Osimertinib's Role in EGFR+ Metastatic Lung Cancer

Transcript:Benjamin P. Levy, MD: Let’s shift gears completely and start the discussion about specific genotypes. Mirroring what we’ve seen in the advanced NSCLC [non—small cell lung cancer] space without genotypes, there have been exceptional advances over the past 12 to 24 months that have altered the treatment paradigm, and, of course, EGFR is no exception. EGFR mutations occur in around 15% of our patients with NSCLC, adenocarcinoma. We, of course, know that first- and second-generation TKIs [tyrosine kinase inhibitors] outperform chemotherapy in this patient population in terms of response rate, progression-free survival [PFS], and perhaps the underrepresented quality of life. But we have new data that have come out in the past 12 to 24 months. Ram, you were instrumental in leading this trial. Do you want to talk about the phase I trial and FLAURA experience with osimertinib in EGFR-mutant lung cancer?

Suresh S. Ramalingam, MD: I think this is an area, once again, where advances are coming in very fast to lung cancer. EGFR mutations are present in approximately 15% of the western patient population and about 40% of the Asian patient population. When you look at the whole landscape of EGFR mutations, we’re now dicing that up as well. You have the common mutations with exon 19 and exon 21. They’re representing about 85% of all EGFR mutations. And then, the rest of them are the less common mutations, which are not typically associated with being sensitive to EGFR tyrosine kinase inhibition.

When we look at the exon 19 and 21 mutations, the most common mutations, the standard of care there is shifting very fast. For a long time, we had erlotinib and gefitinib as the approved options. These are the first-generation drugs that have a response rate of about 60% and a median PFS of about 10 months. Then came the second-generation drugs, afatinib and, more recently, dacomitinib. These are irreversible inhibitors. They seem to have an advantage over erlotinib or gefitinib, but they also have more adverse events in the form of skin and gastrointestinal toxicity.

What’s most exciting for me, not just because I was fortunate enough to lead the trial, is the fact that osimertinib belongs to a new generation of drugs that are very specific to the mutant receptor. In other words, the selectivity of the drug to the mutant receptor compared to the wild-type receptor is much higher than the first- and second-generation drugs, so you see less toxicity.

In the phase I study with osimertinib, which was initially being developed specifically for the T790M mutation—acquired resistance mechanism, we also treated 60 patients in the first-line setting and saw that the response rate was close to 80% and the median PFS was approximately 19 months. That really fueled the FLAURA study, which was a head-to-head comparison of osimertinib given at 80 mg per day compared to either erlotinib or gefitinib. That study has now been published in the New England Journal of medicine. We saw a statistically significant improvement in progression-free survival from about 10 months in the control group to approximately 19 months for patients treated with osimertinib, and the hazard ratio was 0.46.

I also saw that there was a great effectiveness against brain metastases with osimertinib, and I think that’s an important point for our audience to keep in mind because brain metastases are common in EGFR-mutated patients. Osimertinib provided better systemic control and better CNS [central nervous system] control, and it was also better tolerated. We now have a new standard of care in the United States and slowly in the other parts of the world as well. The United States FDA approved osimertinib as first-line therapy several months ago now. More and more, patients in our clinics are now getting first-line osimertinib. We still have not seen the mature survival results of the FLAURA study. But when we look at the initial analysis, the hazard ratio was 0.63. It’s not statistically significant at this point because the maturity is low but favoring osimertinib in that setting.

Now, when the full survival data come we will learn even more about what is the impact on disease biology at the larger level with osimertinib. For now, I think osimertinib is perhaps the best EGFR TKI in the class, and it is moving into the first-line space. If there are patients who have not received osimertinib in the frontline setting, if they got gefitinib or erlotinib, when they progress I think testing for T790M is critical because about 50% or 60% of them will have the T790M mutation. You can start with the blood. You can give them osimertinib as second-line therapy. If you don’t have a T790M mutation in the blood, or if you don’t have access to blood, then a tumor biopsy testing for T790M is the standard approach. And there, when you give osimertinib as second-line therapy for T790M mutation—positive disease, the response rate is about 65% and the median PFS is approximately 10 months. We now have phase III evidence that it’s superior to chemotherapy in the second-line setting for patients with T790M mutations.

There are 2 indications for osimertinib. The first indication was in the second-line setting. Now, more and more, a shift towards the first-line setting is happening, definitely in the United States.

Benjamin P. Levy, MD: Before I get the global perspective, I have a question related to what you just talked about regarding sequencing. This has come up in our tumor boards before. For patients who are on a first-generation TKI and who you can’t identify the T790M mutation in, would you still consider giving osimertinib in the absence of T790M? We have response rates in the 23% to 25% range, which is not that far off from what chemotherapy does. Is that ever a consideration or is it really still the paradigm for the T790M mutation and only in the resistant setting?

Suresh S. Ramalingam, MD: If I know for sure after testing tumor, blood, or both that T790M is negative, my approach is to go to chemotherapy. We all know that there is something called the reintroduction response phenomenon. If you’ve been off of a TKI for a few months, coming back with an EGFR TKI will result in a response in a subset of patients. That’s the setting where I would reintroduce osimertinib, after they’ve had chemotherapy or something else.

Benjamin P. Levy, MD: We’ll come back to that.

Transcript Edited for Clarity