Molecular testing in Patients With Metastatic NSCLC

Mark Socinski, MD: We had another presentation at ASCO [the American Society of Clinical Oncology Annual Meeting], the CTONG 1104 trial, the Chinese trial. Different design. It compared a lesser TKI [tyrosine kinase inhibitor], gefitinib, with chemotherapy. There was a disease-free survival benefit reported initially, but the hazard ratio wasn’t 0.17; it was 0.6. The 5-year survival was not different at the end of the day. We have to realize that the DFS may not drive overall survival, but I want to get your thoughts about that.

Stephen Liu, MD: I think you’re right. When we saw the CTONG data that were updated by Professor Yi-Long Wu, we saw a trial with a very different design. It’s not as clean of a trial. It’s not as well designed of a trial as ADAURA because you’re comparing chemotherapy with TKI, not TKI with placebo after chemotherapy. Those patients weren’t as well staged. There wasn’t that CNS [central nervous system] staging, so the concern with CTONG is that a lot of patients on that trial might have had stage IV disease, where we know that TKI is superior. But the point from that trial that’s relevant to ADAURA is that DFS, PFS [progression-free survival] benefit didn’t translate to a survival benefit at the end. That’s 1 of the trains of thought with ADAURA.

When Dr Herbst presented those data, there was a collective still in all our homes, in all our rooms, because we’re not used to seeing curves like that separate so quickly, and to separate so deeply over time, to see at 90% disease-free survival rates at 2 years versus 44% with placebo. It reminded us of how poorly patients with stage II and III EGFR-positive lung cancer do after surgery, that recurrence is so frequent and what an impact TKIs can have there. That DFS hazard ratio of 0.17 was profound. I do think it justifies it as a standard of care. But the question is will it translate to an OS [overall survival] benefit, but we won’t know for some time?

Unlike the PACIFIC data, we know that when patients relapse after chemoradiation, it’s very difficult to salvage patients after recurrence. With someone that has an EGFR mutation, osimertinib does a very good job of controlling disease in the stage IV setting. It’s a good drug, and so we feel more confident that we can deliver that drug safely at the time of relapse. If I’m watching closely and deliver osi [osimertinib] at recurrence, will I be able to rescue the OS curve?

We know from practice that you’re never able to rescue 100% of people. The question that time will tell is, how many we can rescue, and will that translate to an OS benefit?

Mark Socinski, MD: Brendon, from the surgeon’s perspective, you’ve obviously seen this data. How does this resonate in the surgical world?

Brendon Stiles, MD: Surgeons are incredibly impressed. Caveats apply about overall survival, about whether the placebo group will get osimertinib upon progression, and how that will affect overall survival. It’s hard to ignore. I hope this is going to lead to widespread EGFR testing in the early stage. The benefit in stage IB still remains to be seen. Obviously people need to work out the details of chemotherapy followed by osi [osimertinib] versus just going straight to osi [osimertinib] and what the trials implications are for that. But this should mandate testing in early stages of lung cancer.

Mark Socinski, MD: That’s 1 point. We’re going to transition in a second to the role of immunotherapy in the surgical disease setting. Does this make lack of a testing in early stage disease something we should do up front? Obviously, the only specimen we’ve had to test is going to be the surgical specimen perhaps. What are the implications here, Roy or Brendon?

Brendon Stiles, MD: We’re at a place that fortunately tests all our biopsies but particularly sites that are active in neoadjuvant immunotherapy trials. Given this data, it should be their responsibility to test for these mutations.

Mark Socinski, MD: Roy?

Roy S. Herbst, MD, PhD: Just a few comments. One of my colleagues on the steering committee of this trial, Dr Masahiro Tsuboi, is a surgeon. We talked about this earlier today, and my sense is some patients hopefully will be cured in that we’re looking at earlier disease and less heterogeneity. Hopefully these EGFR inhibitors given for 3 years will knock it out. There will be some dormant cells and some resistors that will move forward. We’ll have to follow that, but with a hazard ratio as good as it is, there’s a good chance that this will show survival as well. Even if it doesn’t show disease-free survival, the fact that patients aren’t recurring in the brain, liver, or bone, and we all know that sometimes you can’t rescue somebody if they come back with multiple brain metastases or if they’ve had a seizure.

We’ll have more data on this as the year goes on. It tells us that at the time of surgery now, reflexively we should be getting PD-L1 status, and we should be getting at least EGFR mutations status and maybe even do a whole next-gen path on it. I was impressed at ASCO by all the posters that were showing the same amount of tissue—you can get 50 or 100 genes versus just 1 or 2. It’s your best chance of getting it including a Flatiron Health analysis that showed if you do next-generation sequencing right away, then you almost never have to go back and do something again, whereas if you just do 1 or 2 mutations or you do nothing, then you do have to go back.

We’re going to be seeing much more testing that comes out of the ADAURA trial, which is going to help patients across the board.

Mark Socinski, MD: Which does raise the issue that Brendon raised: Given the treacherous relationship between exposure to immunotherapy and subsequent specifically osimertinib where most of the concern is focused, should trials of preoperative immunotherapy strategies exclude patients with EGFR mutations?

Brendon Stiles, MD: We have a trial where we had hoped to jump-start immune response with low-dose SBRT [stereotactic body radiation therapy] and saw poor responses in the EGFR patients. Our sense is moving away from it. Everybody probably saw Catherine Shu’s paper in Lancet Oncology, though. It was chemotherapy and atezolizumab, and notable at the end was that they did have 4 patients with EGFR mutations and 2 seemed to have major pathological responses. That seems to be an outlier for most of the neoadjuvant trials. You could maybe make an argument if you’re giving combination therapy, but certainly not for single-agent immunotherapy.

Transcript Edited for Clarity