Practical Perspectives on Treatment of Advanced Gastric/GEJ Cancers - Episode 10

Targeting VEGF in Gastric/GEJ Cancer Treatment


David Ilson, MD, PhD: In other solid tumors, VEGF has been shown to be a viable target for anti-VEGF therapies, and bevacizumab showed positive results in a number of solid tumors, including colon cancer. In esophagogastric cancer, bevacizumab was studied combined with first-line chemotherapy on the AVAGAST trial. Although it did show improvements in response and progression-free survival, ultimately it did not translate into a survival benefit. Right now, we’re not using VEGF-targeted therapy first-line. Ramucirumab, which is a receptor-blocking antibody that blocks the VEGFR2 receptor, was shown in a phase I trial to have some activity in metastatic gastric cancer. That led to 2 randomized trials of this drug. One looked at patients progressing on first-line chemotherapy and randomized patients to supportive care versus ramucirumab monotherapy. That was a positive trial showing that ramucirumab improved progression-free and overall survival compared with supportive care, demonstrating that the drug had single-agent activity. It didn’t induce responses, but it did stabilize the cancer.

The more clinically relevant trial was in patients failing up-front fluorinated pyrimidine/platinum-based chemotherapy. When they were randomized to standard second-line weekly paclitaxel with or without the addition of ramucirumab, paclitaxel and ramucirumab was the superior arm. All the endpoints were improved. Progression-free survival was improved by a little bit less than 2 months, overall survival was improved by 2 months, and the response rate was increased by 12% to 15%. Based on that very positive trial, after patients progress on first-line FOLFOX [oxaliplatin/fluorouracil/folinic acid] or fluorinated pyrimidine/platinum-based chemotherapy, the standard of care is for patients to get paclitaxel/ramucirumab.

That being said, there was a lot of interest in studying ramucirumab with first-line chemotherapy, and the results from that trial were recently presented at the Gastrointestinal Cancers Symposium earlier this year. Unfortunately, it was a negative trial. They did show an improvement in progression-free survival with the addition of ramucirumab to first-line 5-FU [fluorouracil] platinum-based chemotherapy, but it didn’t translate into a survival benefit and there was no improvement in response rate. Based on that negative trial, ramucirumab will not likely be pursued as first-line treatment. We don’t clearly have a first-line VEGF-targeted drug. These drugs should be used second-line in combination with paclitaxel.

Minaxi Jhawer, MD: Ramucirumab, which is another interesting targeting drug targeting VEGFR, has made its way in gastric cancer. Patients have been studied in 2 clinical trials, the REGARD and the RAINBOW clinical trials, both in the second-line setting. These patients were seen to have an improvement in median overall survival when ramucirumab was used as a single agent versus when it was used with paclitaxel in both trials. We clearly see that there has been an improvement with median overall survival—yes, by just a few months, but we clearly made a significant improvement in gastric cancer with the combination of ramucirumab with paclitaxel. There was a recent trial published called the RAINFALL trial, which used ramucirumab in the first-line setting, and unfortunately that was a negative trial. For now, ramucirumab stands as a good option for second-line therapy with or without the paclitaxel combination.

David Ilson, MD PhD: Although ramucirumab as monotherapy has disease stabilization, it’s inferior to ramucirumab plus chemotherapy. Virtually none of us are going to give ramucirumab monotherapy second-line. It induces no responses, and the benefits are marginal, so we’re pretty much going to give chemotherapy second-line. The ramucirumab/paclitaxel data argue that should be the standard. NCCN [National Comprehensive Cancer Network] guidelines actually list ramucirumab as a less optimal treatment alone because it really offers no responses in patients and only briefly stabilizes the cancer.

Transcript Edited for Clarity