Ben Levy, MD: Let’s move on to our next section, which is on the specific gene mutations in lung cancer. We’ll start out with EGFR mutations. We’ve come a long way. We have first- and second-generation TKIs [tyrosine kinase inhibitors] like erlotinib [Tarceva], gefitinib [Iressa], and afatinib [Gilotrif]. They were compared with chemotherapy early on and showed improvements in response rates and in PFS [progression-free survival] specifically with patients with sensitizing mutations, and also improvement in the quality of life.

More recently, we have a head-to-head trial comparing a third-generation TKI, osimertinib [Tagrisso], to erlotinib and gefitinib in the FLAURA trial. That showed improvement in PFS and in OS [overall survival]. Based on its tolerability, OS, intercranial response, and proclivity to penetrate the blood-brain barrier, osimertinib is now considered the standard of care for at least sensitizing mutations in exon 19 and 21. It seems pretty simple, but it isn’t. I tell fellows that osimertinib is just the beginning of the story, that there are going to be combinations, and that we’ve got to understand how to tackle resistance.

But first, let’s talk about these first-line combination trials. Hatim, walk us through some of the ones that you think are important to look at and where we’re heading in the field with combination strategies for sensitizing EGFR mutations.

Hatim Husain, MD: It’s a great question. Thank you, Ben. The first-line management of EGFR historically has been driven with an EGFR TKI. That has been the historical standard. Some of the ways that are being explored in clinical trials are combinations of TKIs plus chemotherapy, combinations of TKIs plus anti-VEGF–directed therapy, and even combinations of EGFR plus bispecific with EGFR/MET in the frontline as well. The frontline management is getting somewhat complex, and combinations may have some importance. The critical question is whether there are a population of patients who are going to be best served with a combination vs monotherapy with a TKI.

At ESMO [European Society for Medical Oncology Congress] 2021, there were a few abstracts presented around anti-VEGF combinations with erlotinib therapy, including the final results of the BEVERLY study, which looked at frontline erlotinib and bevacizumab [Avastin] in an Italian population and showed improvement in overall survival with the addition of bevacizumab in that study.

There was another trial presented that looked at how TP53 could segregate patients from erlotinib and ramucirumab [Cyramza] frontline. This was an important study to emphasize the importance of co-alterations with EGFR, as there might be some patients with EGFR and co-alterations, whether it be TP53, CDKN2A, or other co-alterations, that may segregate 1 combination, perhaps EGFR plus chemotherapy or EGFR plus VEGF. The jury is still out in that regard. The last abstract that also came out at ESMO 2021 looked at osimertinib plus bevacizumab. It didn’t show an improvement in PFS. We’re eagerly awaiting the chemotherapy plus TKI data from FLAURA2, osimertinib plus chemotherapy, and also a little more clarity with TKI plus VEGF.

Ben Levy, MD: The VEGF story is a little confusing to me. We’ve had some data that looked like improvement in PFS, but we haven’t seen that in combination with a third-generation TKI. The chemotherapy plus osimertinib is intriguing. We’ve got a Japanese study and an Indian study showing that chemotherapy plus first-generation TKI is better than first-generation TKI alone. We’ll have to see how this this plays out. If FLAURA2 is positive, I’d like to know who benefited, because it would be nice to not have to give chemotherapy to everybody. We’ll have to see how this shakes out over time.

I’m going to deviate a little here. Patients who are on osimertinib who develop disease progression are a challenge. This is a real challenge as to what to do. Martin, how do you handle patients who are on osimertinib who develop disease progression? What do you do with these patients?

Martin Dietrich, MD: The proper answer is that we don’t know. There’s a big difficulty in guiding this, and everything that’s post–EGFR progression is basically off label, with the exception of standard chemotherapy. The first step is to understand why it’s progressing, so I get at least a liquid biopsy, preferably a repeat biopsy. We’ve seen fusions and amplifications as resistance mechanisms. We’ll see more of this as we get into more precise testing. We have a bit of a diagnostic disadvantage by not being as aggressive about tissue biopsies, amplifications, and fusions, which are very difficult to see on liquid biopsy, depending on the circumstance.

We try to see if there’s a straight progression with EGFR overactivity that maybe overrides the activity of osimertinib. Looking at clinical trials, looking at some of the new allosteric ErbB inhibitors that we have in clinical trials. And certainly, in combinations of TKIs, we’ve seen cMET as a frequent escape mechanism overriding EGFR in combination therapies, both in trial as well as off label. That’s a consideration. If none of these are options, my standard would be the IMpower150 regimen. We’ve seen sustained benefit with the addition of immunotherapy, interestingly so and not quite well understood, with a differential effect between the EGFR and the ALK subgroup where EGFR seems to benefit. There was an update as well that showed that it seemed to maintain the benefit overall.

IMpower150 would be my standard answer. They were included and were also approved in Europe for the use for patients with EGFR. The FDA [Food and Drug Administration] excluded them, even though they were permitted in the clinical trial, which I thought was an interesting decision. That would be my standard approach. First, testing, then evaluating clinical trial opportunities, because that honeymoon period of osimertinib, which is both very effective and well tolerated, should be followed up by genomic guidance in the second-line setting. For the all-comers, chemoimmunotherapy plus an antiangiogenic agent is the current and most available standard.

Ben Levy, MD: That’s a great summary. We’re still in a vacuum as to what to do for these patients. I agree that tissue and liquid makes a lot of sense here, understanding mechanisms of resistance, wedding those mechanisms of resistance to particular therapies.

Transcript edited for clarity.