Suresh S. Ramalingam, MD, FASCO
Testing for driver mutations is essential before initiating therapy in patients with non–small cell lung cancer (NSCLC), because there is a risk that the type of upfront treatment chosen may add to toxicity and spur resistance to targeted therapy options, Suresh S. Ramalingam, MD, FASCO, said at the 14th Annual
New York Lung Cancers Symposium®
“Once you go in the wrong direction, there can be significant costs,” said Ramalingam, the Roberto C. Goizueta Chair for Cancer Research, professor, Department of Hematology and Medical Oncology, and deputy director of the Winship Cancer Institute of Emory University.
In his presentation, Ramalingam highlighted current and emerging therapies for 6 key actionable driver mutations in NSCLC: EGFR
(exon 19/21), ALK
, and NTRK
“If you have to start treatment and you don’t have time to wait [for next-generation sequencing (NGS) results], then I would suggest starting patients on a chemotherapy doublet alone,” explained Ramalingam. “By the time the results come back, if you have to shift gears and switch them to targeted therapy after [immunotherapy] exposure has already happened, there is a high incidence of regression no matter which targeted agent you’re considering—some more than others.” Starting off with a less-than-ideal therapy can also complicate the toxicity picture, he added.
For patients with actionable mutations, targeted therapy is the preferred frontline treatment “regardless of PD-L1 expression levels,” said Ramalingam.EGFR-Mutated NSCLC
In patients with EGFR
-mutated NSCLC, osimertinib (Tagrisso) has shown potency in comparison with earlier-generation EGFR TKIs, Ramalingam noted. The phase III FLAURA trial randomized 556 patients with previously untreated EGFR
mutation–positive (exon 19 del or L858R) advanced NSCLC to receive either osimertinib or standard EGFR TKI therapy with gefitinib (Iressa) or erlotinib (Tarceva). In the primary analysis, median progression-free survival (PFS), the primary end point, was 18.9 months for osimertinib versus 10.2 months for standard EGFR TKIs (HR, 0.46; 95% CI, 0.37-0.57; P
The trial was not powered for overall survival (OS), but Ramalingam noted that a nearly 7-month advantage in OS was seen with osimertinib. The median OS was 38.6 months for the osimertinib group versus 31.8 months for the comparator EGFR
Because crossover was allowed, “The control group had one of the highest OS [rates] we have seen for the EGFR first-line setting, and despite this, we’ve seen an overall improvement in survival with osimertinib,” Ramalingam said.
Osimertinib is the preferred first-line treatment for EGFR
-positive NSCLC, according to the National Comprehensive Cancer Network guidelines.
Also in this setting, dacomitinib (Vizimpro) outperformed gefitinib with regard to median PFS benefit (14.7 months vs 9.2 months; HR, 0.59; 95% CI, 0.47-0.74; P
<.0001) for the first-line treatment of patients with advanced EGFR
-positive NSCLC, according to data from the phase III ARCHER 1050 trial.4
Data presented at the 2018 ASCO Annual Meeting demonstrated that at a median follow-up of 31.3 months, the median OS with dacomitinib was 34.1 months versus 26.8 months with gefitinib.5
Looking ahead to potential therapeutic advances in this setting, Ramalingam noted that various trials are evaluating EGFR TKIs in combination with angiogenesis inhibitors. One such trial is EA5182 (NCT02803203), which is comparing osimertinib with osimertinib plus bevacizumab (Avastin) in untreated patients with metastatic EGFR
-positive NSCLC. Furthermore, studies of chemotherapy plus gefitinib have shown wide margins of improvement in median PFS and OS, Ramalingam added.
For example, in the phase III NEJ009 study, the median PFS for gefitinib versus chemotherapy plus gefitinib in advanced NSCLC with EGFR
mutations was 11.2 months versus 20.9 months, and the median OS was 38.8 months versus 52.2 months, respectively.6ALK-Positive NSCLC