PracticeUpdate Oncology February 2019

EXPERT OPINION 21

First- vs Next- Generation TKIs for NSCLC With Driver Mutations Interview with Benjamin Besse MD by Tyeese L. Gaines DO Dr. Besse is Head of the Thoracic Cancer Unit at the Department of Medicine, Institut Gustave Roussy in Villejuif, France.

Dr. Gaines: A number of newer-generation TKIs have been developed for NSCLCwith driver mutations, such as EGFR and ALK. Starting with the EGFR-mutant pop- ulation, can you discuss which agents have recently been approved? Dr. Besse: Yes. We had already three drugs approved, two first-generation TKI – gefitinib and erlotinib – one second-generation TKI, afatinib. While…lately, we had a new second-generation EGFR TKI, dacomitinib, that was approved because the randomized trials show that it increased PFS over the first-generation TKI and the PFS is around 15 months. And then a bit before, we had approved a third-generation osimertinib, and osimerti- nib again was compared to third-generation TKI, and again it improves PFS and here it’s roughly 19 months. Dr. Gaines: So how should clinicians select between these agents when they’re deciding on their front- line therapy? Dr. Besse: So you have today two options. Either you go directly to the last generation, so the third generation, because it can inhibit the activating EGFR mutation. It’s roughly exome 19 and 21, but also the main mech- anism of resistance, T790M. The first and the second generation are notable to inhibit T790M, so if you use them, it means that you have to be able to re-biopsy the patient. So it’s either a tissue or a liquid biopsy but you need these two to look at the resistance mecha- nism, T790M. And then you will sequence the TKIs, first off, second generation first, and if you find the T790M mutation, you will give osimertinib. So you have two different strategies.

Dr. Gaines: In the ALK-mutant population, what are some of the newer agents that have been developed and approved? Dr. Besse: We had recently seen the data of the ALEX trial that compared the second-generation alectinib and its activity was compared to the first-generation crizotinib, and it improved a lot, it increased a lot the PFS, the hazard ratio is 0.5, so it’s major. It’s almost 3 years PFS with alectinib compared to roughly 1 year with crizotinib. And impressively, the brain metastases were really well controlled with alectinib, and brain mets is really one big issue in all patients. Dr. Gaines: So how should clinicians select between those two agents? Dr. Besse: While, we as always, we discuss tolerability with the patients because the toxicity profile of both drugs are different. Then you can discuss the costs if there is a major issue because usually the next gen- eration are a bit more expensive. But in probably an ideal world, you would like to see what is the best for the patient based on the resistance mechanism because we know that this disease is moving, is chang- ing. Depending how it’s inhibited by TKI and what we would like to achieve as you start with whatever gen- eration, but you monitor the resistance mechanism and you adapt the next TKI based on that. In that regard, brigatinib is also a second-generation inhibitor and it has been compared with crizotinib, with the same range of benefit of a ratio for PFS is 0.5. It has a different toxicity profile compared to alectinib and it inhibits different resistance mutations. So between these two second-generation inhibitor, osimertinib that is already on the market, well, you have a lot to discuss with your patient and it’s true that biology should help for these patients. www.practiceupdate.com/c/75524

" Depending how it’s inhibited by TKI and what we would like to achieve as you start with whatever generation, but you monitor the resistance mechanism and you adapt the next TKI based on that. "

VOL. 3 • NO. 1 • 2019