Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.

Three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n=457) received gefitinib, those in 5 trials (n=513) received erlotinib, and those in 3 trials (n=498) received afatinib. Rash and diarrhea of grade ≥3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade ≥3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade ≥3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity.

Takeda M ，Okamoto I ，Nakagawa K 《-》

Clinical outcomes of gefitinib and erlotinib in patients with NSCLC harboring uncommon EGFR mutations: A pooled analysis of 438 patients.

The purpose of this study was to investigate the outcomes of gefitinib and erlotinib in patients with non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. Relevant researches were identified by a literature search of the PubMed database. Patients with EGFR mutations other than exon 19 deletion and L858R were eligible for the study. Clinical outcomes included objective response rate (ORR), progression free survival (PFS), and overall survival (OS). We categorized all uncommon EGFR mutations as: single uncommon EGFR mutations and compound mutations that containing 2 or more kinds of EGFR mutations. We also assessed outcomes in patients categorized by EGFR-TKIs: (1) gefitinib group; (2) erlotinib group. A total of 438 patients with NSCLC harboring uncommon EGFR mutations were included in this study. The ORR for gefitinib and erlotinib was 43.8 %, with a median PFS (mPFS) of 6.00 months and a median OS (mOS) of 20.50 months. Patients with compound mutations had an ORR of 56.3 % and an mPFS of 8.10 months. Both of them were significantly better than these in patients with single uncommon EGFR mutation, which were 29.3 % and 3.90 months, respectively (odds ratio (ORa): 2.74, 95 % confidence interval (CI): 1.86-4.05, P < 0.001; hazard ratio (HR): 0.58, 95 % CI: 0.48-0.71, P < 0.001). Moreover, patients with compound mutations containing 19 deletion or L858R had a superior response and survival benefits compared to patients with other compound mutation patterns. In addition, the gefitinib group showed a favorable efficacy advantage (P = 0.003) and PFS benefit (P = 0.021) compared to the erlotinib group. Uncommon EGFR mutations exhibit favorable but inconsistent treatment responses and survival outcomes to gefitinib and erlotinib, which are closely related to the mutation pattern, the cooccurring partner mutant genes, and the type of EGFR-TKIs received.

Wang C ，Zhao K ，Hu S ，Dong W ，Gong Y ，Li M ，Xie C ... -  《-》

Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers.

Costa DB ，Kobayashi S ，Tenen DG ，Huberman MS ... -  《LUNG CANCER》

Pooled analysis of the reports of erlotinib after failure of gefitinib for non-small cell lung cancer.

The use of erlotinib after gefitinib failure in patients with non-small cell lung cancer (NSCLC) is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of erlotinib after failure of gefitinib. We searched published reports including erlotinib and gefitinib. Eleven reports were identified (published between November 2004 and December 2008). Advanced NSCLC who documented progressive disease (PD) for gefitinib 250 mg/day, received erlotinib 150 mg once daily. A total of 106 patients were pooled from these studies. Asian was observed in 70.8%, women in 72.6%, adenocarcinoma in 85.1%, never smoker in 75.3%. In erlotinib therapy, there was observed in 9.9% in partial response (PR), 18.9% in stable disease (SD) and 70.8% in PD. Disease control (DC) rate for gefitinib and erlotinib was 71.7% and 29.2%, respectively. No significant difference of disease control rate (37.5% vs 21.7%, p=0.1503) and response rate (6.3% vs 8.7%, p=1.000) was observed between patients with EGFR mutations and those with wild type EGFR. The significantly different response on erlotinib therapy was observed in patients who had shown SD for gefitinib therapy (p=0.0095) and those who had a PFS of more than 6 months during gefitinib treatment (p=0.0261). The common toxicities were skin rash and diarrhea. Erlotinib may produce clinical benefits in patients who had shown long SD on prior gefitinib therapy. Moreover, EGFR mutations were not positive predictors for erlotinib response after gefitinib failure.

Kaira K ，Naito T ，Takahashi T ，Ayabe E ，Shimoyama R ，Kaira R ，Ono A ，Igawa S ，Shukuya T ，Murakami H ，Tsuya A ，Nakamura Y ，Endo M ，Yamamoto N ... -  《-》

What is the optimal first-line regimen for advanced non-small cell lung cancer patients with epidermal growth factor receptor mutation: a systematic review and network meta-analysis.

There are currently various tyrosine kinase inhibitor (TKI)-based regimens available, and it can be challenging for clinicians to determine the most effective and safe option due to the lack of direct comparisons between these regimens. In this study, we conducted a network meta-analysis comparing the efficacy and safety of distinct regimens to determine the optimal regimen for patients with EGFR-mutated non-small cell lung cancer, thereby facilitating clinical decision-making. The PubMed, Embase, Cochrane Library databases and international conference databases were comprehensively searched from their inception to 02 April 2024 for collecting data regarding efficacy and safety from eligible randomized controlled trials (RCTs). Following literature screening and data extraction, a NMA was conducted to compare the efficacy and safety among 21 regimens with a random-effects consistency model in a Bayesian framework using a Markov Chain Monte Carlo simulation technique within the GEMTC package. A total of 35 RCTs were included, involving 9718 individuals and 21 regimens. Compared with other interventions, combination therapies based on third-generation TKIs, especially osimertinib plus ramucirumab, showed the most favorable PFS prolongation in overall patients. Consistently, subgroup analyses showed that third-generation TKIs-based combination regimens were superior to other regimens in most prespecified subgroups with distinct clinicopathological characteristics. In terms of overall survival, despite the combination regimens based on third-generation TKIs also showing relatively superior outcomes, erlotinib plus chemotherapy and gefitinib plus chemotherapy were ranked more favorably. In terms of safety profile, combination therapies based on third-generation TKIs did not significantly increase the incidence of grade 3 or higher adverse events compared with other regimens. Our study concluded that combination regimens based on third-generation TKIs (osimertinib plus ramucirumab, osimertinib plus chemotherapy, osimertinib plus bevacizumab, amivantamab plus lazertinib and aumolertinib plus apatinib) could be the new and clinically preferable first-line, standard of care for EGFR-mutated advanced non-small cell lung cancer. The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO CRD42023480596).

Zhang W ，Zhang X ，Zhao W ，Guo Z ，Liu X ，Ye L ，Chen Z ，Xu K ，Liu Y ，Wang H ，Zhao L ，Zhang Q ，Li Y ，Chen X ，He Y ... -  《BMC Pulmonary Medicine》