Johanna Bendell, MD: Now that we have everything changing in the first-line setting, what do we do in the second-line setting? Let’s talk a little bit about how we approach these different cancers in terms of second-line treatment. What’s the current standard? I think Dan gave us a good overview as to what that looks like, but what other data do we have once patients have progressed on first-line therapy outside of immunotherapy [I/O]? Let’s talk a little bit about antiangiogenic therapy. Ian, can you talk about ramucirumab and how we approach second-line treatments of these patients with gastroesophageal cancer?

Ian Chau, MD: Certainly, as we heard, the standard has been to use a first-line platinum plus fluoropyrimidine, and for those patients who progress on first-line treatment, there were 3 randomized studies that have shown the benefits of chemotherapy versus standard of care; the use of second-line chemotherapy really has been seen as the standard of care. Then we have 2 phase 3 studies that look at ramucirumab. The REGARD study [NCT00917384] was looking at ramucirumab on its own versus placebo, and showed a significant improvement over placebo, and survival is very similar to chemotherapy alone. But then the RAINBOW study [NCT01170663], which showed a significant overall survival benefit of adding ramucirumab to paclitaxel compared to paclitaxel alone, and that really has defined our standard second-line therapy with paclitaxel plus ramucirumab. Since that RAINBOW study’s original publication, there have been a number of phase 3 studies looking at either adding another drug to paclitaxel or another novel drug versus paclitaxel. There are at least 5 randomized controlled phase 3 trials, and none of them actually showed a benefit over taxane alone, whereas the combination of ramucirumab plus paclitaxel appears to show a benefit over paclitaxel. Really, that is the standard treatment option.

Then a lot of clinicians think about, well, how about HER2-positive disease because, obviously, in the first-line setting, we have chemotherapy plus trastuzumab, and we look toward our breast cancer colleagues and think whether we should continue trastuzumab in the second line. Certainly, there are registry data to say that if you continue trastuzumab beyond progression, there may be some benefits, but then I think as Yelena Janjigian, MD, showed in her paper in Cancer Discovery, actually a lot of things happen in the second-line setting after patients have been retreated with trastuzumab, including loss of HER2 expression and other mutations that drive trastuzumab resistance. There’s a randomized phase 2 study that was done in Japan, which again showed that continuing trastuzumab beyond progression does not show real benefit compared to using the chemotherapy alone. For all these, putting it together, in the second-line setting at the moment, it remains paclitaxel plus ramucirumab, whether HER positive or negative.

Whereas we discuss a lot about all these new data on I/O in first line, I don’t think that would particularly impact on what we do second line at the moment. There is a subgroup analysis that was presented as a poster in patients who were recruited in KEYNOTE-061 [NCT02370498], so these are the second-line pembrolizumab, and then they looked at how many people got ramucirumab afterward. It seemed to have similar benefits to get ramucirumab afterward. At least as I can see, there is no biological rationale to say if you’ve been treated with I/O in the front line, then you will have less benefit from having angiogenic in the second line. To me, even the standard first line is likely to change. The second-line setting is probably going to remain as paclitaxel plus ramucirumab. That’s my viewpoint at the moment.

Johanna Bendell, MD: Ken, in Japan, is that also the case? Is there a lot of ramucirumab usage in Japan and do you ever use it as a single agent?

Ken Kato, MD, PhD: Yes, in Japan, ramucirumab is frequently used for the patient with second-line gastric cancer, mostly with paclitaxel because paclitaxel can be administered easily, even for the patient who cannot take medication orally. Before the approval of ramucirumab, we frequently used paclitaxel for patients with second-line gastric cancer. Patients achieved some response to ramucirumab plus paclitaxel, and neurotoxicity was increased. So we used ramucirumab monotherapy for such patients.

Transcript Edited for Clarity