Chemotherapy + Ramucirumab as Second-Line Therapy in mGC

Salah-Eddin Al-Batran, MD: In the second-line setting, we mostly use ramucirumab plus paclitaxel, so we prefer the combination over monotherapy. However, ramucirumab monotherapy still plays an important role in patients who do not want to have cytotoxic agents or in patients who have contraindications against paclitaxel or irinotecan. There’s also a group of patients for whom we try monotherapy. This group consist of patients who have very minimal metastatic disease at remission, such as small lymph nodes only, where you could try with monotherapy. In most cases, we prefer a combination of paclitaxel and ramucirumab over the ramucirumab monotherapy.

David H. Ilson, MD, PhD: The other issue that comes up with the use of ramucirumab is that the drug did get regulatory approval by itself as a second-line treatment. The trial of ramucirumab versus best supportive care without chemotherapy was also a positive trial, indicating modest improvements in progression-free and overall survival. But ramucirumab alone really doesn’t induce responses, and it’s at best a stabilizing drug. Really, because patients in the second line are often going to be more symptomatic with an advancing disease burden, the preference would be to combine ramucirumab with an active chemotherapy drug, paclitaxel. We saw a response rate approaching 30%, which is clinically meaningful.

Ramucirumab alone achieved no greater response than placebo, although there was more disease control and disease stabilization. There would be rare, if any, circumstances in which I would give a patient ramucirumab alone. The argument is that we can give this drug to the sicker patient with poor functional status, but that’s the patient who’s not going to benefit because there’s no response. If some patients are on paclitaxel/ramucirumab and they develop cumulative taxane toxicity, neuropathy, and other issues, and they’ve shown response, we might consider ramucirumab maintenance therapy later, but that would be the exception.

Another consideration—and we’ll talk about this in the discussion of adjuvant treatment—is that the standard preoperative chemotherapy for gastric cancer now is the FLOT regimen, which is infusional 5-FU [fluorouracil], leucovorin, oxaliplatin, and docetaxel. Increasingly, patients will have had previous exposure to a taxane, so when there’s recurrence, we could argue that the patient has already seen a taxane and that combining a taxane with ramucirumab as a salvage option may not be optimal. We’re particularly concerned in patients who have disease progression within six months of receiving a perioperative or adjuvant treatment. Based on this, there was a recent clinical trial conducted in Germany. It was a randomized phase 2 trial that has only been published in abstract form, but they compared second-line treatment with paclitaxel/ramucirumab to FOLFIRI [folinic acid, fluorouracil, irinotecan] plus ramucirumab. It’s a phase 2 trial, and many of the patients on this trial had received a previous taxane as an adjuvant or neoadjuvant treatment. The trial did suggest a higher response rate for FOLFIRI/ramucirumab versus paclitaxel/ramucirumab.

Acknowledging that many patients will now be getting a taxane as part of their preoperative or adjuvant treatment, we don’t really expect that the benefit of ramucirumab is a chemotherapy-dependent one. We think it’s a biologic drug that enhances the efficacy of chemotherapy, and we don’t expect that benefit to be limited to a taxane. Based on this, the NCCN [National Comprehensive Cancer Network] guidelines have endorsed—in appropriate patients, particularly if they had recent taxane exposure or progression on a taxane—considering FOLFIRI/ramucirumab as an appropriate partner for a second-line treatment, which makes sense clinically.

Kei Muro, MD: In Western countries, FLOT is increasingly being used as a perioperative treatment, as well as first-line treatment. In Japan, S-1 [tegafur/gimeracil/oteracil] plus docetaxel has become the new standard treatment for stage III advanced gastric cancer as adjuvant therapy. In Asia, DOS—docetaxel, oxaliplatin, and the S-1 triplet regimen, including taxanes—is increasingly used as a perioperative chemotherapy. Please refer to the PRODIGY trial. If taxanes are already being used in previous therapy, I believe that irinotecan-based therapy should be used in the second-line setting. Of course, it is reasonable to add ramucirumab to it. It is a strategy that is already widely used in colorectal cancer.

Transcript edited for clairty.