Edgardo S. Santos Castillero, MD, FACP: I’m going a bit deeper on the issue of the RELAY trial because what you said is correct. When you have exon 21, I don’t know what you do in your practice, but it is our duty as physicians to disclose the information to the patient. For example, if you have an exon 21 but no brain metastases, you can easily go to osimertinib. It is different if it’s an exon 21, L858R in which the PFS [progression-free survival], if you compare it with the FLAURA analysis, is significantly lower than what you see in the RELAY trial, which was basically the same number that they did in the analysis population: 19.4 months. We have never seen that for that specific population. It’s something that, in a practice, I would discuss with the patient, and I would obviously go over the toxicity and ask the patient what they would like to do. What do you think about the toxicity described in the RELAY trial, the most cumbersome of which to me seems to be the hypertension, grade 3 level? Tell me your opinion in that regard.
John V. Heymach, MD, PhD: It’s fair to say that it was predictable, it was manageable, and it was consistent. We’ve had a lot of experience with ramucirumab from using it in combination with docetaxel where it’s been approved for a number of years, and what’s been seen there has been consistent. As you noted, the main adverse event noted was hypertension. Other adverse events were pretty mild and pretty easy to manage. There was a little more proteinuria of course, but there was little else that was significantly increased.
One of the concerns is always hemoptysis, which VEGF inhibitors have historically had. A lot of this is from the early work with bevacizumab, where a number of patients had hemoptysis. There was no increase in fatal hemoptysis or life-threatening hemoptysis with ramucirumab. Patients now get a bit more bleeding; it tends to be nose bleeds in my experience. The mucus membranes get a little dried out, so they sometimes get dysphonia, where their throat feels a little dry and their voice box gets dried out a bit. They sometimes get epistaxis, which is persistent nose bleeds. In terms of life-threatening or serious hemoptysis, there was not an increase observed here. The management of hypertension is something that can be done readily; it’s a manageable toxicity.
They had a quality-of-life analysis in the RELAY study, and the addition of ramucirumab did not hurt the quality of life at all. In fact, it maintained it for a longer period of time, so there was good evidence that it didn’t cause a detriment in the quality of life there. It is absolutely manageable.
The ability to get osimertinib after then, to me, is a pretty strong plus. I think very highly of osimertinib. It’s a good drug. We recently reported that, even after patients progress on osimertinib, if they had T790M, you can often radiate 1 or 2 sites and keep them going on the drug, and they can often go for another year. We noticed the PFS2 [second progression-free survival] was a year in that study. We can often keep people going for a long time on osimertinib before they become resistant, and from my perspective, if we have something we can use even before osimertinib, and if you can get a year and a half before you even move to it, that’s an attractive option. It’s valuable to have a couple of different options.
Edgardo S. Santos Castillero, MD, FACP: Yes, John. Another thing we learned from that RELAY study was that the incidence of T790M mutation was not affected whatsoever by the addition of ramucirumab. When they analyzed different populations in the trial, the incidence of those patients getting erlotinib alone vs erlotinib and ramucirumab in terms of the incidence of T790M mutation at progression of disease was similar. That’s an important point.
John V. Heymach, MD, PhD: Yeah, that’s right. You do retain the ability to get osimertinib later. If you look at the time until you get chemotherapy, it was delayed in the study, especially for patients who ended up moving to osimertinib afterward. This is why, as you said, Eddie, I have a discussion with patients and understand their priorities. It is sometimes their priority to have the simplest therapy right now and not visit the doctor. In Texas, we often have long drives for people. They may live 6 hours away. If they say, “It’s not feasible for me to get there very often,” then you might say osimertinib. If somebody wants to be aggressive and hold on to their other options, and they can get the intravenous therapy with ramucirumab, it’s absolutely a tenable option to offer it to patients, and it obviously gives us information for building new regimens later.
Transcript edited for clarity.