Ramucirumab for Relapsed-Refractory Metastatic NSCLC

Benjamin Levy, MD: I’ve been encouraged with the doublet of docetaxel with ramucirumab in my patients. Both in terms of patients who are not rapidly progressing, and in patients who are. I think that to be fair, balanced, and transparent, we have to be mindful of toxicity with this regimen. And the problem with this regimen is not the ramucirumab; it’s the docetaxel. So we have to be mindful of dose reductions for these patients. I generally start at a lower dose of docetaxel, perhaps 60 or even 50 in combination with ramucirumab. The approved dose of course is 75 mg/m² of docetaxel.

But my clinical experience has mirrored the data, which are that not everybody responds, but certainly there are opportunities and to add, to have a meaningful therapy for patients who are progressing or whose tumors are progressing on treatment. Keep in mind, post KEYSTONE-189, for patients who are on carboplatin, pemetrexed, pembrolizumab, really the only second-line drugs we have approved in this setting are docetaxel with or without ramucirumab. So outside a clinical trial, I would say that I am not reluctant at all. In fact, I try to use docetaxel-ramucirumab for all these patients if they can’t go on a clinical trial. But mindful of the toxicities, mindful of quality of life, and mindful of being able to make some dose reductions on the docetaxel.

Roy Herbst, MD, PhD: I got you. I’ve had some patients who don’t do well, of course, but I’ve had some very good responses, patients who have responded and have durable responses, and they’ve tolerated it well. The docetaxel is not a drug that anyone loves to use, but you can nurse people through it reasonably well. I would use that now, especially in somebody who’s been on immunotherapy. I think the response rates to chemotherapy tend to be a little bit better after patients have been on immunotherapy. We’ve seen that. So immunotherapy plus ramucirumab, I think, is a very reasonable regimen to think about.

Well, the toxicity would be, the docetaxel toxicities is edema, neutropenia, low blood counts, and then of course you’re adding in the ramucirumab which can have hypertension as a VEGFR2 agent. There were concerns about bleeding, but I don’t think that those are that well founded.

Benjamin Levy, MD: There are several factors that go in what treatment you’re going to use second line for patients who are, whose tumors are progressing frontline, looking at patient-performance status, looking at their tumor burden, looking at their willingness to go on to subsequent therapies is all very important. I would say that patients who are symptomatic but motivated and fit who are, whose tumors are growing on either a platinum doublet with chemo, platinum doublet with immunotherapy. These are patients I would, I wouldn’t offer docetaxel with ramucirumab.

I think patients who are rapidly progressing, who remain fit and motivated, should also receive this regimen. But this regimen is not for everybody. I think that’s important. Patients who have significantly declined or you don’t think can tolerate 2 drugs, or patients whose performance status has waned so much that they can get only 1 drug. I think that treatment decisions in second line are almost as new as they are in first line. We have to look at all those factors. But I would say for a motivated fit patient who’s either symptomatic or not, who’s progressing on a triplet regimen, this should be a regimen to consider with an understanding that dose modifications may have to be made with the docetaxel.

Roy Herbst, MD, PhD: Well, patient selection for ramucirumab is easy because you can give it to all patients. Anyone who has already had immunotherapy and needs to have docetaxel should get docetaxel with ramucirumab, based on the very positive REVEL trial led by Edward Garon, et al.

If someone has a really poor performance status, one might not want to use the ramucirumab. But if someone’s performance status is 2 or greater, certainly 1 or greater, I would give them the ramucirumab. If it is 2 or greater, you have to wonder whether you should treat them at all with a docetaxel-containing regimen.

Anne Tsao, MD: In stage IV metastatic disease the paradigm has completely shifted in the frontline setting. So across all histologies, everybody is now receiving a platinum doublet with an immunotherapy if they’re a candidate for immunotherapy or they’re receiving potentially the quadruplet regimen with IMpower150.

So this has changed our options for salvage because generally, if you’ve progressed on a triplet or a quadruplet regimen, I don’t think that your disease will be well controlled with a monotherapy checkpoint inhibitor. And so in this case I would reach for the docetaxel-ramucirumab regimen to try to reestablish control of the patient’s disease. That’s not to say that later on down the line we might not reinvestigate immunotherapies. I think that’s always an option, particularly with these novel combination immunotherapy regimens. But for right now in daily practice, the docetaxel-ramucirumab regimen is very reasonable to give after you’ve had progression on a frontline triplet or quadruplet regimen.

Roy Herbst, MD, PhD: Well, docetaxel is a second-line agent, and ramucirumab has all its approvals with docetaxel, so as such it will be second line. And second line has been moved out to third line now, and what is third line, because if you’re giving chemotherapy and immunotherapy together, you’re basically giving 2 regimens in 1. It’s all 1 regimen. So now ramucirumab-docetaxel has been moved to the second-line setting, but it really is after immunotherapy and after chemotherapy. And that’s where it should stay because that’s where docetaxel has its approval, and I wouldn’t move that frontline. As I said earlier, I think immunotherapy—in all patients that you can—should be used up front. Use it and get your best benefit, and then in the second line you can move to this.