Johanna Bendell, MD: In the second-line setting they looked at ramucirumab plus FOLFIRI or FOLFIRI alone for patients, and all of these patients had previously taken bevacizumab. So, that was an interesting thing. This was a continuation of antiangiogenic therapy into the second-line. And we saw a hazard ratio of 0.80 with this study, but it was very consistent with even the TML study, where we continued bevacizumab into the second-line setting. And those were also previously exposed bevacizumab patients, similar to the VELOUR study where we used aflibercept, and about a third of those patients had bevacizumab, and a third had not. All of the hazard ratios across the board in those second-line studies were 0.80, certainly showing that there is a patient population that benefits from the continuation of antiangiogenic therapy. So, ramucirumab is now also in our armamentarium.

The very interesting thing that came out of this—and this has been data published in non-small cell lung cancer, gastric cancer, and colorectal cancer—is something that makes ramucirumab a little bit different than bevacizumab. And what they’ve seen is that patients who had increasing pharmacokinetic (PK) levels of ramucirumab in their blood, had the most benefit from the ramucirumab in addition to the chemotherapy. And so it begs a couple of questions. One is, if you have low PK levels, do you get benefit at all? But, should you actually push the dose of ramucirumab? And I think that’s very different than what we’ve thought about with bevacizumab, where lung cancer is the poster child for looking at dose differences in bevacizumab. So, I think that there are some very interesting data that have yet to be generated there.

Mark A. Socinski, MD: Yes, that is interesting about the PK aspect of that. Manish.

Manish A. Shah, MD: Actually, in gastric cancer, there is an ongoing study looking at a higher dose of ramucirumab with chemotherapy versus chemotherapy alone in the first-line setting, asking two questions. One is, is there benefit in the first-line setting? But two, is a higher dose going to allow more patients to achieve the adequate PK levels to get the benefit that everybody else sees?

Mark A. Socinski, MD: With regard to when a drug works in second-line, we usually like to test it in first-line. I’m not aware of any, although there have been some small ramucirumab trials in the first-line setting in various combinations in lung cancer. As you would expect, it’s hard to draw firm conclusions about that. In gastric cancer, what about frontline?

Yelena Y. Janjigian, MD: As we mentioned a little bit earlier, VEGF is an important target, and I think right now we don’t have enough data to say that it’s an important target in first-line, although there is some preliminary phase II data to suggest that it may be important. We just completed a FOLFOX/regorafenib study. As Johanna was mentioning earlier, regorafenib is a tyrosine kinase inhibitor that targets VEGFR-2 and also other growth factors. And the FOLFOX/regorafenib combination in first-line—again, small, single center phase II—has very promising activity in terms of response and tolerability because we were using an alternate dosing of regorafenib.

The RAINBOW study is a large phase III study that’s ongoing that’s exploring ramucirumab with chemotherapy in first-line setting, higher doses of ramucirumab to try to get to this next PK level. As you know, for a lot of these monoclonal antibodies, the phase I and II dosing is determined, not necessarily based on. There’s very little maximum tolerated dose assessment in terms of toxicity because patients don’t get diarrhea, they don’t get rash, and they don’t get other effects that will preclude you to raise the dose. And so, the RAINBOW study is going to that level. We know certainly in gastrectomy patients, at least for oral drugs, there’s a huge variation of pharmacokinetics and absorption. I think the RAINBOW study will provide, and it’s rapidly accruing. Hopefully, we’ll have the results soon.

Mark A. Socinski, MD: How many patients, total?

Yelena Y. Janjigian, MD: It’s close to 500.

Transcript Edited for Clarity