A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population

Heredia, David; Más, Luís; Cardona, Andrés F.; Oyervides, Víctor; Guerrero, Rodrigo Motta; Gálvez-Nino, Marco; Lara‐Mejía, Luis; Aliaga-Macha, Carlos; Carracedo, Carlos; Varela‐Santoyo, Edgar; Ramos‐Ramírez, Maritza; Davila-Dupont, David; Martínez, Juan; Cruz‐Rico, Graciela; Jordi-Remon,; Arrieta, Óscar

doi:10.1016/j.lungcan.2022.11.002

Cited by 9 publications

(4 citation statements)

References 34 publications

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“…The subsequent activation of the JAK-STAT, the PI3-K-Akt-mTOR, and the RAS-RAF-MEK-ERK pathways leads to cell proliferation, inhibition of apoptosis, and tumor microenvironment development ( 3 , 5 ) . The prevalence of EGFR mutation is higher in younger non-smokers or light-smokers and those with wood smoke exposure ( 6 ) . The frequency of EGFR mutation varies widely worldwide and occurs more commonly (40%–60%) in the southeast of Asia ( 7 ) .…”

Section: Introductionmentioning

confidence: 99%

“…EGFR mutant (EGFRm) metastatic non-small cell lung cancer (NSCLC) is generally sensitive to tyrosine kinase inhibitors (TKIs), considered the standard first line of treatment (11,12) . TKIs have revolutionized the EGFRm metastatic NSCLC treatment landscape since the introduction of the first-generation TKIs as first-line treatment (6) . Second-generation and third-generation TKIs improved survival in comparison with the first-generation TKIs (13)(14)(15)(16)(17) .…”

Section: Introductionmentioning

confidence: 99%

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Effectiveness and safety of the bevacizumab and erlotinib combination versus erlotinib alone in EGFR mutant metastatic non-small-cell lung cancer: systematic review and meta-analysis

Motta-Guerrero,

Leon Garrido-Lecca,

Failoc-Rojas

et al. 2024

Front. Oncol.

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BackgroundThe EGFR gene encodes a protein that stimulates molecular pathways that allow the growth and development of the tumor microenvironment. The current preferred tyrosine kinase inhibitor (TKI) for the first-line treatment of EGFRm metastatic non-small cell lung cancer (NSCLC) is osimertinib. However, the combination of angiogenesis inhibitors and TKI has produced discordant results. We aimed to assess the effects of the bevacizumab and erlotinib combination in EGFRm metastatic NSCLC.MethodsUsing eligibility criteria focused on patients with EGFRm metastatic NSCLC treated with bevacizumab and erlotinib, we searched databases including clinical trial randomized studies and reviews published until April 15, 2023 in Medline (PubMed), Scopus, and Embase. Eight clinical trials (1,052 patients) were selected from 1,343 articles for quantitative and qualitative assessment. The risk of bias was assessed using the Cochrane Risk of Bias tool. Data were synthesized through random-effects meta-analysis.ResultsThe bevacizumab and erlotinib combination significantly improved the progression-free survival (PFS) (log(HR) = 0.63; 95% CI: 0.54–0.73, p < 0.001) and overall response ratio (ORR) (RR = 0.79; 95% CI, 0.64–0.97, p = 0.03). However, it did not improve the overall survival (log(HR) = 0.93; 95% CI, 0.78–1.10, p = 0.38) and was associated with higher serious adverse events (SAEs) (OR = 3.48; 95% CI, 1.76–6.88, p = 0.005). A subgroup analysis suggested similar benefits in different mutation subtypes and brain metastasis condition. The evidence is limited by a moderate risk of bias across studies and heterogeneity in the reporting of SAEs.ConclusionsThe bevacizumab and erlotinib combination significantly improved PFS and ORR in EGFRm metastatic NSCLC but were also associated with higher-grade (≥3) adverse events. These results suggest that while the combination therapy may enhance progression-free survival and overall response, it does not improve the overall survival and is associated with higher toxicity. Thus, the treatment should be personalized based on individual patient comorbidities. Further prospective trials are needed to validate these results.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#searchadvanced, identifier CDR 42022364692.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effectiveness and safety of the bevacizumab and erlotinib combination versus erlotinib alone in EGFR mutant metastatic non-small-cell lung cancer: systematic review and meta-analysis

Motta-Guerrero,

Leon Garrido-Lecca,

Failoc-Rojas

et al. 2024

Front. Oncol.

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“…Treatment might be dependent on which mutation has the higher allele frequency (19) or which other cancer-related genes have co-occurring mutations (20,21). For example, TP53, the most commonly mutated gene in NSCLC, co-occurs in ~65% of cases of EGFRm+ NSCLC, and has been associated with poor prognosis and primary/acquired resistance to EGFR TKIs (22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Activity of afatinib in patients with NSCLC harboring novel uncommon EGFR mutations with or without co-mutations: a case report

Christopoulos,

Herster,

Hoffknecht

et al. 2024

Front. Oncol.

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10–20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to afatinib.

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“…To date, in advanced EGFR ‐mutated NSCLC, co‐occurring mutations and/or amplifications in the tumor protein p53 ( TP53 ), HER2 , MET , CDK4/6 gene, etc., have been reported to negatively affect the survival outcome of the patients treated with EGFR‐TKIs [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. We hypothesized that in the adjuvant setting, the benefits of gefitinib might be clinically meaningful by selecting patients who have specific molecular biomarkers among those with EGFR mutations.…”

Section: Introductionmentioning

confidence: 99%

NOTCH1 and CREBBP co‐mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR‐mutated NSCLC: translational research of phase III IMPACT study

Ikeda,

Tsuboi,

Sakai

et al. 2023

Molecular Oncology

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The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC). Although the primary endpoint of disease free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer‐related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co‐mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co‐mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co‐mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07‐28.00), with a significant interaction (P for interaction=0.039). In patients with CREBBP co‐mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction=0.058). In completely resected EGFR‐mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

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A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population

Cited by 9 publications

References 34 publications

Effectiveness and safety of the bevacizumab and erlotinib combination versus erlotinib alone in EGFR mutant metastatic non-small-cell lung cancer: systematic review and meta-analysis

Effectiveness and safety of the bevacizumab and erlotinib combination versus erlotinib alone in EGFR mutant metastatic non-small-cell lung cancer: systematic review and meta-analysis

Activity of afatinib in patients with NSCLC harboring novel uncommon EGFR mutations with or without co-mutations: a case report

NOTCH1 and CREBBP co‐mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR‐mutated NSCLC: translational research of phase III IMPACT study

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