TKI Combinations in Metastatic EGFR+ Lung Cancer

Benjamin Levy, MD: Let’s move on to the advanced stage, which unfortunately, is the large majority of EGFR-mutant lung cancer that I see in the country.

We’re trying to optimize strategies for treating EGFR-mutant lung cancer. We’ve made some significant headway. We started with first-generation and second-generation TKIs [tyrosine kinase inhibitors]. They were compared with chemotherapy and showed response rate advantages, PFS [progression-free survival] advantages­­­—underrepresented in the literature— and quality-of-life advantages. But we didn’t see any OS [overall survival] advantages when comparing TKIs with chemotherapy, at least in the preliminary intent-to-treat analysis.

We’ve learned recently of FLAURA showing a benefit in not only PFS but OS, when comparing osimertinib with first-generation TKIs. I mention that study only because some of these strategies that have come around are looking at first-generation TKIs.

Becca, do you want to walk us through some of the combination strategies that are evolving in EGFR-mutant lung cancer and where we’re going?

Rebecca Heist, MD: Sure. In the first-line setting, there are multiple combination strategies being pursued. In broad categories, I’ll talk about 1. One is combination with angiogenesis inhibitors, and the other is combination with chemotherapy.

First, I’ll discuss the combination with angiogenesis inhibitors. There were some updates recently at ASCO [American Society of Clinical Oncology 2020 Annual Meeting] that are worthbriefly reviewing. NEJ026 was a study that compared first-line erlotinib versus erlotinib with bevacizumab in patients with activating EGFR mutations and advanced lung cancer. They reported a significant PFS benefit. The median PFS was something like 17 months versus 13 months.

In the follow-up data for OS, the median OSs were not significantly different, which is a bit disappointing but not surprising, based on some prior phase 2 data that had been reported. A randomized phase 2 showed PFS benefits but not OS benefits.

There are other angiogenesis agents being combined with the EGFR TKIs. RELAY was published within the past year or so, and that looked at a combination of erlotinib with bevacizumab, versus erlotinib with placebo. They also they saw a PFS benefit, but the OS data were not mature.

In general, it’s an interesting scientific idea that if you improve tumor vascularization and drug delivery, perhaps there will be better outcomes. But we have not seen an OS benefit here, and there is combination toxicity when you use the 2 together. I’d be interested in hearing what others say, but I haven’t offered this to my patients for the most part. We would really like to see the results of the osimertinib versus osimertinib-bevacizumab combination. Those data will be a little out in terms of when they come.

Benjamin Levy, MD: Maybe we can stop there quickly before you talk about chemotherapy combinations. You mentioned RELAY. I think you meant ramucirumab with erlotinib.

Rebecca Heist, MD: Yes, sorry.

Benjamin Levy, MD: That’s OK. That regimen is now approved. It got approved probably 2 or 3 weeks ago, and we’re now in June 2020. Is there any traction in this regimen? It’s a first-generation TKI with ramucirumab, not with osimertinib. Is there any patient you would consider using this for?

Rebecca Heist, MD: It’s hard to think of a situation where I would be saying, “I really want to use erlotinib rather than osimertinib as my TKI backbone.” With the aggregate of data so far in angiogenesis combinations, there’s been PFS benefit but no OS benefit, which obviously has not been reported in RELAY yet. But in other studies, it’s hard to imagine for me that I would be willing to take the added toxicity of angiogenesis agents for what I consider a lesser TKI.

Benjamin Levy, MD: Got it. Josh and Lyuda, before Becca talks about some of the chemotherapy combinations, what are your thoughts on RELAY, if it’s an approved regimen? Is there traction with antiangiogenesis strategies with first-generation TKIs? Lyuda?

Lyudmila Bazhenova, MD: The train has moved on. This was a good idea at the time it was designed, but I completely agree with Becca. I will not use that combination, nor am I ready to take the leap of using angiogenesis inhibitors with osimertinib without having osimertinib-specific data, as Becca mentioned, because of toxicity. When we give an extra toxicity to our patients, we want to know why, and I don’t have a why yet.

Benjamin Levy, MD: Josh, what are your parting thoughts on antiangiogenesis in TKIs?

Joshua Bauml, MD: It’s interesting. I agree with everything that Becca and Lyuda have said. The toxicity associated with the angiogenesis inhibitors is binary. It ends up being either no toxicity whatsoever, or really, really, really, really, really bad toxicities.

Benjamin Levy, MD: How many reallys was that?

Joshua Bauml, MD: That was a lot of reallys. It was enough reallys to bring the point home. It’s either nothing, or it’s bowel perforation, hemoptysis, and clots. These are significant adverse effects that, with a questionable benefit, make me less excited about using it. In addition to that, I’m not entirely convinced that there are impressive preclinical or clinical data to support the idea that VEGF blockade has special efficacy in the EGFR-mutant population. I just don’t believe that. I’m hesitant to use it.

Benjamin Levy, MD: I eagerly await the ECOG study of osimertinib plus bevacizumab versus osimertinib alone, which Becca mentioned.

Transcript Edited for Clarity