Afatinib demonstrated clinical activity against uncommon and compound <em>EGFR</em> mutations in patients with EGFR tyrosine kinase inhibitor-naive non–small cell lung cancer, a patient population for which limited data exist on the efficacy of treatment with EGFR- tyrosine kinase inhibitors, according to Yang et al.
Martin Schuler, MD
Afatinib (Gilotrif) demonstrated clinical activity against uncommon and compoundEGFRmutations in patients with EGFR tyrosine kinase inhibitor (TKI)-naïve nonsmall cell lung cancer (NSCLC), a patient population for which limited data exist on the efficacy of treatment with EGFR-TKIs, according to Yang et al. These findings are from a prospective analysis of an ongoing program of clinical trials to help develop afatinib in lung cancer.
The results of the time to treatment failure (TTF) analysis showed that in evaluable patients with EGFR TKI-naïve tumors (n = 272), those with compoundEGFRmutation had the longest median TTF, which was 14.7 months (95% CI, 6.8-18.5). In particular, patients with at least 1 major uncommonEGFRmutations had a longer median TTF of 16.6 months (95% CI, 6.8-18.7). After almost 1 year, the median TTF was 10.8 months in patients with major uncommon mutations (95% CI, 8.1-16.6).
Among the uncommon mutations groups were patients with G719X, L861Q, and S768I mutations, who had a median TTF of 14.7, 10.0, and 15.6 months, respectively. Patients who harbored exon 20 insertions had a lower median TTF of 4.2 months (95% CI, 2.8-5.3). Individuals with T790M mutations also had a lower TTF of 4.7 months (95% CI, 1.8-6.5), as did patients with other uncommon mutations whose median TTF was 4.5 months (95% CI, 2.9-9.7). Treatment continued for more than 3 years in 7 patients who had major uncommon mutations and 4 of the patients who harbored exon 20 insertions.
The best response observed was a complete response (CR), which occurred in 10 patients across all mutational groups. The other responses included partial responses (PRs), stable disease (SD), and progressive disease (PD), which occurred in 61, 35, and 9 patients, respectively.
In the major uncommon mutation group (n = 110), 5 (4.5%) patients achieved a CR, 55.5% achieved a PR (n = 61), 31.8% had SD (n = 35), and 9 (8.2%) had PD. These responses resulted in a disease control rate (DCR) of 91.8% and an overall response rate (ORR) of 60.0%. The duration of response (DOR) in this cohort was 17.1 months (95% CI, 11.0-20.8). In the compound mutation group (n = 35), there were no CRs; but 27 (77.1%) patients achieved a PR and 5 (14.3%) patients had SD overall. Three (8.6%) patients had PD. The DCR in this group was 91.4%, and the ORR was 77.1%. Responses lasted for a median of 16.6 months (95% CI, 13.8-18.7).
Patients with exon 20 insertions (n = 70) had a 2.9% CR (n = 2), and 21.4% had a PR (n = 15), 58.6% had SD (n = 41), and 17.1% had PD (n = 12). This group of patients had an 82.9% DCR and a 24.3% ORR. The DOR was 11.9 months (95% CI, 5.4-26.7). There were no individuals with a T790M mutation (n = 25) who achieved a CR, but 24.0% of patients achieved a PR (n = 6), and 52% of patients had stable disease (n = 13). There was PD in 6 (24.0%) patients with a T790M mutation. The DCR in this group was 76%, and the PR was 24%. The median DOR was 4.7 months (95% CI, 3.8-11.0). In the group with all other mutations (n = 23), no patients achieved a CR, 65.2% of patients had a PR (n = 15), 21.7% had SD (n = 5), and 13% had PD (n = 3). The DCR in this group was 87.0% and the ORR was 65.2%. The median DOR was 9.0 months in these patients (95% CI, 3.5-11.9).
When compared with patients with previously treatedEGFR-mutant NSCLC, responses were better for EGFR TKI-naïve patients overall.
The study included date from patients treated in randomized clinical trials, compassionate-use, expanded-access programs, phase IIIb trials, and non-interventional trials, as well as a systematic literature review of the LUX-Lung trials. Overall, 11% of the study population came from clinical trials (n =75), 77% were from CUP/EAP/PhaseIIIb/NIS (n = 532), and the remaining patients were from case reports or series (n = 86). Only patients from the LUX-Lung had central testing. Different methodologies were performed to test patients in other clinical trials.
Based on the results of this study, Yang et al support the use of afatinib for the treatment of NSCLC tumors that harbor several uncommon mutations, but they note that further investigation is required.
“This work provides the most comprehensive clinical resource for targeted therapy of patients with metastatic lung cancers harboring "uncommon" EGFR mutations. Many patients with such tumors indeed have clinically benefitted from afatinib. Now, this experience can be shared to help future patients with this neglected entities, which on a global level comprise a sizeable population of all lung cancers,” Martin Schuler, the director of the Department of Medical Oncology, West German Cancer Center in Essen, Germany and co-author of the study toldTargeted Oncology.
Yang JC, Schuler M, Popat S, et al. Afatinib for the treatment of non-small cell lung cancer harboring uncommon EGFR mutations: a database of 693 cases. Journal of Thoracic Oncol. DOI: https://doi.org/10.1016/ j.jtho.2019.12.126.