Tagrisso (osimertinib), a third-generation EGFT inhibitor, is already showing potentially paradigm-shifting efficacy for patients with non-small cell lung cancer (NSCLC) who have the EGFR T790M mutation. Ongoing clinical trials are trying to find the role of the therapy when it is in combination with other agents.
The TATTON trial, whose preliminary results were presented at the 2015 ASCO Annual Meeting, is a phase 1b multi-arm trial exploring Tagrisso with a couple of regimens: the MET inhibitor savolitinib or the MEK inhibitor selumetinib. Firstly, findings are indicating that both regimens had good safety and were synergistic. Two partial responses (PRs) were reported with Tagrisso/savolitinib and two PRs with Tagrisso/selumetinib.
Additionally, an ongoing phase 1 study is concerned about the safety and maximum tolerated dose of the combination of Tagrisso and Portrazza (necitumumab) in patients with stage 4 or recurrent EGFR-positive NSCLC that has progressed on a prior EGFR tyrosine kinase inhibitor (TKI; NCT02496663).
With Tagrisso being added, potentially even in the frontline setting, even more, sequencing questions for physicians as they decipher which EGFR TKI to administer to their patients first.
There are many different targets in lung cancer currently. The focus is on EGFR and ALK because we have got the most knowledge about them. We had a discussion about identifying EGFR and ALK and what to do when you find it. Now, more than 10 years after we found EGFR, we have multiple different drugs for treating the patients with EGFR-positive lung cancer or with ALK-positive lung cancer. The question now is, “How do you sequence these drugs, and is there a rationale for sequencing them?”
This is a wonderful problem to have because we many different options for our patients but we need to think very critically about the delivery of drugs in the specific sequence to optimize the effects we get against the tumor.
What should physicians know about the available EGFR TKIs?
There are three different classes of EGFR TKIs that are being used currently. There are the first-generation inhibitors Tarceva (erlotinib) or Iressa (gefitinib); these are the ones that we have had around the most and we have the most experience with. They are both FDA approved as a frontline therapy for patients with metastatic EGFR-mutant NSCLC.
The second is Gilotrif (afatinib), which is a second-generation EGFR TKI. There is a little difference in this and Tarceva and Iressa in that it’s an irreversible inhibitor. That is important to know because Gilotrif is more toxic — skin rash and diarrhea — than Tarceva or Iressa.
However, all those drugs were made against wild-type EGFR. This needs to be considered because the newest class of EGFR inhibitors is the third-generation inhibitor Tagrisso. This was designed against the EGFR mutations, which are found in the lung cancer itself. The thing that makes it important is those drugs tend to have better efficacy against the tumor with fewer side effects—less diarrhea and less rash than you see with the first- and second-generation inhibitors.
What are the next steps with these agents?
There are many exciting directions for these therapies. We identify these mutations, and patients can be treated for years with different specific targeted therapies and now, especially with the evolution of these mutant-selective inhibitors like Tagrisso, as with having less toxicity that also gives us potentially a greater therapeutic window for combining the therapies. One of the big things in the field right now is how to put drugs together with Tagrisso in rational combinations to make the good results we see with this drug even better.
The big question which needs to be considered is, “Should Tagrisso become the first-line therapy for patients with EGFR-mutant NSCLC?” It would replace Tarceva, Iressa and Gilotrif. There is an international phase 3 trial asking that question right now, and results should be reported probably within the next year. We will see what happens—whether there is going to be a complete change in our paradigms or if we are going to sequence Tarceva, Iressa or Gilotrif followed by Tagrisso.