Available Treatment Options for Patients With EGFR Mutant NSCLC

Tony S.K. Mok, MD: The I-PASS study created gefitinib [Iressa] as the standard of care for patients with an EGFR mutation. Today, we’ve got a lot of choices. We have a total of 5 different TKI [tyrosine kinase inhibitors] that have been approved. Two in the first generation, erlotinib [Tarceva] and gefitinib, and 2 in the second generation, afatinib [Gilotrif] and dacomitinib [Vizimpro]. The one in the third generation is the osimertinib [Tagrisso]. There are already data showing that the osimertinib is superior to the first generation TKI in terms of both the progression-free survival [PFS] and the median time to progression in the brain. There’s an advantage of that consideration. Additionally, there are a number of studies on the combination of osimertinib with bevacizumab [Avastin], or other EGFR-TKI with bevacizumab. Also, there is a combination with the chemotherapy that demonstrates improvement in progression-free survival. However, the uptake of combination is not high. A lot of patients can achieve good results without chemotherapy. We want to give them the benefit of the doubt and try 1 single agent first before we consider the role of chemotherapy. Overall, we have a number of good options. Osimertinib is the single agent and current standard, but it’s not wrong to do other TKI first, especially if there is a financial concern.

Solange Peters, MD, PhD: We’ve been testing a series of new strategies in the front-line EGFR- mutated non-small cell lung cancer. This comes from the time we were evaluating similar combinations, but with first- and second-generation EGFR-TKIs. How can you go beyond osimertinib as the front-line, which has been established as the standard of care. We’ve been seeing from second-line setting and front-line setting that there might be room for combination with an antiangiogenic. We have several trials now combining mainly erlotinib with bevacizumab that show an improvement in PFS. It looked very rational to try to combine osimertinib with bevacizumab and an antiangiogenic front-line. This was done in a phase 2 trial presented recently at the ESMO [European Society for Medical Oncology] 2021 meeting. Unfortunately, it did not show the expected benefit looking at PFS, like it was the case for the other trials with a first-generation TKI or looking at OS [overall survival]. No benefits in response rate, or for osi plus bev [osimertinib plus bevacizumab] versus osi [osimertinib] front-line. Interestingly, there’s, in most of these trials, a signal that might be observed in this patient with EGFR mutation, being smokers. The question remains, why would smokers EGFR-mutated patients benefit more from the antiangiogenic? It might be related to the fact that smokers might have more mutations. They are potentially the p50 mutation, which has been shown to be related to a sensitivity to antiangiogenic drugs. All of these are hypothesis, and to make a long story short, osi plus bev [osimertinib plus bevacizumab] is not better than osi [osimertinib] until you have established potential subgroups who benefit. The second question is to know if potentially, like we’ve been doing with gefitinib, giving chemotherapy-TKI is better than giving the TKI only. It has been shown in the Japanese trial and in the Indian trial that gefitinib plus chemotherapy improves survival above gefitinib frontline. But it was really never implemented because the complexity of giving this combination over an oral drug is something that puts some bottlenecks and barriers for the investigator. But the same question remains true for Osimertinib. Some trial are now trying to combine chemotherapy and osimertinib in the front-line setting versus, of course, osimertinib immunotherapy. We would potentially expect a benefit in OS, and it would potentially be established as a new standard depending on the magnitude of difference. Because why would you make a patient come to the hospital for chemotherapy while he could be at home with an oral drug? These are data strongly awaited. Then, of course, remains always the question of knowing if antiangiogenic combined with the TKI and chemotherapy might improve the outcome above the absence of the antiangiogenic we had at phase 2 trial testing. In my opinion, it’s always very difficult if you don’t have a comparison to judge about CNS [central nervous system] response when you use osimertinib. Osimertinib is very efficacious at the brain level. All questions about osimertinib efficacy at the brain level should have a standard arm. So maybe there should be promises for bevacizumab at the brain level, but we need to have comparative data with a control arm. Thus, I would say these are the first 2 questions, and, mainly, the combination with chemotherapy is the most interesting 1.

This transcript has been edited for clarity.