Dacomitinib Stands Out in EGFR-Mutated Subtype Response

Yi Long Wu, MD

Second-generation epidermal growth factor receptor (EGFR) inhibitor dacomitinib showed clear superiority over first-generation tyrosine kinase inhibitor (TKI) gefitinib (Iressa) in a comparison of performance in EGFR mutation subtypes exon 19 deletion (del 19) and L858R in advanced non—small cell lung cancer (NSCLC), according to results presented at the IASLC 18th World Conference on Lung Cancer (WCLC).¹

Findings were based on a prospective subgroup analysis of the ARCHER 1050 study (NCT01774721), and were presented at WCLC by Yi-long Wu, vice-president of the Guangdong General Hospital and Guangdong Academy of Medical Sciences and a director of the Guangdong Lung Cancer Institute.

In June at the 2017 ASCO Annual Meeting, investigators reported that in the ARCHER 1050 clinical trial, dacomitinib cut the risk of disease progression by more than 40% and resulted in an average 6.5-month improvement in response duration compared with gefitinib as first-line therapy in advanced, EGFR-mutated non-small cell lung cancer (NSCLC).²

The data presented by Wu advanced the understanding of dacomitinib’s potential beyond the del 19 subtype, showing evidence that contrary to prior reports, TKIs have strong efficacy in patients with the L858R mutation.

“Dacomitinib was effective in patients with both exon 19 deletions and L858R mutations,” he said, noting that dacomitinib prolonged progression-free survival (PFS) versus gefitinib in both patient populations; the objective response rate (ORR) was comparable between dacomitinib and gefitinib, also in both patient populations; and the duration of response was significantly improved with dacomitinib.

ARCHER 1050 was the first randomized phase III study to compare a second-generation EGFR TKI with a standard first-generation EGFR TKI in advanced EGFR-mutated NSCLC. Patients enrolled had no prior systemic treatment for advanced NSCLC, no central nervous system metastases, no prior EGFR TKI or other TKI treatment, and an ECOG performance status of 0 or 1. Patients were stratified by race: Japanese versus mainland China, other East Asian, and non-Asian. They received 45 mg dacomitinib daily (n = 227) or 250 mg gefitinib daily (n = 225).

The primary endpoint was PFS by blinded independent review, and secondary endpoints were investigator assessed PFS, duration of response (DOR), time to treatment failure, overall survival, and patient reported outcomes.

In patients with del 19, PFS by independent radiologic central (IRC) review was a median 16.5 months (HR, 0.55; 95% CI, 11.3-18.4; P <.0001) in the dacomitinib arm (n = 134) versus 9.2 months (HR, 0.55; 95% CI, 9.1-11.0; P <.0001) for those on gefitinib (n = 133).1 By investigator assessment, the median PFS for patients with del 19 was 16.6 months (HR, 0.66; 95% CI, 12.9-18.4; P = .0027) on dacomitinib versus 11.0 months (HR, 0.66; 95% CI, 9.3-12.8; P = .0027) on gefitinib.

PFS was not quite as robust for patients with an L858R mutation, but dacomitinib still encouraged a lead of roughly 2 months by IRC review, Wu stated. For patients on dacomitinib, median PFS was 12.3 months (HR, 0.63; 95% CI, 9.2-16.0; P = .0034). Median PFS for those on gefitinib by IRC review was 9.8 months (HR, 0.63; 95% CI, 7.6-11.1; P = .0034).

By investigator assessment, median PFS for the L858R subgroup on dacomitinib was 14.7 months (HR, 0.58; 95% CI, 12.8-18.4; P = .0010) and 11.0 months in the gefitinib arm (HR, 0.58; 95% CI, 9.2-12.9; P = .0010).

In the del 19 group, there were 7 complete responses (CRs) and 95 partial responses (PRs) for patients on dacomitinib versus 3 CRs and 90 PRs in the gefitinib group; the overall response rate (ORR) was 102 versus 93, respectively, by IRC review. DOR was 15.6 months (95% CI, 13.1-19.6) versus 8.3 months (95% CI, 7.9-10.1).

In the L858R mutation subgroup, dacomitinib notched 5 CRs and 63 PRs, with an ORR of 68. Patients on gefitinib had 1 CR, 67 PRs, and an ORR of 68. The median DOR was 13.7 months in the dacomitinib arm (HR, 0.454; 95% CI, 9.2-17.4) versus 7.5 months (HR, 0.403; 95% CI, 6.5-10.2) for gefitinib.

References

1. Wu Y, Cheng Y, Zhou X, et al. First-line dacomitinib versus gefitinib in advanced non-small cell lung cancer with EGFR mutation subgroups. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract OA 05.01.
2. Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase 3 trial. J Clin Oncol. 2017;35(suppl; abstr LBA9007).