Heather A. Wakelee, MD
The scope of non–small cell lung cancer (NSCLC) has been progressively transforming every few months, with regulatory decisions and emerging regimens making their way through the pipeline, most recently with EGFR inhibitors and immunotherapy agents.
For example, the second-generation EGFR inhibitor dacomitinib was found to reduce the risk of disease progression by more than 40% and resulted in an average 6.5-month improvement in response duration versus gefitinib (Iressa) as a first-line treatment for patients with advanced, EGFR
-mutant NSCLC, according to data from a phase III trial presented at the 2017 ASCO Annual Meeting.1
However, dacomitinib’s potential impact could be lessened, as the results of the phase III FLAURA trial, which compared osimertinib (Tagrisso) with gefitinib or erlotinib (Tarceva) in the frontline setting of patients with EGFR
-mutant NSCLC who harbor the acquired T790M
mutation, demonstrated that osimertinib significantly improved progression-free survival (PFS).
In the immunotherapy realm, Heather Wakelee, MD, says that oncologists are still grappling with the May 2017 FDA approval of pembrolizumab (Keytruda) with pemetrexed/carboplatin as a frontline treatment for patients with NSCLC regardless of PD-L1 expression, which was based on results from cohort G of the small, phase II KEYNOTE-021 trial. In the cohort, the median PFS was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy alone (HR, 0.53; 95% CI, 0.31-0.91; P
During the 2017 OncLive®
State of the Science SummitTM
on Advanced Non–Small Cell Lung Cancer, Wakelee, associate professor of medicine (oncology) at the Stanford University Medical Center, discussed the latest developments with EGFR inhibitors and immunotherapy agents in NSCLC.
OncLive: You had a few presentations today. What did your lecture on on EGFR-mutant NSCLC encompass?
The field of EGFR
-mutant lung cancer keeps growing as far as the number of agents we have to help people. There has also been movement in the best testing techniques. Since EGFR
mutations were identified, the primary tests have been based on tissue. Now, there is a movement toward some of the liquid biopsies with plasma testing. There was the approval of the first one of those about 1 year ago to look for the primary activating mutations, and now for one of the resistance mutations, as well.
When a patient comes in with newly diagnosed lung cancer with an EGFR mutation, we have 3 drugs to choose from. There is a lot of discussion around which one is going to be best for individual patients, looking at the differences in toxicity and potency. In the United States, we are still using a lot of erlotinib, afatinib (Gilotrif), and gefitinib, which are also very good choices.
At the 2017 ASCO Annual Meeting, we heard about dacomitinib, which wasn’t really a new drug but it is one we hadn’t heard about in many years—so it wasn’t on anyone’s radar anymore. However, they did a head-to-head study, the ARCHER 1050 trial, of dacomitinib versus gefitinib and showed that dacomitinib had a significantly better PFS, well in excess of 1 year at 14 months. For most of the phase III trials with any of the first-line EGFR tyrosine kinase inhibitors (TKIs), it has been under 1 year or close to it, but not in that range. That was very interesting and exciting to see that bar get moved.
The issue, though, is that the drug is more toxic and we have seen that in other agents where there is more potency and more toxicity, so a lot of patients needed dose reductions. Therefore, it is going to be interesting to see how that plays out. Once the drug actually makes it to the market in the United States, I am not sure we know exactly what is going to happen there.
One of the challenges is that with one of the next-generation drugs, osimertinib, there is a head-to-head study right now of osimertinib versus other first-line EGFR TKIs. If that ends up showing superiority, there is a chance that will change. It is better tolerated.
There is a lot that is going to depend on how good the PFS is, because right now with dacomitinib, erlotinib, gefitinib, or afatinib, once one of those drugs stops working, we have the next step, which is to go to osimertinib. If you start with osimertinib, we don’t have that next step. Those are going to be the questions we have to grapple with. Is it going to be better to go from a first-generation drug to a third-generation drug? Or, should we just skip and start with the third-generation drug? We don’t know that yet. If it turns out that it is better to start with the third-generation drug, then, unfortunately, dacomitinib came too late for us to really be using it too much.