Benjamin Levy, MD: Becca, we’ve reviewed the antiangiogenesis strategies. Do you want to talk briefly about the chemotherapy strategies that have shown an overall survival [OS] benefit used in combination with first-generation TKIs [tyrosine kinase inhibitors].

Rebecca Heist, MD: Yes. As you mentioned, those have shown OS benefit, and there are 2 papers that were published. First was Vanita Noronha, et al, from Tata Memorial Centre in Mumbai, India, and the other was Yukio Hosomi, et al, or NEJ009. Both studies looked at the comparison of gefitinib versus gefitinib with chemotherapy using carboplatin plus pemetrexed.

Both studies showed that there were improvements in progression-free survival and overall survival. There was a median OS in the Tata Memorial Centre study of 16 months with gefitinib alone, and it was not reached with the combination with chemotherapy. In the NEJ009, the median OS was 38 months with gefitinib alone, and 50 months with the combination with chemotherapy.

Those are interesting data. Those show OS benefit. It comes, of course, at the price of toxicity. If you look at the AE [adverse event] table, there’s more toxicity when you combine with chemotherapy, as you would expect. The rate of significant toxicity was about doubled in both studies.

One of the issues with these studies is that when you look at the postprogression treatment, very few patients got what we would consider the optimal TKI treatment with osimertinib. What exactly happens in the postprogression setting in people who, for example, in this country would be offered osimertinib, we don’t know. As someone alluded to before, there is a study of osimertinib versus osimertinib with chemotherapy, whose data I’m waiting for to make a decision about whether that should be considered.

In my mind, the increased toxicity is real. There’s such a huge quality-of-life benefit to being on TKIs alone, that it’s hard to jump on these first-generation combinations just yet.

Benjamin Levy, MD: Yes, that’s a very nice overview. We’re still waiting. There’s the FLAURA2 trial, compares chemotherapy-osimertinib with osimertinib alone. Again, that is similar to the ECOG study using the strategies already combined with a first-generation TKI that’s shown a benefit in using them with third-generation TKI. That is more emblematic of how quickly things are moving.

Josh, I’ll start with you. Is there any time you would think about adding chemotherapy to osimertinib prior to the data coming out? There are a few investigators and thought leaders out there who will do this from time to time. Do you have any thoughts?

Joshua Bauml, MD: I’m quite optimistic that the FLAURA2 study will be positive, and the chemotherapy plus TKI combination is intriguing. Would I do it now, in the absence of a clinical trial? No. I sometimes give it after progression on osimertinib. I’ll graft chemotherapy onto that, but that’s a different question.

This is an intriguing option. I would use the chemotherapy plus gefitinib if I didn’t have access to osimertinib. This clearly would be my second choice if I didn’t have access to osimertinib.

Benjamin Levy, MD: Yes, I agree. All these points are well taken, and we’ll have to see how it all shakes out in FLAURA2 and in the ECOG trial before making routine decisions for this. I don’t think RELAY is an option. I’m not sure which patients would benefit from that unless they have an absolute contraindication to osimertinib, and we’re pretty familiar with the toxicities. We’ll have to see how the data shake out with those 2 strategies.

Rebecca Heist, MD: One thing these studies highlight is that chemotherapy is good treatment, as are TKIs. There’s been a bit of a reluctance sometimes. I have some patients who say, “I love being on a TKI. I’m really not enthusiastic about chemotherapy.” One thing we have to have a conversation with our patients about is that chemotherapy works, and people with driver mutations still should be getting chemotherapy. Whether it’s up-front in combination, versus some sequence down the line, that still needs to be worked out. But chemotherapy is definitely part of what we should be using to treat patients with driver mutations.

Benjamin Levy, MD: I agree. For now, chemotherapy is here to stay for many of these patients, either as a first-line treatment, or oftentimes as a second- or third-line therapy after TKI exhaustion.

Transcript Edited for Clarity