled. Ramucirumab was well tolerated in this patient population, with similar rates for most adverse events between the ramucirumab and placebo groups.

The way of obtaining benefit from anti-angiogeneic agents still needs more understanding. In subset analyses of the AVAGAST trial, survival benefit for bevacizumab was limited to non-Asian patients.

In a biomarker evaluation from the AVAGAST trial, patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival (hazard ratio [HR], 0.72; 95% CI, 0.57 to 0.93) versus patients with low VEGF-A levels (5).

In the era of targeted therapy, we need more biomarkers as predictive and prognostic factors to be more able to tailor treatment for the patients, especially when the treatment is associated with toxic side effect and increase the cost of treatment.

References:

  1. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687–97.  
  2. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011;29(30):3968-76.
  3. Lordick F, Kang YK, Chung HC, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 2013;14(6):490-9.
  4. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383(9911):31-9.
  5. Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol 2012; 30(17):2119-27.

Discussion question:

What is the best way to tailor treatment with targeted therapy in gastric cancer?

The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.

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