*For medical professionals only
Lung cancer is the leading cause of cancer-related deaths, and non-small cell lung cancer (NSCLC) accounts for approximately 85 percent of lung cancers [1]. The advent of EGFR tyrosine kinase inhibitors (TKIs) has changed the treatment landscape for patients with advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutations. Studies have shown that about two-thirds of newly diagnosed lung cancer patients are over 65 years of age, and this proportion is expected to increase in some regions given the aging trend [2]. The efficacy and safety of EGFR-TKI therapy in elderly patients with EGFRm(19del/21L858R) NSCLC have been explored, and this article takes a Japanese prospective clinical study published in Cancer Manag Res in 2021 as an example.
Study design
The study[3] is a prospective clinical study to evaluate the efficacy and safety of osimertinib in the first-line treatment of elderly (aged ≥ 75 years) patients with EGFRm (19del/21L858R) advanced NSCLC. Endpoints include: progression-free survival (PFS), objective response rate (ORR), time to treatment failure (TTF), and safety.
A total of 43 patients were enrolled in the study from August 2018 to January 2021. The age range of patients was 75~90 years old, the median age was 79 years, 65% were females, 77% had good PS scores (0 or 1 points), and 9 patients (21%) had brain metastases at baseline. Forty-three patients were all lung adenocarcinoma, of which 24 patients (56%) had exon 19 deletion (19del) and 19 patients (44%) had 21L858R mutation.
Enrolled patients were treated with oral osimertinib 80 mg daily until disease progression or intolerable adverse events (AEs).
Results: Effectiveness
As of July 2021, 21 patients were still receiving osimertinib, with a median follow-up of 17.2 months. The results of the study are as follows:
Median PFS:
- The median PFS of the 43 patients was 22.1 months.
- The median PFS in the group with good PS and the group with poor PS was 24.5 months and 10.5 months, respectively, P=0.068.
- The median PFS of patients without brain metastases and patients with brain metastases was 24.5 months and 13.7 months, respectively, P=0.14.
- The median PFS of exon 19 deletion patients and L858R mutation patients were 24.5 months and 22.1 months, respectively, P=0.94.
TTF：
- The median TTF of the 43 patients was 14.6 months.
- The median TTF of the group with good PS and the group with poor PS was 15.2 months and 5.8 months, respectively, P=0.063.
- The median TTF of patients without brain metastases and patients with brain metastases was 15.0 months and 10.0 months, respectively, P=0.17.
- The median TTF of patients with exon 19 deletion and L858R mutation was 13.7 months and 15.0 months, respectively, P=0.70.
ORR：
- The ORR was 60.5%.
- The ORR of the group with good PS and the group with poor PS were 66.7% and 40.0%, respectively, P=0.17.
Findings: Safety
Forty-three patients had no treatment-related deaths, and the most common AEs were acne (18 patients, none patients ≥ grade 3), diarrhea (14 patients, no patients ≥ grade 3), and paronychia (12 patients, none ≥ grade 3).
discuss
The results of this study showed that in the elderly NSCLC patient population with EGFRm (19del/21L858R), the first-line osimertinib ORR was 60.5% and the median PFS was 22.1 months, which was basically consistent with the results of the Japanese subgroup analysis of the FLAURA study [4], indicating that the elderly patients with EGFRm(19del/21L858R) NSCLC can achieve clinical benefit from osimertinib. At the same time, the data of the brain metastasis subgroup of this study showed that there was no significant difference in PFS and TTF in patients with or without brain metastases at baseline, and there was no progression of brain lesions during osimertinib treatment, which further verified the excellent intracranial efficacy of osimertinib. In terms of safety, osimertinib was well tolerated overall in older patients.
Ametinib is another third-generation EGFR-TKI. Results from the real-world study of ametinib in the first-line treatment of patients with EGFRm(19del/21L858R) NSCLC were presented at the 2022 European Society for Medical Oncology Asia Conference (ESMO ASIA) [5]. A total of 66 patients with stage IIA-IVB EGFRm(19del/21L858R) NSCLC who received first-line ametinib were included in the study, including 35 patients aged ≥ 65 years, with the primary endpoint being ORR and the secondary endpoints being PFS, OS, disease control rate (DCR) and safety. Subgroup analysis showed that there was no significant difference in ORR and DCR between the elderly subgroup (≥ 65 years old) and the younger subgroup (< 65 years old) (71.4% vs. 77.4%, 97.1% vs. 96.8%, P>0.05). In terms of safety, the incidence of AEs between the two groups was 45.7% and 58.1%, respectively, and there was no statistical difference (P>0.05). The results suggest that the efficacy and safety of ametinib in elderly patients with EGFRm(19del/21L858R) NSCLC are basically consistent with those of younger patients.
Studies have also explored the efficacy and safety of next-generation EGFR-TKIs in elderly patients. A retrospective study in Japan [6] analyzed the efficacy and safety of first-line treatment with gefitinib in 55 elderly NSCLC patients aged ≥ 75 years with EGFRm (19del/21L858R). The study had a median follow-up of 16 months, and the results showed that the ORR and DCR of the 55 patients were 72.7% and 92.7%, respectively, and the median PFS was 13.8 months. The safety analysis showed that the most common adverse reaction during treatment was skin toxicity, with skin rash in 41.8% of patients, in addition, 20% of patients experienced elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels, of which 7.3% of patients achieved grade 3 or above, and patients with grade 3 and above AEs improved after temporary use of gefitinib or alternate-day dosing.
summary
For patients ≥ 75 years of age with EGFRm (19del/21L858R) advanced NSCLC, first-line osimertinib is an effective and well-anticipated treatment option.
bibliography
[1] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362(25):2380–2388.
[2] Barta JA, Zinner RG, Unger M. Lung cancer in the older patient. Clin Geriatr Med. 2017; 33:563–577.
[3] Igawa S, Kasajima M, Ono T, et al. A Prospective Observational Study of Osimertinib for Chemo-Naive Elderly Patients with EGFR Mutation-Positive Non-Small Cell Lung Cancer. Cancer Manag Res. 2021 Nov 20;13:8695-8705.
[4] Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018; 378(2):113–125.
[5]2022 ESMO ASIA. 371P
[6] Tateishi K, Ichiyama T, Hirai K, et al. Clinical outcomes in elderly patients administered gefitinib as first-line treatment in epidermal growth factor receptor-mutated non-small-cell lung cancer: retrospective analysis in a Nagano Lung Cancer Research Group study. Med Oncol. 2013 Mar; 30(1):450.
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