Potential Role Revealed for EGFR Inhibition Beyond Progression in NSCLC

Tony Mok, MD

Continued treatment with gefitinib (Iressa) beyond progression exhibited a trend toward better outcomes in patients with T790M-negative non­—small cell lung cancer (NSCLC), according to biomarker data from the phase III IMPRESS trial presented at the 2015 World Conference on Lung Cancer (WCLC).¹

In patients with T790M-negative NSCLC, median progression-free survival (PFS) was 6.7 months with gefitinib and 5.4 months with placebo, a nonsignificant difference (HR, 0.67; 95% CI, 043-1.03; P = .07). However, this lack of a statistically significant benefit could have resulted from the small number of patients included in the analysis, explained Tony Mok, MD.

In those with T790M-positive tumors, gefitinib was associated with a median PFS of 4.6 versus 5.3 months with placebo (HR, 0.97; 95% CI, 0.67-1.42; P = .88). For the full population of the study, PFS, overall survival (OS), objective response rate (ORR), and disease control did not differ significantly between patients treated with gefitinib and placebo.

“For patients who are plasma positive for T790M at the time of RECIST progression, gefitinib should not be continued when platinum doublet chemotherapy is used as second-line therapy,” said Mok, a professor of clinical oncology at the Chinese University of Hong Kong. “For patients who are plasma negative for T790M at the time of RECIST progression, gefitinib in combination with doublet chemotherapy may offer clinical benefit that would require further confirmation in a prospective randomized study.”

EGFR TKIs are standard therapy for patients with EGFR-positive NSCLC. Almost all patients who initially respond to EGFR TKI therapy eventually develop resistance to the therapy—a result of the T790M mutation in 50% to 60% of cases.

Optimal management for patients with acquired resistance to EGFR TKI therapy remains undetermined. Some evidence has suggested that continuation of EGFR TKI in addition to platinum-containing chemotherapy at progression might be beneficial because of potential tumor heterogeneity. The data are supported by retrospective clinical studies, said Mok.

The strategy of continuing EGFR TKI therapy at disease progression was evaluated for the first time in the phase III IMPRESS trial. In the study, 265 patients were randomized to continue gefitinib plus platinum-based chemotherapy or chemotherapy alone at disease progression. Gefitinib was administered at 250 mg, cisplatin at 75 mg/m², and pemetrexed at 500 mg/m2. PFS was the primary endpoint.

The molecular subgroup was explored using an investigational circulating tumor DNA biomarker analyses known as BEAMing. The analyses focused on predose levels of T790M, L858R, and exon 19 deletion EGFR variants. Blood samples were available for 98% of participants, with 54.4% testing T790M-positive and 40.2% returning T790M-negative. T790M status was indeterminate in the remaining patients.

OS remained immature at 41% of required events in the T790M-positive subgroup and 23% in the T790M-negative subgroup. In the T790M-positive group, the hazard ratio favored treatment with placebo over gefitinib (HR, 2.16, P = .0067). However, there was a slight trend toward a reduction in the risk of death with gefitinib in patients with T790M-negative tumors (HR, 0.83, P = .6644).

ORR did not differ significantly between treatment arms according to T790M status but showed a trend toward a higher response rate with gefitinib in the T790M-negative subgroup (37% vs 27.1%; P = .206). The disease control rate also was slightly better in the T790M-negative subgroup with gefitinib (93.5% vs 83.1%).

In addition to the molecular group, an extensive subgroup analysis of PFS showed no significant differences between groups but generally showed trends in favor of the gefitinib arm. This analysis examined age, gender, region, time from progression, and prior responses to gefitinib.

“Patient testing—by plasma and/or tumor—for the T790M resistance mutation is warranted at RECIST progression following first-line EGFR tyrosine kinase inhibitor therapy, to best inform second-line treatment decisions,” Mok concluded.

For patients with the T790M mutation, a variety of options are under exploration. Following progression on frontline EGFR inhibition, these third-generation inhibitors have demonstrated encouraging clinical benefit in patients with NSCLC.

In findings from the phase II AURA2 trial also presented at WCLC, the ORR in patients with T790M-mutant NSCLC was 71% and the disease control rate was 92% with the third-generation TKI osimertinib (AZD9291).² Based off this study, and the phase II AURA trial, osimertinib received a priority review designation from the FDA as a treatment for patients with T790M alterations. The FDA will make a decision on the therapy in early 2016.

1. Soria J, Kim S, Wu Y, et al. Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 3287.
2. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA2 Phase II Study. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.

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