Mok Debates First-Line Versus Second-Line TKI Use in Oncogene-Driven NSCLC

Lisa Astor
Published: Saturday, Jul 28, 2018

Tony S. Mok, MD
Tony S. Mok, MD
The use of frontline versus second-line tyrosine kinase inhibitor (TKI) use is controversial in many oncogene-driven non–small cell lung cancers (NSCLCs), Tony S. Mok, MD, said during a presentation at the 19th Annual International Lung Cancer Congress.

Many options currently exist for treating patients with EGFR-mutant advanced NSCLC with a targeted first-line therapy; however, not as much data currently exist for treating patients harboring other targetable driver oncogenes with targeted therapy upfront, he explained. Mok, the Li Shu Fan Medical Foundation Professor of Clinical Oncology at the Chinese University of Hong Kong, detailed the frontline treatment options for patients with advanced NSCLC harboring EGFR, ALK, ROS1, and BRAF alterations.

Frontline EGFR-Targeted Therapies

Many first-line treatment options currently exist for treating patients with EGFR-mutant NSCLC with single-agent targeted therapy, and combinations with EGFR-targeted therapies are also making their way into clinical practice internationally, Mok said. “How then are you going to choose [which treatment regimen to give], I really don’t know,” he added.

He raised the question as to whether next-generation TKIs could be better for frontline treatment than first-generation TKIs. First-generation EGFR TKIs gefitinib (Iressa) and erlotinib (Tarceva) have shown similar efficacy, but second-generation TKIs, including afatinib (Gilotrif) and dacomitinib, and the third-generation osimertinib (Tagrisso) have demonstrated improved survival rates over first-line agents in head-to-head trials.

The phase III ARCHER 1050 trial compared frontline dacomitinib with gefitinib in patients with advanced EGFR-mutant NSCLC, and updated results from the trial were presented at the 2018 ASCO Annual Meeting.1 The median PFS with dacomitinib (n = 227) was 14.7 months (95% CI, 11.1-16.6) compared with 9.2 months (95% CI, 9.1-11.0) with gefitinib (n = 225; HR, 0.59; 95% CI, 0.47-0.74; P <.0001). At 2 years, the PFS rate with dacomitinib was 30.6% versus 9.6% with gefitinib.

The median overall survival (OS) was 34.1 months (95% CI, 29.5-37.7) with dacomitinib and 26.8 months (95% CI, 23.7-32.1) with gefitinib (HR, 0.760; 95% CI, 0.582-0.993; 2-sided P = .0438). At 30 months, the OS probability was 56.2% in the dacomitinib arm compared with 46.3% in the gefitinib arm. Additionally, central nervous system metastases were noted in 11 patients on the gefitinib arm at progression compared with 1 on the dacomitinib arm.

“This is the first study ever to prove the presence of an overall survival benefit when you compare TKIs,” Mok said. “So, in a sense, we can say ‘yes’, a second-generation TKI may be better than a first-generation TKI; however, the toxicity is also high.”

Dacomitinib was granted a priority review designation by the FDA in April 2018 for the treatment of patients with previously untreated EGFR-positive locally advanced or metastatic NSCLC based on the results of the ARCHER 1050 trial.

The phase III FLAURA study looked at the third-generation EGFR inhibitor osimertinib in comparison with erlotinib or gefitinib in patients with EGFR-mutant NSCLC.2 Patients treated with osimertinib showed a median PFS of 18.9 months (95% CI, 15.2-21.4) compared with 10.2 months (95% CI, 9.6-11.1) with the first-generation EGFR TKIs (HR, 0.46; 95% CI, 0.37-0.57; P <.0001). Mok explained that this trial was very important as the survival rates exceeded expectations.

The question with all of these agents is not only which agent should be given in the frontline setting, but also what the optimal sequencing of these EGFR TKIs is, Mok said.

He also highlighted combination regimens with EGFR TKIs as first-line treatments, although none of these combinations have yet been approved for use in the United States.

Gefitinib in combination with carboplatin and pemetrexed chemotherapy was explored in patients with treatment-naïve stage IIIb/IV EGFR-mutant NSCLC in the Japanese NEJ009 trial.3 Patients were randomized 1:1 to either the combination or gefitinib alone. The combination arm went on to receive gefitinib and pemetrexed maintenance, and the monotherapy arm went on to receive a platinum-based regimen.

The median PFS in the combination arm was 20.9 months (95% CI, 18.0-24.0) compared with 11.2 months (95% CI, 9.0-13.4) in the single-agent treatment arm (HR, 0.494; 95% CI, 0.391-0.625; P <.001). The combination regimen demonstrated a median OS of 52.2 months (95% CI, 44.0-not available) versus 38.8 months (95% CI, 31.1-50.8) with gefitinib monotherapy (HR, 0.695; 95% CI, 0.520-0.927; P = .013).

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