Options for Up-front Therapy in EGFR-mutant NSCLC

Transcript:Benjamin P. Levy, MD: Erlotinib and gefitinib are first-generation tyrosine kinase inhibitors, and they work by binding to the EGFR tyrosine kinase domain through competitive binding with ATP. Afatinib is a second-generation TKI, and it works by covalently binding to the EGFR tyrosine kinase domain which is then irreversible. One difference is that second-generation TKIs, like afatinib, are irreversible versus reversibility with the first-generation TKIs. The second difference is afatinib tends to hit a broader target range. First-generation TKIs generally only inhibit EGFR, but the second-generation TKIs may have a broad spectrum hitting both HER2 and HER4. So, theoretically, the second-generation TKIs, through their irreversible binding and more broad spectrum, should have better activity, clinically. And I’m not sure we’ve seen that in some of the data sets in terms of survival, but certainly, there’s a theoretical advantage to using second-generation TKIs over first-generation TKIs.

There have been multiple trials now that have shown that either first-generation or second-generation TKIs (erlotinib, gefitinib, or afatinib) improve response rates, improve progression-free survival, and, importantly, improve quality of life when compared to chemotherapy in treatment-naïve advanced adenocarcinoma patients that harbor EGFR mutations. So, we have an embarrassment of riches. We have multiple options here with either first-generation or second-generation TKIs up front. I think that underscores the importance of identifying EGFR mutations up front. Whether there are any real differences between these 3 depends on the medical oncologist you ask. Certainly, we do have some head-to-head data suggesting that afatinib may be better than gefitinib in terms of response rate and progression-free survival, but no overall survival advantage. And we also have data in a subset analysis from the LUX-Lung 3 and 6 trials that compared afatinib to platinum chemotherapy up front, showing that in the subset of patients with exon 19 mutations, there was a survival advantage with afatinib. So, I think for del19 patients, there should be a consideration for afatinib. However, second-generation TKIs, like afatinib, tend to be more toxic than first-generation TKIs, and we have to weigh the benefit-risk ratio with these drugs. And certain scenarios may warrant one drug versus another. I think what’s important, however, is we have 3 drugs and that really is emblematic of drug discovery for lung cancer over the past 5 to 10 years.

The LUX-Lung 7 trial is the only trial that we have comparing a first-generation versus a second-generation TKIs for treatment-naïve, EGFR-positive patients. And what we saw in that trial was that afatinib was superior to gefitinib in terms of response rate and in terms of progression-free survival, albeit at the cost of toxicity. So, kudos for doing a head-to-head trial showing a benefit of one over the other in terms of response rate and progression-free survival. However, 2 caveats: one is that this study was updated at ESMO recently showing no survival difference between those 2 arms, and secondly is that afatinib does tend to have more toxicities, more grade 3/4 rash and diarrhea. This has to come down to an individualized treatment decision when you’re thinking about which drugs to use up front, weighing the benefits of the drug versus the risks.

For L858R mutations I would generally consider using erlotinib up front. For most of my patients, erlotinib is the drug that I consider. For some very fit patients, I would consider erlotinib plus bevacizumab, although I haven’t done that in my practice too often. For exon 20 mutations, this is an educational point here, and that is that exon 20 mutations generally confer resistance to TKI mutations. I think in those cases that we identify exon 20 mutations, we have to default to chemotherapy. Now, not all exon 20 mutations are the same, but most of them confer resistance to TKI therapy, and for those patients, I will consider chemotherapy.

Transcript Edited for Clarity