TKI Plus Antiangiogenic Combination Therapy

Edgardo S. Santos Castillero, MD, FACP: What is the rationale behind combining TKI [tyrosine kinase inhibitors] in patients with EGFR mutations with VEGF inhibitors, for example. What is behind the dual inhibition, if you can tell us?

John V. Heymach, MD, PhD: It’s a great question. I’ll start by saying that, for a long time with angiogenesis inhibitors, it’s been observed that patients with EGFR mutations seem to be particularly sensitive to VEGF inhibitors. It’s not intuitively obvious why that should be the point. KRAS-mutant patients are not sensitive to VEGF inhibitors. For squamous cell carcinoma, you can go through the list: None of them seems to be particularly sensitive. The most sensitive group we’ve identified has been EGFR mutants. In my laboratory [at The University of Texas MD Anderson Cancer Center], we looked at this, and back in 2009 we reported that the combination of EGFR inhibitors and VEGF inhibitors seemed to be particularly active, even in resistant tumors.

As we tried to dissect the mechanism, it looks as though the EGFR mutations drive VEGF expression up very high in these tumors. They do it through a pathway called HIF. This is the same pathway in kidney cancer that’s up-regulated for a different reason. In that case, it’s because of VHL mutations. In a similar vein, kidney cancer is sensitive to VEGF inhibition as well, and it’s 1 of the few diseases in which bevacizumab by itself can be active. In that sense, we think there’s an overlapping biology between kidney cancer and EGFR-mutant tumors that we’ve observed.

That’s prompted a number of different studies. Early on, there was a study called BeTa that Roy Herbst led, and the study overall was negative. This was erlotinib plus bevacizumab vs erlotinib. Bevacizumab overall didn’t add benefit, but when they pulled out the EGFR-mutant subgroup, there was a huge benefit for adding the VEGF inhibitor there. That then led to a couple of randomized studies, and almost all the randomized studies have been consistent in terms of demonstrating at least a PFS [progression-free survival] benefit when you add a VEGF inhibitor to an EGFR inhibitor. There have been a couple of studies now of erlotinib and bevacizumab, 1 led by Takashi Seto and colleagues in Japan, and 1 by a cooperative group in the United States with Thomas Stinchcombe and others. They show a strong trend or a significant improvement in PFS.

For bevacizumab, the improvements haven’t translated into overall survival benefits, and the reasons for that are debated. The studies were not powered for overall survival, so that’s 1 thing that’s important to say. These were positive studies because they were powered for PFS, and PFS was positive. All this supported the notion that EGFR-mutant tumors seemed to be particularly sensitive to VEGF inhibitors, and these studies had impressive hazard ratios: hazard ratios in the 0.6 range. When you consider chemotherapy plus bevacizumab in the nonsquamous population, the hazard ratio there is closer to the high 0.7s, so this is a much more relative benefit.

That’s now prompted a number of different studies. One of them is called the RELAY study. I can talk about this study. It was erlotinib with ramucirumab vs erlotinib, and this was the first properly powered, randomized phase 3 trial that has readout. Just to remind everyone, ramucirumab is approved for lung cancer. It’s a VEGF receptor 2 antibody. Unlike bevacizumab, which blocks the VEGF ligand, this blocks the receptor. This study was a strongly positive study in terms of its primary end point, which was PFS. The PFS was 19.4 months, and that was about a 7-month improvement compared with erlotinib alone. When you think about that, 19.4 months is about the same as osimertinib. Osimertinib was 18.9 months, so it was similar benefit for an EGFR inhibitor plus a VEGF inhibitor as osimertinib did.

There are a couple of points that are worth noting. It didn’t include patients with brain metastases. If somebody had brain metastases at the start, I would stick with osimertinib because this combination doesn’t have the same track record in brain metastases, but it did show similar benefit if you had L858R or exon 19 deletion. If you look at that L858R population, that’s tougher to treat. They didn’t seem to get as much benefit with osimertinib in the FLAURA study, but they did very well in the RELAY study. They had a very similar benefit here.

The FDA has recently approved this regimen, the erlotinib-ramucirumab regimen. It’s a good thing to give options to patients, and you can think of pluses and minuses for both. On 1 hand, you could say, “Osimertinib is a little better tolerated than erlotinib and ramucirumab, and it’s easier not to get an IV [intravenous], so just get a pill and go home. It’s simpler.” That’s a good argument. The better CNS [central nervous system] activity is a good argument. On the other hand, especially for people who want to be aggressive, they can get the same PFS as osimertinib with the RELAY regimen of erlotinib and ramucirumab. If you get a T790M mutation, which about half the patients do, you can still get osimertinib after that and get both drugs, whereas if you start with osimertinib, you have no other targeted agents after that. That’s an interesting argument.

If you’re looking at what delays the time until you get chemotherapy, you may say that the goal is to avoid chemotherapy, because that’s where patients start to have a significant impact on their quality of life. For a significant number of patients, they can get a similar outcome in the first-line regimen, with the RELAY regimen, and then still get osimertinib for meeting the 10 to 12 months afterward. It is sometimes longer than, then they really push back the time when you need chemotherapy much longer. It’s good to offer options to patients. There are some patients, patients with L858R, patients without brain metastases, who want to be aggressive, and I do discuss this option with them. I’ve just started giving it recently.

Edgardo S. Santos Castillero, MD, FACP: Good, I agree. Sometimes, when I listen to you speak, I say, “Maybe John and I went to the same school,” because it seems as if we have the same professor and the same teacher almost aligning on the same concept. For me, in 2020, and perhaps for you and all of us who treat lung cancer, the North East Japan 026 trial presented at ASCO [American Society of Clinical Oncology Annual Meeting]—with an overall survival that you briefly mentioned that was negative—was a disappointment. I saw that study with the impressive PFS that was presented a few years ago. I had hoped it would be positive for overall survival, but that was not the case. When I see that, I say, “Wow.”

Where are we going to put RELAY, which also came this year? There is a difference between bevacizumab and ramucirumab: the mechanism of action is totally different. By blocking the receptor, you block all the ligand, and maybe that is the difference. The other is the dosing. In the RELAY trial, the ramucirumab is given every 2 weeks, which is different from the North East Japan study in which the ramucirumab was every 3 weeks and erlotinib on the standard dose.

Transcript edited for clarity.