Clinical Cases in Lung Cancer - Episode 10

Case 2: FLAURA Study for EGFR+ Metastatic NSCLC

Mark Socinski, MD: Let’s ask Tim to comment on the 1-cm lesion we found in the CNS in this patient, and we’ve all agreed that we’re going to start osimertinib here. What are your thoughts as a radiation oncologist about that finding, and what would your recommendation be knowing she has an exon 19 deletion mutation?

Tim Kruser, MD: We run into this scenario a lot. In this particular case presentation, fortunately it seems the patient was not symptomatic and got the test results pretty quickly. If we knew that the patient was neurologically intact and this was not in an eloquent area, I would be on board for starting drug therapy and watching this. There was a nice secondary presentation of the FLAURA results for brain metastases specifically, and 90% response rate, and maybe more importantly, no actual progression events. So you don’t have to worry about the 1-cm lesion blossoming into a neurologic deficit or requiring a craniotomy. That said, it’s more challenging as we framed the case originally when people have this finding at diagnosis and it takes a couple of weeks. Very commonly, if someone has something that’s radiosurgery-friendly and we’re waiting for those mutation results, we might use radiosurgery up front while we wait to decide on the systemic therapy, especially if it’s relatively sizeable, and 1 cm is getting toward being relatively sizeable. So it’s a case-by-case decision.

Mark Socinski, MD: Yes, I like to say you have little room for error when you’re dealing with CNS disease. If you start people on drug therapy with known CNS disease, how soon do you repeat the MRI to make sure they’re responding?

Tim Kruser, MD: I like to see these people and get them in my clinic and tell them along with the medical oncologist here, I treat a lot of lung as well as CNS disease. I think having a neurosurgeon or a radiation oncologist who specializes in brain management is good in terms of localizing these and their eloquence. Typically to your question, 6 weeks would be a reasonable first MRI timeframe, and then you can space them out pretty aggressively. We know that time to progression for these post osimertinib is 18 months or so. Every 3, 6 months I think is reasonable for surveillance.

Mark Socinski, MD: Great. Let’s talk a little bit about some data we’ve been alluding to. Here’s the design of the FLAURA trial. This specifically took exon 19 and 21 EGFR mutations, good performance status patients, stable; CNS metastases were permitted in the trial. The randomization was to dealer’s choice on the control arm of one of the first-generation drugs, erlotinib or gefitinib, and the investigational arm was osimertinib, 80 mg daily. The primary end point was progression-free survival. You can see the secondary end points are included on the bottom of the slide. The stratification factors were nature of the mutation as well as race, Asian versus non-Asian. Any way you want to see, the investigational arm wins right out of the gate, these curves separate early. The control arm of erlotinib/gefitinib, median PFS of 10 months is exactly what we’ve seen in multiple other trials involving these agents, so the control arm performed as we expected. We see almost a doubling, up to 18.9 months, for osimertinib, hazard ratio of 0.46. So a slightly more than 50% reduction in the risk of death or progression over time. Not only statistically, but I think clinically significant in this population.

Ed, I’ll ask you to comment on this slide. I think we’re all waiting for these data, thinking that many of the control arm patients may cross over with T790M to second-line osimertinib. I don’t know that we have the final answer on that yet, but there was a clear survival advantage seen in this trial here with a hazard ratio of 0.8, which is certainly in the range of what we’ve accepted to change therapy in the survival setting. But your thoughts, were you surprised at the survival advantage or not?

Edward Kim, MD: I have to say more relieved, Mark, because I’m a big believer in response and PFS. I think in the metastatic setting, those add value. I think we as scientists and researchers get very hung up on overall survival, especially again in a metastatic setting. I think it’s a little different there, especially with crossover, and certainly I’m glad we’re not going through the exercise of talking about these curves, saying, “Oh, it was probably crossover that confounded the data, etc.”

Mark Socinski, MD: Right, yes.

Edward Kim, MD: I’m just relieved that now this chapter is closed, everybody can see this is the best therapy, and we can move on.

Mark Socinski, MD: We alluded to the ramucirumab data, and I completely agree with you, I think the FLAURA data established osimertinib as the undisputed world champion of TKIs [tyrosine kinase inhibitors] in the EGFR space. It was a very convincing trial.

Transcript edited for clarity.