Third-Generation Versus Earlier-Generation Agents

Roy S. Herbst, MD, PhD: It's amazing what we have in terms of EGFR inhibition. I'm old enough to remember the first-generation drugs, gefitinib and erlotinib. In fact, when I was a young attendant at [The University of Texas] MD Anderson [Cancer Center], I actually ran the first phase 1 trials with others for those drugs. In those days, we had good inhibitors, but they were not EGFR mutation-selective, so they targeted the EGFR receptor in normal cells, too. A great deal of toxicity, with rash on the skin and diarrhea.

I recall when we used to do the randomized trials, we could tell who was on the control versus the treatment arm, because of who had a rash or not. Of course, with time, we learned about EGFR mutations, around 2004. That was 1997. Then agents were developed that were mutation-specific, such as osimertinib, which only targets the mutation-specific EGFR receptor. It still has some leaking to the normal receptor. That's why there's some toxicity but is so much better tolerated.

Also, it targets T790M, which is the most frequent cause of resistance for patients who have EGFR mutations and are treated with first-generation drugs. That's a big bonus. As an added bonus, it has great CNS, central nervous system, penetration and has great activity in brain METs [metastases]. Why is that important? Because this drug, as opposed to other drugs that have been studied in the adjuvant setting, is better tolerated, more effective because of the T790M, the brain [metastases], it can be given for longer periods.

Three years was felt to be a longer and better period to have a lasting effect in the adjuvant setting. So this trial brings the best of surgical treatment and the best of EGFR treatment together for the best result.

In my opinion, the disease-free survival benefits seen, 81% of the stage II/III patients and 79% of the stage I/II/III patients, by itself is enough for me to be compelled to change practice. If I have a patient with EGFR-mutated disease, I'm going to want to use this drug. Importantly, it still needs to have regulatory approval and it still would need to be reimbursed as well. I think that more data are going to be accumulated in the next 6 months or so, including sites of recurrence. We predict these data are going to show how meaningful it is for patients who have lung cancer and have resection not to have recurrence in delicate sites, like the brain, the lung, the bone, the pain and morbidity that goes with that. Then ultimately, we are going to want survival data. That's going to take several years. We showed an initial survival curve at the ASCO [American Society of Clinical Oncology] annual meeting. It’s only 5% mature, it's heading in the right direction, but it's way too early to discuss that. But this trial will have to be followed for that, ultimately. It's my opinion that as we wait for that, we don't want patients to be denied the benefit of this if at all possible.

The ALCHEMIST trial, which is another trial that's ongoing looking at erlotinib in this setting, is being amended now to make sure that patients are informed of these data before they go into that randomized trial, erlotinib versus placebo. So I think these are compelling data. They're not even close. Certainly, we'll continue to file for all the other endpoints I mentioned.

But it's a big step forward and really shows, very much like in breast cancer 15 years ago when Herceptin was brought into the adjuvant setting after it was shown to be useful in metastatic disease, that when you take the best drugs, the best biology, and use the best targeted treatments earlier in disease, you get better results and help patients earlier. And the hope would be to cure these patients of their disease. We've always been able to cure patients in early lung cancer. Now hopefully we can cure more of them and prevent recurrence to difficult-to-treat sites.

Transcript edited for clarity.