FDA Approval of Cyramza Offers Hope for Gastric Cancer Patients

Alexandria Phan, MD

Ramucirumab is a fully humanized monoclonal antibody against the vascular endothelial growth factor receptor 2 (VEGFR2). This is a biological agent that has been tested in several cancers including stomach and lung cancers. On Monday, the FDA approved this agent for the treatment of patients with advanced gastric or gastro-esophageal junction (GEJ) cancers.

Ramucirumab’s safety and effectiveness were evaluated in a clinical trial of 355 participants with inoperable or metastatic stomach or GEJ cancer. The trial was designed to measure the length of time participants lived before death (overall survival).

Results showed participants treated with ramucirumab experienced a median overall survival of 5.2 months compared to 3.8 months in participants receiving placebo, and they also had a delay in tumor progression (progression-free survival) compared to placebo. Additional study with ramucirumab in combination with paclitaxel (a chemotherapy agent) versus paclitaxel alone also showed improved survival.

The most common side effect experienced by participants treated with ramucirumab was elevated blood pressure.

Both studies clearly demonstrated that ramucirumab is an effective option for patients with inoperable or metastatic stomach cancer.

While the incidence of stomach and gastro-esophageal cancers is decreasing in the USA, stomach cancer is still one of the top five cancers worldwide where there is no cure and its prognosis is very poor, especially for those with advanced/metastatic stage disease. Treatment for this deadly disease is very limited, and the approval of ramucirumab for these patients provides additional hope and additional treatment options for patients and their families.

Richard M. Goldberg, MD

The approval of ramucirumab as a single agent for the treatment of patients with metastatic gastric cancer is significant for many reasons.

Gastric cancer is the fourth leading cause of cancer death worldwide. Treatment for patients with advanced gastric cancer has been limited to chemotherapy except in the minority of cases where the tumor cells overexpress HER-2. In those cases, trastuzumab plus chemotherapy can be beneficial.

Patients with advanced gastric cancer often are older and symptomatic from their cancers, making combination chemotherapy difficult for them to tolerate. Ramucirumab targets blood vessel growth and is effective as a single agent. As a targeted therapy rather than chemotherapy its main side effect was hypertension, a condition readily amenable to treatment.

The drug’s ability to improve survival when administered as a single agent as compared to placebo and its modest side effect profile in a large cohort of previously treated patients with advanced gastric cancer distinguishes it from a multitude of other targeted agents that have proven ineffective in this setting. It holds great potential for combination with chemotherapy and will serve as a model for drug discovery in a disease for which new developments are sorely needed.

The medical oncology community will likely rapidly adopt this agent as a cornerstone drug for treatment of this disease.

Rachel Webster, DPhil, MSc

Two positive phase 3 studies of ramucirumab (REGARD and RAINBOW) and the recent FDA approval of ramucirumab as a single agent (based on results from the REGARD trial) confirm that there is a role for angiogenesis inhibitors in treating gastric cancer. These positive data have reignited interviewed physicians’ enthusiasm for this class of agents in gastric cancer, and ramucirumab is a welcome new biologic addition to the gastric treatment armamentarium.

Worth noting is the fact that ramucirumab is the first targeted therapy to secure regulatory approval for patients with advanced or metastatic gastric cancer who have progressed on or following fluoropyrimidine- or platinum-containing chemotherapy (i.e., second- and later-line treatment). This is a patient population for which treatments are extremely limited.

There is no universal standard second- or later-line chemotherapy for gastric cancer, and administering therapy in these patients is particularly challenging given the aggressive nature of the disease and patients’ rapidly declining performance status. A sizable proportion of patients in the second- and later-line settings will receive best supportive care (BSC) only or be enrolled in a clinical trial.

It is notable that ramucirumab has been approved as a single agent, as most other targeted therapies in gastric cancer are being evaluated as adjuncts to therapy. Ramucirumab thus provides a chemotherapy-free treatment option and an alternative therapy to patients who are unable to tolerate chemotherapy’s side effects. As such, drug treatment rates in second- and later-line populations may modestly increase, particularly in the United States where we anticipate that ramucirumab will, at least initially, be more frequently utilized as a monotherapy.

However, ramucirumab does carry a black-box warning for increased risk of potentially fatal hemorrhagic events. The incidence of bleeding in the REGARD trial was reported as 3.4% for ramucirumab versus 2.6% for placebo. Even so, life expectancy in the approved treatment setting is short, as are ramucirumab treatment durations (approximately 2 months). Therefore, we do not expect this side effect will significantly hinder ramucirumab’s uptake in gastric cancer.

Additionally, ramucirumab (in combination with paclitaxel) is the first therapy to achieve more than a 2-month improvement in overall survival in later-line treatment settings, as shown in the RAINBOW trial, and the company has plans for separate regulatory submission of the agent in combination with paclitaxel.

While there is no universal standard of care for the second- and later-line patient populations and the REGARD trial (which evaluated ramucirumab vs. BSC) was sufficient for regulatory approval in the United States, it is possible that the European Medicines Agency, for example, takes a different view. Other countries might view non-approved second-line therapies such as irinotecan and paclitaxel as the standard of care, and in this instance, the RAINBOW trial (which evaluated ramucirumab/paclitaxel vs. paclitaxel) could carry weight for regulatory approval in these countries.

In Europe and Japan, we expect that ramucirumab will predominantly be used in combination with chemotherapy (i.e., paclitaxel), and thus add sales to the market rather than replacing sales of current treatments. In the United States, we expect that FDA approval of ramucirumab in combination with paclitaxel will fuel its uptake.

In the short term, with the absence of approved second- or later-line competitors, ramucirumab should enjoy robust uptake and commercial reward. In the absence of a predictive biomarker for selecting patients who will most benefit from ramucirumab treatment, ramucirumab could be used in both HER2-negative and HER2-positive second- and later-line gastric cancer patients.

However, we would expect ramucirumab will have a greater role in the larger, more lucrative HER2-negative population because a sizable proportion of HER2-positive patients eligible for a second-line treatment in the United States will receive trastuzumab (Herceptin) beyond disease progression while switching chemotherapy regimen, which is similar to the breast cancer treatment algorithm, even though trastuzumab is only approved as a first-line treatment in gastric cancer.

Notably, owing to ramucirumab’s lack of a biomarker, we anticipate that market entry of T-DM1 (Kadcyla) as a second-line treatment for HER2-positive gastric cancer (in approximately 3 years’ time in the United States) will push ramucirumab’s use to the HER2-negative patient population.