EGFR-Positive NSCLC Is Emerging as Model for Precision Medicine

Gina Columbus @ginacolumbusonc
Published: Friday, Nov 10, 2017

Edward S. Kim, MD
Edward S. Kim, MD
It has been a “renaissance” in the non–small cell lung cancer (NSCLC) landscape with the rapid evolution of targeted treatment for patients with EGFR-mutation–positive disease, Edward S. Kim, MD, said in a presentation at the 35th annual CFS®.

“It has been gratifying to see the change that has occurred since the early 2000s and late 1990s,” said Kim, who is chair of Solid Tumor Oncology and Investigational Therapeutics and the Donald S. Kim Distinguished Chair for Cancer Research at the Levine Cancer Institute, Carolinas HealthCare System. “The closer we get to 2020, [we learn] the ways we can help patients with our different tests.”

In an era where immunotherapy is becoming the new cornerstone in the field, Kim added, comprehensive gene panels are able to detect molecular biomarkers—EGFR, ALK, ROS1, PD-L1, or BRAF—that can guide treatment. In EGFR-mutant NSCLC, the standard frontline tyrosine kinase inhibitor (TKI) choices include afatinib (Gilotrif), erlotinib (Tarceva), and gefitinib (Iressa).

“All [3 EGFR inhibitors] target the L858R mutations but, as we have seen over time, there have been some differences with these drugs,” said Kim. “There have been subsets pulled out; it’s no longer just EGFR. There are specific mutations that exist within this family and we're going to have to know what [drugs] work better with what [mutations].” 

When the third-generation EGFR TKI osimertinib (Tagrisso) entered the landscape, it was explored in comparison to pemetrexed in the AURA3 trial for patients who progress on a first-line EGFR inhibitor and harbor the T790M resistance mutation.

“When this drug was first tested, we saw tremendous activity to the resistance mutation T790M,” Kim recalled. “What a strategy—you could start someone with an EGFR TKI who had a sensitizing mutation that would do well for a long time and then, eventually, the drug would stop working, the tumors would start growing, you do a biopsy, you find T790M in about half of those patients—and then you give them another pill. Theoretically, you could treat a lung cancer patient who is fortunate to have these mutations for quite some time. It has been shown that if you look at osimertinib versus chemotherapy in T790M-positive patients, it is better than chemotherapy.”

Outside of the 3 EGFR TKIs approved in the frontline setting, the EGFR-mutant NSCLC paradigm transformed in September 2017 with the phase III FLAURA findings at the 2017 ESMO Congress. Here, the oncology community saw the magnitude of benefit with the use of frontline osimertinib when compared with either gefitinib or erlotinib in patients with EGFR-mutant NSCLC.

Results of FLAURA showed that frontline osimertinib was associated with a 54% reduction in the risk of progression or death versus standard therapy, which included erlotinib or gefitinib. Additionally, the median progression-free survival (PFS) was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 12.5-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57; <.0001). The median duration of response was doubled with osimertinib versus standard therapy at 17.2 and 8.5 months, respectively.

“It was pretty impressive PFS; it has convinced most of the lung cancer community that, when it becomes approved, it will become a first-line treatment,” Kim said. “Osimertinib is the new standard for 2017 based on these frontline data; it’s not approved yet there but I know people are going to be using it.”

Though overall survival data remain immature, there is an encouraging trend that favors osimertinib (HR, 0.63; 95% CI, 0.45-0.88; P = .0068) yet it is not yet statistically significant. A P value of <.0015 was required for statistical significance at 25% maturity.

Additionally, the trial’s findings highlighted a benefit with osimertinib in patients who also had brain metastases. In those with CNS disease evaluable for response (n = 46), CNS overall response rate (ORR) was 70% with osimertinib compared with 31% for patients treated with platinum-based doublet chemotherapy (odds ratio [OR], 5.13; 95% CI, 1.44-20.64; P = .015). Across the full population (N = 416), CNS PFS also favored the osimertinib group at 11.7 months versus 5.6 months (HR, 0.32; 95% CI 0.15-0.69; P = .004).

The CNS activity with osimertinib in EGFR-mutation–positive NSCLC mimics that of the ALK inhibitor alectinib (Alecensa) in ALK-positive NSCLC, Kim explained.

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