Combo Regimens, Optimal Sequencing Key to Advances in EGFR+ and ALK+ NSCLC

Christine M. Lovly, MD, PhD, discusses the changing treatment landscape for patients with EGFR-mutant and ALK-positive NSCLC.

Christine M. Lovly, MD, PhD

The third-generation EGFR inhibitor osimertinib (Tagrisso) has already demonstrated game-changing efficacy for patients with EGFR T790M-mutant non—small cell lung cancer (NSCLC). Now, ongoing clinical trials are looking to see how much more power the agent could have when used in combination with other therapies.

The TATTON trial, preliminary results of which were presented at the 2015 ASCO Annual Meeting, is a phase Ib multi-arm trial exploring osimertinib with 2 regimens: the MET inhibitor savolitinib or the MEK inhibitor selumetinib. Early findings showed that both regimens had good safety and were synergistic. Two partial responses (PRs) were reported with osimertinib/savolitinib and 2 PRs with osimertinib/selumetinib.

Secondly, an ongoing phase I study is looking at the safety and maximum-tolerated dose of the combination of osimertinib and necitumumab (Portrazza) in patients with stage IV or recurrent EGFR-positive NSCLC that has progressed on a prior EGFR tyrosine kinase inhibitor (TKI; NCT02496663).

The addition of osimertinib, potentially even in the frontline setting, poses even more sequencing questions for physicians as they decipher which EGFR TKI to administer to their patients first.

OncLive: Please provide an overview of your talk on EGFR- and ALK-targeted therapies in NSCLC.

Christine M. Lovly, MD, PhD, an assistant professor of medicine (hematology/oncology), assistant professor of cancer biology, medical oncologist, Vanderbilt-Ingram Cancer Center, discussed the changing treatment landscape for patients with EGFR-mutant and ALK-positive NSCLC during the 2017 OncLive® State of the Science Summit on Advanced Non—Small Cell Lung Cancer.Lovly: There are a lot of different targets in lung cancer right now. We focused on EGFR and ALK because we know the most about them. We talked 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 to treat 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 rationale for sequencing them?”

What should physicians know about the available EGFR TKIs?

This is a wonderful problem to have, because we have lots of options for our patients but we need to think critically about how we deliver the drugs in a specific sequence to optimize the effects we get against the tumor. There are 3 different classes of EGFR TKIs that we use now. There are the first-generation inhibitors erlotinib (Tarceva) or gefitinib (Iressa); those are the ones that we have had around the most and we have the most experience with. They are both FDA approved as frontline therapy for patients with metastatic EGFR-mutant NSCLC.

There is also afatinib (Gilotrif), which is a second-generation EGFR TKI. It is a little bit different than erlotinib and gefitinib in that it’s an irreversible inhibitor. That is important to know because afatinib tends to have a little bit more toxicity—skin rash and diarrhea—than erlotinib or gefitinib.

What are the next steps with these agents?

However, all those drugs were designed against wild-type EGFR. That is important because the newest class of EGFR inhibitors is the third-generation inhibitor osimertinib. This was designed against the EGFR mutations, which we find in the lung cancer itself. That is important because 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. There are lots of 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 osimertinib, because they have less toxicity that also gives us potentially a greater therapeutic window to do combination therapies. One of the big things in the field right now is how to put drugs together with osimertinib in rational combinations to make the good results we see with this drug even better.

Which of these combination strategies appear promising?

One big question is, “Should osimertinib become the first-line therapy for patients with EGFR-mutant NSCLC?” It would replace erlotinib, gefitinib, and afatinib. There is an international phase III trial asking that question right now, and results should be reported probably within the next year. We will see what happens—whether we are going to completely change our paradigms or if we are going to sequence erlotinib, gefitinib, or afatinib followed by osimertinib. There is an ongoing study called the TATTON trial looking at combinations of either osimertinib with the MEK inhibitor selumetinib, or osimertinib with the MET inhibitor savolitinib. Those are 2 rationally designed combination therapies. That study has been reported in abstract form, with some promising results seen with both regimens. We will see how those therapies continue to advance.

Regarding sequence, how do you currently determine which agent to give in each line of therapy?

There are also some clinical trials ongoing that are combining osimertinib with EGFR-targeted antibodies and these studies follow suit to a study that was done with afatinib with cetuximab (Erbitux). This also goes with the thinking that we can use osimertinib as it has less toxicity than some of the EGFR wild-type inhibitors to make combination therapy better. That is an exciting trial that is going on at multiple institutions right now combining EGFR inhibitors like necitumumab with osimertinib. That is a very important question, but is very much a question in flux right now because we have multiple generations of inhibitors for both EGFR and ALK. The question is, “Should the most potent inhibitors come right away to the first treatment that patients get, or should you get the first- and second-generation drugs and then get the third-generation inhibitors? We have a lot of data right now showing that if you get a first-generation inhibitor, followed by a second or third-generation inhibitor, the progression-free survival on both of those is going to be months to years.

What other ongoing clinical trials are you particularly excited about?

It will take systematic evaluation of clinical trials to determine the appropriate sequence, to establish efforts, and try to understand what resistance to any sort of line of therapy looks like. It is our job as physicians and scientists to always try to keep 1 step ahead of the tumor. Part of that is understanding the molecular basis for acquired drug resistance. We want to be able to tell our patients, “This drug is going to work for this long, then we are going to give you this therapy, and we have science behind that therapy that can explain why we think it is going to work.” This is the topic that is very near and dear to me, so with EGFR, I am excited to see all of these osimertinib combination trials that are coming out. With the osimertinib plus necitumumab trial and the TATTON trial, I am excited to see the basic science that is going to make rational combination therapies.

For ALK, there are several interesting trials going on right now comparing the different inhibitors. One thing that is particularly exciting in the field is that the National Cancer Institute is putting together an effort to make what they call an ALK Master Protocol trial. This is going to ask questions of how can we appropriately sequence these drugs—when we need a very strong community effort to be able to capture these patients—to answer these questions that we really want the answers to.

What do you hope community physicians took away from your lecture to apply to clinical practice?

Patient advocacy [is also important] and we need to make this as much [about] teamwork as possible because these patients are incredibly knowledgeable and drive the field forward just as much, if not more, than any physicians or scientists do. Targeted therapies are still alive and well in lung cancer, and we should be genotyping patients’ tumors. Even though resistance develops to targeted therapies, patients can receive multiple lines of targeted therapies for years and that is not an uncommon situation. The other thing is that rational drug design and understanding what resistance looks like is critically important for us to continue to be able to offer the best therapies for our patients. This includes tissue collection, studying the tissue, rationally designing drugs, and keeping that hope alive that even though resistance might develop, we can overcome it.

There are many other targets that are exciting and are really coming to the forefront. MET amplification and MET exon 14 skipping in lung cancer is in about 4% of all lung adenocarcinomas, which is just about as much as ALK. It is important to think about targeted therapies for MET-mutant NSCLC, as well. There are several different types of MET inhibitors; they are just as nuanced as the EGFR and ALK inhibitors, but can be extremely effective in patients with MET mutations.

Also, there is BRAF-mutant lung cancer. There is a much lower percentage of this in lung cancer than in melanoma, but you can find BRAFV600 in lung cancer and those patients can effectively be treated with a BRAF inhibitor or a BRAF inhibitor plus a MEK inhibitor in paradigms that are analogous to those used in melanoma.

We talk a lot about EGFR and ALK because that is where we have the most data. There are other cohorts, including MET, HER2, RET rearrangement, ROS1 rearrangement, and NTRK rearrangement. These are all low-frequency events, but it is low frequency in a huge number of patients. I look forward to seeing how these other targeted inhibitors against ROS1, RET, NTRK, and MET come to fruition in the next few months to years.

Oxnard GR, Ramalingam SS, Ahn MJ, et al. Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. J Clin Oncol. 2015;33 (suppl; abstr 2509).