Anti-Angiogenic Therapy in Lung and GI Cancers - Episode 6
Transcript:Mark A. Socinski, MD: Let’s switch gears a little bit. I’ll go back to Yelena, and let’s make the transition from bevacizumab to ramucirumab, and give us your thought. Obviously, gastric has been an area of huge success with this drug, right?
Yelena Y. Janjigian, MD: That’s right. So, there were two large studies, the REGARD and RAINBOW study that really validated our observation that in gastric cancer, VEGF inhibition is an important strategy. And, these trials were randomized phase III trials, with ramucirumab—which is a monoclonal antibody that targets VEGFR-2—as the actual receptor. And, both, as a single agent and in combination with paclitaxel, there was an overall survival and progression-free survival benefit which really led to expedited approval of this medicine in patients with second-line gastric cancer. And, the reason why it gained such expedited approval is because, unlike lung cancer, where there is a plethora of biomarkers and targeted agents, it’s almost impossible to demonstrate overall survival benefit in EGFR mutant lung cancer. It’s like HER2-positive breast, they just live forever and do well, knock on wood, it’s great. But in gastric that’s not the case. At least, before ramucirumab came on the market in second-line setting, the landscape was bare. A lot of the trials with mTOR inhibition and others, the tyrosine kinase inhibitors have failed. And, so, ramucirumab really opened the door and reignited the interest for this pathway again in gastric.
Mark A. Socinski, MD: Forgive me for not knowing this, but in those trials, had patients received any antiangiogenic agents before that?
Yelena Y. Janjigian, MD: No.
Mark A. Socinski, MD: Or they were naïve?
Yelena Y. Janjigian, MD: They were all naïve because bevacizumab is not FDA-approved and not used anywhere really in the world in gastric. So, for these patients who progressed on, usually 5-FU platinum therapies are a mainstay of treatment. And these patients were carefully selected. If you look at the clinical trial enrollment, at least for the single-agent ramucirumab study, these are not just your average gastric patients who come in. They excluded people with large-volume peritoneal carcinomatosis, patients with any risk of serious bleeding. On average, it was a younger patient population. But, in that patient population—who were considered to be perhaps better players, in general, because peritoneal carcinomatosis is a terribly negative prognostic factor—those patients did better with ramucirumab. And, at least, it really had a disease stabilization benefit. As a single agent, VEGFR-2 inhibition won’t make your tumor shrink, but it really does stabilize it.
Mark A. Socinski, MD: As I say to my patients, I don’t have to shrink your tumor to make you live longer.
Yelena Y. Janjigian, MD: Stable is good. That’s my mantra.
Mark A. Socinski, MD: Stop it from growing.
Yelena Y. Janjigian, MD: No change is a good thing.
Manish A. Shah, MD: Can I add?
Mark A. Socinski, MD: Yes, please.
Manish A. Shah, MD: Just to take off from what Yelena started, the very interesting thing in gastric cancer is that in the last 2 years, it’s become clear—and with clinical trial evidence proven—that second-line chemotherapy is a standard option, and the median survival with second-line therapy is 5 months versus 3 months, or so, with best supportive care. And remarkably that’s what we saw in the REGARD study, exactly the same thing. So, with a non-cytotoxic drug—ramucirumab in this selected population—we saw the exact same benefit as you do with chemotherapy. Then the question is, do you want chemotherapy to shrink the tumor? So, patients have choices. We can choose a relatively nontoxic drug in the second-line setting to give you the same median survival benefit, or we could choose chemotherapy with ramucirumab, if you wanted to get a higher response rate for symptom control and things like that.
Mark A. Socinski, MD: Has it been proven that adding ramucirumab to chemotherapy is a better option in this population?
Yelena Y. Janjigian, MD: No one’s ever done a trial with ramucirumab versus Taxol, or ramucirumab with a trial of paclitaxel versus paclitaxel. Ramucirumab has shown really, I would say, clinically meaningful response rates. And that’s where I think the excitement lays. I think very few patients, at least in my practice, would go on single agent ramucirumab at this point because usually they’re fitter, they’re more motivated, and they do have symptoms. In second-line therapy, the combination of paclitaxel/ramucirumab is really the mainstay of therapy. Again, extrapolating from other disease types, colon cancer particularly, the hypothesis is continuation of ramucirumab beyond progression, an important factor. I do tend to believe in that flare event you can perhaps get with stopping angiogenesis inhibition. And so, again, it’s an open-ended question. The trials have not been done yet.
Transcript Edited for Clarity