Targeted therapies ensure more durable responses, better overall responses, and lower toxicity than historical therapy for patients whose tumors harbor oncogenic drivers, such as EGFR, ALK, ROS1,
though questions remain on their placement beyond progression.
From a population-based standpoint, Jose M. Pacheco, MD, argued that osimertinib (Tagrisso) should be the preferred frontline EGFR inhibitor for patients with EGFR
mutations. Following the results of the phase III FLAURA trial, the FDA approved the agent as a first-line treatment for patients with non–small cell lung cancer (NSCLC) whose tumors contain exon 19 deletions or exon 21 L858R substitution mutations within EGFR.
Patients randomized to osimertinib had a 54% reduction in the risk of progression or death compared with the first-generation tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) or gefitinib (Iressa). The median progression-free survival (PFS) with osimertinib and standard TKI therapy was 18.9 months (95% CI, 15.2-21.4) and 10.2 months (95% CI, 9.6-11.1), respectively (HR, 0.46; 95% CI, 0.37-0.57; P
For patients with ALK rearrangements, the phase III ALEX trial and subsequent FDA approval positioned alectinib (Alecensa) as the preferred frontline therapy for patients with ALK
-positive metastatic NSCLC. The trial reported a 47% improvement in PFS with alectinib compared with crizotinib (Xalkori), a first-generation ALK inhibitor (HR, 0.53; 95% CI, 0.38-0.73; P
Pacheco noted that though second- and third-generation ALK inhibitors, such as brigatinib (Alunbrig) and lorlatinib, have yet to receive FDA approval in the frontline, they are likely to be adopted following progression on alectinib either on trial or off trial.
In an interview during the 2018 OncLive®
State of the Science SummitTM
on Advanced Non–Small Cell Lung Cancer, Pacheco, an assistant professor of Medicine/Medical Oncology at the Colorado University School of Medicine, discussed the preferred therapeutic strategies for treating patients with NSCLC whose tumors harbor genetic alterations in EGFR, ALK,
, and stressed the significance of molecular testing.
OncLive: What are some of the updates with oncogene-driven NSCLC that you shared?
For my presentation, I spoke about the established genetic alterations for which we have approved targeted therapies. Those include EGFR
activating mutations, ALK
fusions, and BRAF V600E mutations. We saw data from the FLAURA study presented within the past year suggesting that first-line osimertinib provides a PFS benefit for patients with traditional EGFR
activating mutations; those include exon 19 deletions and L858R point mutations in exon 21. The PFS benefit for osimertinib compared with gefitinib or erlotinib was [nearly] 19 months versus 10 months.
From a population-based standpoint, it makes sense to give osimertinib first as opposed to [a later setting] for a few reasons. If you think about treating 100 patients with osimertinib, the median PFS could be 19 months if you go by the trial data. If you treat 100 patients with gefitinib or erlotinib, you would expect a median PFS around 10 months, but only 50% to 60% of those patients will be eligible for sequencing with osimertinib. Depending on the clinical trial you look at, 10% to 40% may not even get second-line therapy. From a population-based standpoint, using first-line osimertinib is the preferred thing to do as opposed to sequencing EGFR inhibitors.
I also spoke about ALK
fusions. Within the past year, we saw the results of the ALEX trial looking at first-line alectinib versus crizotinib. There is a clear PFS benefit of 35 months versus 11 months for alectinib versus crizotinib; that is the preferred ALK inhibitor to use initially. While we don't have first-line overall survival (OS) data yet from that particular trial, we have single-arm survival data from a few different alectinib studies where the OS was 70% to 78% in the first-line setting at 3 years.
In the phase III trial with crizotinib, patients were randomized to crizotinib versus chemotherapy. The 3-year OS was only 70%, so it was a little less. We're seeing a clear PFS benefit of 35 months versus 11 months, so alectinib has now moved into the first-line setting as the preferred ALK inhibitor. One of the challenges is we don't know what the best ALK inhibitor to use after alectinib is. There are lots of trials trying to answer that question. Though alectinib is now a preferred first-line ALK inhibitor, that may not hold up after we see the results of the trials with brigatinib versus crizotinib in the first-line setting or lorlatinib versus crizotinib.