Ramucirumab for Progressive Disease in Gastric Cancer
Panelists: Johanna C Bendell, MD, Sarah Cannon Research Institute ; David H Ilson, MD, PhD, Memorial Sloan Kettering Cancer Center; Manish A Shah, MD, Weill Cornell Medicine; Kohei Shitara, MD, National Cancer Center Hospital East
Johanna C. Bendell, MD: We talked about HER2-positive disease and not continuing treatment past the first line. What about our HER2-negative patients who are going past first-line therapy, who now have progressive disease? What treatment options are available, and how do we choose? Ramucirumab? Manish, tell us about ramucirumab and how you use it.
Manish A. Shah, MD: Ramucirumab is an important drug based on 2 large phase III studies that demonstrated benefit in the second-line setting versus best supportive care, as well as in combination with Taxol versus Taxol alone. Ramucirumab is a VEGFR2 inhibitor. It’s different from bevacizumab, which is a VEGFA inhibitor. As you know, we examined bevacizumab in the first-line setting in gastric cancer, and that was a negative study. Recently, ramucirumab was also examined in the first-line setting and was also a negative study. So really, ramucirumab is actually the targeted drug that we would choose, whether you’re HER2-positive or HER2-negative, in the second-line setting. Although it is, as David likes to say, NCCN [National Comprehensive Cancer Network] approved in the second-line setting, we would mostly use it in combination with Taxol, or paclitaxel. The other second-line drugs that are available: single-agent taxane or irinotecan. I don’t think we should use these. I think the go-to regimen in the second-line should be Taxol and ramucirumab.
Johanna C. Bendell, MD: What about for a HER2-positive patient for whom we’re not supposed to continue on treatment? Do you use ramucirumab plus a taxane, David?
David H. Ilson, MD, PhD: Yeah, absolutely. There’s not any differential effect for HER2-positive and HER2-negative patients. I think the development of paclitaxel-ramucirumab really revolutionized and established a global standard for second-line treatment not only in Asia but also in the West. The REGARD trial was proof of principle, really comparing ramucirumab versus best supportive care in second-line treatment. Although there weren’t many responses, there were progression-free and overall survival benefits.
The drug did have some single-agent activity. But more clinically relevant is combining the drug with paclitaxel. You had augmentation of response rates—up to 30% of patients responding to second-line therapy; 2-month improvement in survival where a median survival is extended to 9 months, which was unprecedented for second-line treatment; and improvements in progression-free survival. So without any detriment in quality of life.
Paclitaxel-ramucirumab is really the go-to standard as second-line treatment. I think a complicating issue is now patients are getting FOLFOX, so the neuropathy baseline is an issue now with paclitaxel-ramucirumab patients on taxanes longer. Sometimes we’re treating patients with paclitaxel for a year when we would treat them for 6 months. We have a clearly defined second-line standard of care, and this is probably the most appropriate platform for a combination therapy in the second-line setting.
One of my criticisms about a number of the recent second-line trials is they use paclitaxel alone as a control arm, which arguably is inferior. We can talk about this a little later, but ramucirumab—because of its low-toxicity profile—is a good partner for other drug development.
Johanna C. Bendell, MD: Tell me, would you ever use ramucirumab as a single agent?
David H. Ilson, MD, PhD: I think it’s a stabilizing drug. You do get modest progression-free and overall survival benefits. We don’t really get responses. Sometimes I do consider it as a maintenance therapy in patients. If they’re still responding to paclitaxel-ramucirumab and have neuropathy, we might continue ramucirumab alone as a maintenance treatment. Arguably, however, if the patient isn’t well enough for combination chemotherapy second line, are they really going to benefit from ramucirumab monotherapy? It’s a rare patient who I’ll treat with ramucirumab monotherapy. I think paclitaxel-ramucirumab would be the de facto standard.
Johanna C. Bendell, MD: I’m going to hit you with a couple of clinical pearl questions. One is something that came up when we started using bevacizumab for patients with colorectal cancer. What if you have a known lesion with a history of bleed or maybe slow bleed that you’re suspecting? Would you use ramucirumab in that setting?
David H. Ilson, MD, PhD: We really did not see an increased risk of bleeding or perforation with ramucirumab. They are really rare scenarios. Manish mentioned earlier the use of palliative radiation for a bleeding tumor. I think if someone is actively bleeding and is getting transfusions on a regular basis, I probably would get radiation in first. The other is if the patient had a history of a previous perforation of a tumor that they survived. Those, to me, would be contraindications. Or hypertension that can’t be controlled. But the drug is quite well tolerated.
Johanna C. Bendell, MD: OK, 1 more clinical pearl, and I’m putting you on the spot. You’ve mentioned neuropathy, which is such an issue with our GI [gastrointestinal] cancer patients. I see patients being treated with a full gamut of different agents, from the super B-vitamin complex to ginkgo biloba to gabapentin, bumping the doses higher and higher. What’s your take on pharmacological treatment of the neuropathy?
David H. Ilson, MD, PhD: The only patients I treat with neuropathy are those who have painful neuropathy. And then drugs like gabapentin, I think, play a role. Unfortunately, there really isn’t anything that effectively treats the neuropathy. But if they have painful neuropathy, we use neuropathic pain medications. My colleagues can comment.
Kohei Shitara, MD: I agree.
Johanna C. Bendell, MD: Yes. You’ve used that?
Manish A. Shah, MD: Yeah, that’s an important point—stop and go. And continuing ramucirumab while you’re taking a break from taxanes may be very helpful. The other drug I use for neuropathy is Cymbalta. That sometimes seems to help as well. And then alpha-lipoic acid sometimes has helped as well. The other thing that people have sort of talked about, which I actually haven’t seen to be that effective, is the use of magnesium and calcium during the infusion. I don’t do that for taxanes.
David H. Ilson, MD, PhD: Yeah, the randomized trial data indicated no benefit for calcium and magnesium. It’s really kind of become an abandoned treatment.
Johanna C. Bendell, MD: Kohei, when we originally looked at data from AVAGAST with bevacizumab in the first-line setting with chemotherapy, they said, “Oh, well, it’s just because patients in the East don’t benefit from angiogenic inhibitors. Patients in the West do.” Tell us a little about your take on that. Does that affect your use of ramucirumab treatment? What do the trials tell us?
Kohei Shitara, MD: Actually, we use paclitaxel and ramucirumab as a standard treatment. It is recommended in the Japanese guidelines. We enrolled patients for the RAINBOW trial, and the subgroup analysis suggested the doubling of response rate and the PFS [progression-free survival], and even in the Japanese patient population. The survival in the control arm is remarkably longer than that of an overall patient cohort. The hazard ratio in the Japanese subgroup is 0.87, but still favors their combination arm. That’s why we recommend this combination as a standard treatment in Japan.
In clinical practice, maybe I use the combination in more than 80% of patients. But still, I stop and use for carefully selected patients—if the patient had massive ascites as well as a dilation of a small intestine, or if they may have some risk for GI perforation. I usually start paclitaxel first followed by the combination, carefully. But most patients can receive the combination.
We also can use nab-paclitaxel. This is longer with a reduced frequency of infusion-related reaction. Now paclitaxel is also approved in Japan. Sometimes we use nab-paclitaxel and ramucirumab. And our phase II trial showed more than a 50% response rate in the second-line setting. This is a standard treatment, even in Japan.
Johanna C. Bendell, MD: Tell us a little bit about TAS-102 [trifluridine, tipiracil]. We have the positive TAGS study. Tell us a little about that. Where do you typically use this?
Kohei Shitara, MD: TAS-102 [trifluridine, tipiracil] is already an approved drug for colorectal cancer. And previously, we conducted the phase II investigator-initiated trial and suggested there is some disease standardization in patients who are refractory to 2 or more previous lines of chemotherapy. That’s why we conducted this TAGS study as a global trial, which compared TAS-102 [trifluridine, tipiracil] with placebo in patients who were refractory to 2 or more previous lines of chemotherapy.
This is the criteria for the trial. But actually, in Japan, most patients previously received 3 or more lines of chemotherapy. We are still waiting for the approval in Japan. Maybe in the next few months we can use TAS-102 as a third-line [trifluridine, tipiracil] or later-line option? Or at least after paclitaxel and ramucirumab.