John V. Heymach, MD, PhD: We have some new studies coming out at the ESMO [European Society for Medical Oncology] 2021 Meeting and other meetings here. We had a study of bevacizumab [Avastin] and erlotinib [Tarceva], the BEVERLY study. Vamsi, what were your thoughts about this study?

Vamsidhar Velcheti, MD: I think it’s old wine in a new bottle. I think we’ve heard this story again and again. I think, John, you’ve done one of those important trials with VEGF [vascular endothelial growth factor] inhibitors early on. I think EGFR [epidermal growth factor receptor]-mutant population, clearly, that’s a population where I think there’s benefit for adding BEV [bevacizumab]. We may not know all the mechanisms yet, but I think this study kind of confirms what we already know. But the issue is it’s a combination with erlotinib. But, nevertheless, I think it’s an important, I guess I would say, proof of concept that we’ve had from other trials. I know Heather mentioned about the ongoing trial...osimertinib [Tagrisso] with BEV [bevacizumab]. There are studies with ramucirumab [Cyramza] as well.

John V. Heymach, MD, PhD: Yes. I guess we’ve seen a number now of bevacizumab and erlotinib trials. I think it’s pretty consistent there’s a PFS [progression-free survival] benefit. Obviously, whether or not it translates to an OS [overall survival] benefit is obviously more equivocal. I’ll just mention here, and this is an area we spend a lot of time in, EGFR-mutant tumors seem to be more sensitive to VEGF inhibition than other subgroups than a squamous tumor, for example, nondriver. One of the things I do try to do is make sure patients with EGFR mutants get VEGF inhibitors at some point at least, whether it’s during chemotherapy or if it can be worked into a regimen. Obviously, I know there’s a lot of different options coming down the road. Sandip, do you want to talk about the RELAY study here, using a different VEGF pathway inhibitor, ramucirumab?

Sandip P. Patel, MD: Absolutely. In the frontline metastatic canonical EGFR-mutated population, this is a study of erlotinib with or without ramucirumab. Ramucirumab plays a role in regulating VEGFA [vascular endothelial growth factor A] and VEGFR-2 [VEGF receptor 2] inhibition, and so the basis of this study in particular, which was presented at ESMO, was looking at the p53 subset given that one of the mechanisms that p53 facilitates oncogenesis is through regulation of VEGFA and VEGFR2. Thus, there is an idea that you could potentially have a more targeted antiangiogenic strategy.

Thus, in this analysis, the initial study showed a PFS benefit and they focused on the p53 cohort. Effectively, the objective response rate, disease control rate, and PFS were similar whether patients had p53 mutations or not. I think broadly concerning where does this study have a role? Given osimertinib is commonly used in many countries, and in countries in which osimertinib is not used, it’s unlikely ramucirumab is available I think is kind of a practice question. But I think broadly this is another study combining something old and something new, I guess, so to speak in terms of EGFR inhibitors and VEGF inhibitors but ending up with a result that we’ve seen before, which is some measure of benefit for PFS. But OS is either pending or not positive yet.

John V. Heymach, MD, PhD: Now, the interesting thing about the RELAY trial is the progression-free survival with erlotinib, it was about 19 months or 19.4 in the overall group, which is about the same as osimertinib. There’s an argument that while you get something that lasts as long as osimertinib and you still may have the option of using osimertinib later in about half of the patients versus going right to osimertinib up front but not having the options to do the RELAY regimen later. What are your thoughts in other particular patients where you would offer this or discuss this option with them?

Sandip P. Patel, MD: Yes, it’s a great question. The FLAURA trial, the comparator arm was the first-generation TKI, not a TKI plus VEGF kind of strategy. I think the median amount of time a patient can remain on osimertinib, if you look at FLAURA, it’s almost 3 years and it could be longer for some patients. To come in every 2 weeks for an IV [intravenous] infusion and, for me, not to be able to tell the patient you’re in a subgroup that’s necessarily benefitting or not, it’s tough. I think, like many, I want to make sure that a patient with an EGFR mutation gets a VEGF inhibitor, but typically for me that comes after osimertinib, after we profile for any actionable resistance, as Stephen mentioned. If they don’t have any actionable resistance, I’ll often do CARBO/PEM/BEV [carboplatin/pemetrexed/bevacizumab] and continue those especially if they have CNS [central nervous system] mets [metastasis]. That’s typically while I’ll start to integrate my antiangiogenics because, at that point, they’re coming into the infusion center anyway for their chemotherapy.

John V. Heymach, MD, PhD: OK. Stephen, there’s another study in this space—osimertinib/bevacizumab, and chemotherapy that was presented at ESMO by Qin and colleagues. Do you want to tell us about that one?

Stephen Liu, MD: Yeah, this is sort of an interesting combination. You mentioned the link between sort of EGFR-mutant lung cancer and VEGF-targeted therapies. Clearly, there’s some selected benefit there. But another area where bevacizumab provides a unique benefit is within the brain. This is a drug that we use to treat gliomas. It has a good role in treating radiation necrosis and edema, and so this study really looked at a 4-drug regimen. It was cisplatin/pemetrexed/bevacizumab and osimertinib in patients with EGFR-mutant lung cancer and untreated asymptomatic brain mets.

The primary end point here was intracranial response, a modest sized, single-arm study, 26 patients but every patient had a response at that first scan; really quite impressive. The reduction in the target lesions, on average, 48%, the range anywhere from 33% to 72%. Almost all patients had a drop in edema. Also, the combination pretty well tolerated. It’s a little hard to interpret single-arm phase 2, especially when osimertinib alone is an active drug in the brain but it’s a compelling combination, maybe appealing in cases where OSI [osimertinib] isn’t enough maybe in progression in terms of leptomeningeal disease, so something that warrants further study but an interesting approach.

John V. Heymach, MD, PhD: Yes. I found this really interesting as well because we’re often presented with the situation that somebody shows up and they’ve got maybe an asymptomatic brain metastasis or multiple brain metastases. Sometimes, they’re slightly symptomatic, and there’s a question of do you wait and radiate them first before you start treatment. Heather, what are your thoughts? Would you feel comfortable if this regimen were approved of starting somebody with the regimen like this as opposed to starting with radiation or under what circumstance would that be the case?

Heather Wakelee, MD: I think it’s a very reasonable choice. I’m kind of trying to avoid any brain radiation as long as I can. Stereotactic radiation, that’s fine but I’m really strong opposed to any whole brain radiation regimens just because we do have patients who are the super responders...a number of years, and I’ve lost a number of them to the long-term complications, long-term meaning a year, or 2, or 3 of the whole brain radiation. It’s one of the things that distresses me the most is when a young patient shows up with newly diagnosed disease and brain metastases, and they’ve had their brain radiated before we even know their mutation status. We haven’t even had the decision about which is the best systemic treatment. Then, they end up with ALK [anaplastic lymphoma kinase], or ROS [reactive oxygen species], or something and 5 years later they can’t function. Systemic options that avoid that are great, from my perspective.

John V. Heymach, MD, PhD: Right. Yes, I agree with you. Ani, what’s your practice here? Let’s say somebody is mildly symptomatic when they show up in your clinic with brain metastases and that’s how they presented, do you wait for mutation profiling to come back? I’m sure we’ve all been on this train where you see rad-onc [radiation-oncology] and once rad-onc does a simulation, it’s really hard to get them out there. What’s your approach here?

Ani Balmanoukian, MD: Yes, exactly just as Heather was mentioning. When someone presents and it really does...if they’re symptomatic, I do get them evaluated by neurosurgery just to see essentially what the brain metastasis looks like. If it’s a significantly large brain metastasis, that patient likely has seen neurosurgery before they saw me anyways. But, for the most part, I do wait for mutation testing to come back.

John V. Heymach, MD, PhD: I have a patient very much like Heather was referring to as well. It was a patient who was a young, nonsmoker male, somebody I managed with Ben Levy. It was a decision about SRS [stereotactic radiosurgery] to a couple of brain lesions or not, and they were all...they were all ready to go when ALK came back. I said I think you can get by without it, but the decision, and we didn’t have as much data then, the decision was to go ahead and use the SRS. We’ve been treating that gentleman for radiation necrosis now, I think we’re on our third year of treating for radiation necrosis. Thus, it isn’t a free lunch, Gamma Knife [radiosurgery]. It’s better than the whole brain but it’s not a free lunch.

Transcript Edited for Clarity