Frontline Treatment Strategies in EGFR-Mutant NSCLC - Episode 1

A Case of EGFR-Mutant Non-Small Cell Lung Cancer

May 15, 2018

Heather Wakelee, MD:Our case is a 73-year-old man—relatively healthy except for some emphysema for which he’s using inhaled steroids. His cough, however, started to worsen, and he started losing weight. So, he underwent a chest x-ray, which did reveal a large mass in his right lung that prompted additional evaluation, in addition to biopsy, additional imaging, and brain MRI. And in the end, he was found to have an adenocarcinoma of the lung with nodal involvement and bone metastases but no brain metastases or other sites.

Because it was an adenocarcinoma, even though he had a smoking history, appropriately it was tested for mutational abnormalities, and he was found to have anEGFRmutation, L858R. Based on standard of care, he was therefore started on an EGFR tyrosine kinase inhibitor. In this case, his physician chose osimertinib. That is not yet FDA approved in the first line but is used quite a bit since the FLAURA data were presented in the fall of 2017, which directly compared osimertinib with erlotinib. Other options would have been first-line erlotinib, gefitinib, or afatinib, all of which are other active EGFR tyrosine kinase inhibitors that are approved as first-line treatment in this setting.

For a patient with newly diagnosed adenocarcinoma of the lung, we tend to do a bunch of things all at the same time. So, we are doing PD-L1 testing. We are also doing rapidEGFRtesting because that’s something that’s going to so significantly change therapy. And some of the other mutational analyses can take a few weeks, so we do something that’s going to come back within a week. We’re also doingALKandROS1to get those results back sooner, because we need that information before starting a patient on therapy.

Many of the other mutations we can wait on. The ones that have first-line approvals would beBRAF,EGFR,ALK, orROS, so we want to make sure we know those. If those are negative, then we’re looking at the PD-L1 level to help guide therapy. And if all of that’s negative, then we have everything that we need to know.

I do think it’s important to have a full mutational panel done. I want to know if a patient hasKRAS—that’s going to help me think about some other therapies. I want to know if they haveMETorMETexon 14. We’ve found all of these in many of our patients, and they’ve allowed us to do other treatments. But for someone who’s newly diagnosed, we really just need to knowEGFR,ALK,ROS,BRAF, and then the PD-L1 level. So, in a patient who has one of the known driver mutations, especiallyEGFR,ALK, orROS, those patients were excluded from the trials looking at checkpoint inhibitors and chemotherapy, based on earlier data for the second-line checkpoint inhibitor showing that patients with theEGFRmutations are probably not benefiting as much.

And there were also some recent data published inLancet Oncologyfrom the ATLANTIC trial, which did involve a number of patients withEGFRmutations and a few withALKwhere those patients were treated with single-agent checkpoint inhibitors. And in that trial, the response rates if someone had low PD-L1 were almost zero. If they had high PD-L1, the response rates were still just about 12%. So, putting all of that in context, if someone has anEGFRmutation, regardless of their PD-L1 levels, I know that they’re going to be better off treated with an EGFR TKI. We can extrapolate the same forALKandROS, though we don’t have as much data with as many patients. And then with some of the other drivers, it’s a little bit unclear. WithBRAF, some of those patients do seem to benefit from checkpoint inhibitors. WithKRAS, they probably do. With theMETexon 14, there are some data that they don’t as much, so a little bit less clear. But withEGFR,ALK,ROS, we know what to do. They’ve got to be treated for those particular mutations first before we ever think about checkpoint inhibitors. And we know to treat before we think about chemotherapy in that setting for multiple head-to-head trials of TKI versus chemotherapy.

So, those are all the things I’m thinking about. And so, with this patient who has anEGFRL858R, one of the most common activating mutations, I know that he needs to get treated with an EGFR tyrosine kinase inhibitor. And we know from the FLAURA trial, which is the head-to-head comparison of osimertinib versus erlotinib and/or gefitinib, that the patients who got osimertinib had a longer progression-free survival compared with either of those other 2 drugs.

Where it gets a little bit complicated in trying to interpret everything is, we know that if someone has erlotinib or gefitinib first, at the time of progression, about 60% of them will have developed a T790M mutation. And in that setting, we know that osimertinib will work well for about 70% of the patients. And if you look at the time, on average, of someone who’d get erlotinib or gefitinib, plus the time that they would be on osimertinib in the setting of secondary resistance, that time period is not that different from what FLAURA was for patients who started on osimertinib. So, if we knew every single patient was going to be able to go from erlotinib or gefitinib on to osimertinib versus starting on osimertinib, it would be hard to argue to start osimertinib in the first-line setting.

The challenge, though, is that many of the patients don’t make it to go on to second-line osimertinib. And so, they’re just ending up with a shorter total progression-free survival time, which is related to the fact that not everybody develops T790M as their resistance mechanism. And for those who do, not everybody’s able to then get on to the next line of therapy before some catastrophe happens. So, from that perspective, many of us have started using first-line osimertinib with the idea that we’ve got a more guaranteed longer first progression-free survival before we need to think about the non-EGFR TKI option.

Transcript edited for clarity.

December 2017

  • A 73-year-old Caucasian man was seen in the emergency department for severe dyspnea and chest pain
  • History: symptomatic COPD managed on fluticasone and vilanterol inhaler; 50-pack/year smoking history
  • Imaging studies:
    • Chest X-Ray showed a large mass in the lung right upper lobe
    • CT of chest, abdomen, and pelvis revealed a 6.8-cm mass right-sided mass invading the chest wall, small left pleural effusion, and several small lytic lesions in the T4/5 vertebrae
  • CT-guided transthoracic needle biopsy of the lung lesion showed grade 2 adenocarcinoma
  • Molecular testing, NGS: EGFR exon 21 L858R mutation
  • Staging: T3N0M1
  • ECOG 1
  • The patient was started on osimertinib 80 mg once daily