This transcript has been edited for clarity.
This is Mark Kris from Memorial Sloan Kettering. Just when we thought we were all set with EGFR, suddenly we have some disruptive information that challenges how we're going to treat patients with EGFR-mutated cancers. At the American Society of Clinical Oncology (ASCO) annual meeting this year, three presentations fit this mold.
Adding to TKIs in Lung Cancer
The first one was a trial adding ramucirumab to erlotinib. Patients who received ramucirumab with erlotinib had an improvement in progression-free survival (PFS) of about 7 months, a very substantial improvement.
The second abstract was perhaps an even more disruptive one, demonstrating that adding chemotherapy to gefitinib improves PFS by 8 months.
This kind of information has been around for a while with bevacizumab, but the worldwide oncology community that treats thoracic cancers by and large has chosen not to pursue it. Some of us have. The concept here is that we can improve PFS by giving additional therapies with tyrosine kinase inhibitors (TKIs).
But the field moved on. Osimertinib has become our drug of choice. People have rested on that laurel a little bit, but it's still not good enough. We need to do more. And the data on adding ramucirumab and adding chemotherapy show ways we can do that in 2019.
I know some people are going to say, "The overall PFS in these trials is comparable to osimertinib. Maybe we should give these things first, and then maybe give osimertinib at the time of acquired resistance." I urge you to think hard about this. It's very important that we give our best drug first, and that drug is osimertinib.
But I would urge you to also think in a slightly different way: Do not to go back to erlotinib and gefitinib, but add other drugs to osimertinib. I see a future where we are adding anti-angiogenesis drugs, like bevacizumab or ramucirumab, or adding chemotherapy. There are some clever ways of doing that. There are trials being designed right now on giving chemotherapy only to those patients with persistent EGFR mutations found in the tumoral DNA after several weeks of treatment with osimertinib or a TKI. For EGFR-mutant lung cancer, it's a brave new world again. We have to do better than osimertinib, and we have some direction now.
EGFR-Positive Acquired Resistance
The other abstract was a learning experience for me and, I think, for many people in the lung cancer community. It came from Adam Schoenfeld at our institution [and his colleagues]. This abstract looked at acquired resistance in patients who received osimertinib up front.
Some data have been published about this already, but they're blood-based data. Tissue was not looked at in a large number of cases—however, here tissue was looked at. Adam looked at about 25 or 30 patients pre- and post–comprehensive next-generation sequencing (NGS). Unlike our prior experience with erlotinib and gefitinib where second-site EGFR mutations were the most common method of acquired resistance, he found that transformation to small cell or to squamous cell was the most common form of acquired resistance.
What is that all about? Scientists are scurrying to figure that out. One practical issue is that you are not going to detect these transformational changes—which could lead to a change in therapy—with blood-based testing. There is a large movement now to do blood-based testing; you can't find these on blood-based tests, yet it's the most common form of acquired resistance.
The second thing in the Schoenfeld abstract is that there was only a small amount of on-target resistance in EGFR. Yes, C797S has been found and, yes, it can be targeted with second-generation TKIs. But we just didn't find it; we only found one case out of about 25.
Number one, you need to do tissue-based testing. Number two, you are most likely to find that the cancer has transformed into squamous cell or small cell, not a second-site mutation. Yes, you may find some second-site mutations that can be targeted, but you also find other mechanisms—MET or HER2—that can lead to targets as well. Of course, chemotherapy is a good choice for these people.
It's a brave new world for osimertinib-acquired resistance. Test tissue, and then make the best choice for next-line therapy based on what you find in that tissue.
We thought all the questions with EGFR were answered; this is far from true.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Mark G. Kris. New Data Challenge Current Standard in Treating EGFR+ Lung Cancer - Medscape - Sep 10, 2019.