Survival benefits from afatinib compared with gefitinib and erlotinib among patients with common EGFR mutation in first-line setting.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line treatment in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR-TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first-line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation. A retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first-line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression-free survival (PFS) with first-line EGFR-TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first-line EGFR-TKIs. Among 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first-line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first-line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance. First-line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR-TKI in the first-line setting.

Kwok WC ，Ho JCM ，Tam TCC ，Ip MSM ，Lam DCL ... -  《-》

Clinical outcomes and secondary epidermal growth factor receptor (EGFR) T790M mutation among first-line gefitinib, erlotinib and afatinib-treated non-small cell lung cancer patients with activating EGFR mutations.

Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians' choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression-free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15-9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20-8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10-9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18-20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02-0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients' clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.

Lin YT ，Chen JS ，Liao WY ，Ho CC ，Hsu CL ，Yang CY ，Chen KY ，Lee JH ，Lin ZZ ，Shih JY ，Yang JC ，Yu CJ ... -  《-》

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours. To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life. We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.

Greenhalgh J ，Boland A ，Bates V ，Vecchio F ，Dundar Y ，Chaplin M ，Green JA ... -  《Cochrane Database of Systematic Reviews》

Which Is Better EGFR-TKI Followed by Osimertinib: Afatinib or Gefitinib/Erlotinib?

Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group). This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions. We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195). Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.

Tamiya M ，Tamiya A ，Suzuki H ，Moriizumi K ，Nakahama K ，Taniguchi Y ，Kunimasa K ，Kimura M ，Inoue T ，Kuhara H ，Nishino K ，Hirashima T ，Atagi S ，Imamura F ，Kumagai T ... -  《-》

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

Greenhalgh J ，Dwan K ，Boland A ，Bates V ，Vecchio F ，Dundar Y ，Jain P ，Green JA ... -  《Cochrane Database of Systematic Reviews》