EGFR-Positive NSCLC Is Emerging as Model for Precision Medicine

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; P <.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.

“We are going to hit a point where we have drugs like alectinib, which has a very similar profile in ALK, and osimertinib, and you’re not going to need that radiation oncology consult if you find brain metastases on your staging MRI,” said Kim. “I would even argue that, if you tested for the biomarkers and found EGFR or ALK, and the patient was a good candidate for either of these drugs, you don’t even need the MRI right away…you know it’s going to [spread to] that area. I foresee we are not going to need that down the road; it will be a little bit of a practice change, and it will take some time.”

Safety findings with osimertinib and gefitinib/erlotinib in FLAURA were found to be generally similar in FLAURA. Osimertinib was associated with less dermatitis acneiform (25% vs 48%), less AST elevation (9% vs 25%), and less ALT elevation (6% vs 27%). Moreover, there was a lower incidence of any-cause grade 3/4 adverse event with osimertinib (34% vs 45%).

Kim stated that the FLAURA data demonstrate that osimertinib should now be the frontline standard of care for EGFR-mutated patients.

For patients who develop resistance to osimertinib, an identified mutation is C797S. Anecdotally, Kim added, first-generation EGFR TKIs have been found to help treat this resistance.

However, afatinib is showcasing potential in patients with more uncommon EGFR mutations. In October 2017, the FDA granted a priority review to a supplemental new drug application for afatinib for the frontline treatment of those with metastatic NSCLC whose tumors harbor EGFR exon 21 (L861Q), G719X, or S768I substitution mutations. These types of mutations represent less than 10% of the EGFR mutations found in patients with NSCLC, but are associated with poor prognosis and survival.

“This is an area that is a gap and, if [a patient] gets one of those, afatinib is a very reasonable choice and we haven’t seen any other data from any other TKI,” Kim explained.

Additionally, Kim emphasized the need for tissue testing to accurately diagnose and stage lung cancer and that patients should not be treated with chemotherapy without having biomarker data.

“It makes me very happy to say that lung cancer is the model for precision medicine right now in almost 50% of our patients with NSCLC—it can be covered by some sort of mutation or aberration, such as PD-1 expression, EGFR, ALK, BRAF, and ROS1. This is all giving great hope for patients and that’s what makes it very gratifying.”