David H. Ilson, MD, PhD: Recent clinical trials have more clearly defined lines of treatment in metastatic esophagogastric cancer. We now have randomized trials clearly indicating a benefit for patients in moving on to second-line treatment after progression on first-line therapy. We had some pivotal early randomized trials indicating that after progression on fluorinated pyrimidine platinum, we see a survival benefit for patients receiving docetaxel versus best supportive care alone from British data. Japanese trials looked at allowing patients to receive either paclitaxel or irinotecan versus best supportive care, and those studies also showed a survival benefit for second-line chemotherapy.

In the second line, we have the advent of ramucirumab. That was really a game changer in the second-line treatment of metastatic esophagogastric cancer. The pivotal RAINBOW trial, in patients progressing on first-line treatment, assigned patients to paclitaxel alone weekly or paclitaxel plus ramucirumab. That trial showed unequivocal benefit with ramucirumab. There was an improvement in response rate that was clinically meaningful and improvement in progression-free and overall survival, with a median overall survival of nine months, which arguably approaches what we achieve with first-line FOLFOX [folinic acid, fluorouracil, oxaliplatin] therapy. Paclitaxel/ramucirumab is now the standard second-line therapy in esophagogastric cancer, and really should be the control arm of any future trials trying to evaluate other treatment options in the second-line setting.

We would really reserve irinotecan for third-line treatment. We’ll talk about this later, but immunotherapy drugs have shown benefit in the PD-L1–positive patients in the chemotherapy refractory setting, beyond second- or third-line treatment.

Salah-Eddin Al-Batran, MD: My second-line therapy of choice in metastatic gastric cancer is ramucirumab plus paclitaxel for patients who are not taxane pretreated. In Germany and in many parts of the world, taxane pretreatment is increasing because taxanes have proven to be efficient in the neoadjuvant setting or in the adjuvant setting. In the cases where patients have received a taxane, it’s important to look at how much time has passed since the last administration of taxane. In patients progressing shortly after a previous taxane, we tend to use irinotecan in the second-line treatment.

Kei Muro, MD: In general, the drugs used in the first-line setting are not used in the second-line setting and beyond. Most of the time, it is because patients have built up a tolerance. It is important to wait to link the second- and third-line treatments sequentially through proper timing, using effective agents. Typically, we often use second-line paclitaxel plus ramucirumab or nab-paclitaxel plus ramucirumab. We rarely ever perform ramucirumab monotherapy.

Salah-Eddin Al-Batran, MD: There are a number of cytotoxic agents that have shown some activity in the second-line setting in gastric cancer. These include docetaxel, paclitaxel, and irinotecan. There have been multiple randomized trials with different quality standards showing that these compounds do have activity. However, overall survival rates have been relatively short, being four to five months, with these agents. Overall, I think these agents are valuable and we do use them in different lines of the treatment. But still it’s important to highlight that addition of ramucirumab to paclitaxel is superior to paclitaxel alone, where paclitaxel is not superior to the other drugs like docetaxel and irinotecan.

Transcript edited for clarity.