Expert Explains Efforts to Optimize EGFR TKIs in NSCLC

Howard L. “Jack” West, MD

The use of EGFR tyrosine kinase inhibitors (TKIs)—such as erlotinib (Tarceva), afatinib (Gilotrif), and gefitinib (Iressa)—has become a go-to first-line approach for patients with EGFR-mutated non—small cell lung cancer (NSCLC).

“There’s a statistically better response rate and progression-free survival (PFS) with any of these EGFR TKI’s versus conventional chemotherapy,” explains H. Jack West, MD.

Several phase III clinical trials have assessed the various EGFR TKIs as frontline therapies for patients with NSCLC, including the LUX-Lung 3 and 6 studies, which compared afatinib with cisplatin-based regimens, and the LUX-Lung 7 study, which compared afatinib with gefitinib.

OncLive: Please discuss some of the available EGFR TKI’s for patients with NSCLC.

In an interview with OncLive, West, who is the medical director of the Thoracic Oncology Program at the Swedish Cancer Institute, discusses the benefits of EGFR TKIs in NSCLC, challenges with determining optimal sequencing, and potential combinations on the horizon.West: Looking at the issue of what is the best EGFR TKI in the first-line setting, there have been more than 6 clinical trials that have looked at a different EGFR TKI versus conventional chemotherapy. They have all found the same result: that there's a markedly higher and significantly better response rate and progression-free survival (PFS) with any of these EGFR TKI's, whether it's a first-generation inhibitor like gefitinib or erlotinib, or a second-generation irreversible inhibitor like afatinib.

On the other hand, getting a survival difference compared with chemotherapy has been allusive. This is because these are patients who are fortunately living for 2, 3, or more years, but their first-line treatment often lasts for 10 or 12 months. Therefore, a lot of patients will go on to other therapies and that tends to dilute the survival difference.

Afatinib has shown a survival benefit, particularly seen in patients with exon 19 deletion, which is one of the 2 very common EGFR mutations compared with chemotherapy.

There has been a direct comparison in a trial called LUX-Lung 7 of afatinib to gefitinib, which is a first-generation agent. That trial showed a significantly better PFS with afatinib as well as a higher response rate, but we haven't seen a difference in OS.

Do you have a preferred regimen you use in frontline?

In the end, I would say it's a range of choices without a clear best answer. The toxicity profile of gefitinib is the most benign and erlotinib is somewhere between gefitinib and afatinib. Afatinib has the highest rate of toxicities, such as diarrhea, stomatitis, paramecia, and rash. Therefore, it depends on a patient's and physician’s discussion of whether they want to pursue efficacy that is likely a little bit better with afatinib, but with a greater toxicity challenge.I would say that, in the United States, erlotinib is the most commonly pursued option. I use that on a lot of my patients. I have many patients with activating EGFR mutations who have been on a combination of erlotinib and bevacizumab (Avastin) for 18 months or 2 years. Some people object that it's medicalizing things, since you need to come in every 3 weeks and go to the infusion center.

Do you believe the lung cancer community will have challenges with sequencing TKIs?

However, for some patients who are averse to the toxicity issues, gefitinib is also a fine choice.Right now, we do have good problem of a lot of choices. The question is whether there is an optimal sequence.

I would say that one of the things that has been tried is initially giving an agent such as erlotinib,—a first-generation inhibitor,—and then trying afatinib. Certainly, afatinib and cetuximab (Erbitux) has been looked at in some small clinical trials that looked promising years ago, but we haven't seen subsequent data at this point. It's a challenging regimen in terms of toxicity. There’s a lot of rash, some diarrhea, and other issues. I would say that afatinib after gefitinib or erlotinib is not a very fruitful approach.

The third-generation EGFR TKI osimertinib (Tagrisso), which is now FDA approved for T790M-positive acquired resistance, is a very appealing choice. The question is: where does it fit in?

T790M is the most common mechanism of acquired resistance in the setting of each EGFR-mutant disease. It's seen in 50% to 60% of patients and, with the FDA approval of osimertinib, it makes testing for T790M a standard of care—and all but a mandate.

You have a therapy that has a very good response rate at a range of 60% in the vast majority of patients, is well tolerated, and is an excellent choice if you have T790M.

What do you envision the future of EGFR TKI’s being in the next couple of years?

Perhaps, osimertinib in the first-line setting would be better for everybody because you can give a very active agent with a good tolerability to not just the 50% or 60% with a T790M mutation, but to everybody.We have seen some signals of potential toxicity challenges with immunotherapies, at least with osimertinib, but potentially with other EGFR inhibitors. Each of these agents can be associated with toxicities and, added together, we need to be cautious about that. I would be very disinclined to do it outside of a trial. A sequential approach for these patients—who may be living for years—is that it gives a lot of opportunity for treatment.

Immunotherapies, if anything, seem to have greater activity as the cancer develops more mutations leading to potentially more immunogenic spots to focus on. It may be that a patient who has been on several therapies over 2 or 3 years has a better chance of responding to immunotherapy later than earlier.

I'm more enthused about EGFR inhibitors in combination with antiangiogenic agents. Many companies with a wide range of agents have noticed the Japanese data on combinations such as erlotinib and bevacizumab and are looking more at various EGFR inhibitors in combination with antiangiogenic agents.