First-Line Afatinib plus Cetuximab for <i>EGFR</i>-Mutant Non–Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study

Cortot, A.; Madroszyk, Anne; Leprieur, Étienne Giroux; Molinier, Olivier; Quoix, Élisabeth; Bérard, H.; Otto, Josiane; Rault, Isabelle; Moro-Sibilot, Denis; Raimbourg, Judith; Amour, Elodie; Morin, Franck; Hureaux, J.; Moreau, L.; Debieuvre, D.; Morel, Hugues; Renault, Aldo; Pichon, Éric; Huret, Benjamin; Charpentier, Sandrine; Denis, Marc G.; Cadranel, Jacques

doi:10.1158/1078-0432.ccr-20-4604

Cited by 12 publications

(10 citation statements)

References 39 publications

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“…After confirming the benefit in ORR with osimertinib in the AURA1 trial [58], the phase I/II AURA2 trial [48,59] demonstrated higher ORR and median PFS among patients with T790M secondary mutation combined with common EGFR mutation. The AURA3 study finally concluded with the superiority of osimertinib over platinum-pemetrexed chemotherapy for patients previously treated with EGFR-TKI and harboring a T790M mutation [60].…”

Section: Second-line With Third-generation Egfr-tkismentioning

confidence: 90%

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Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Reita

Pabst

Pencreach

et al. 2021

Cancers

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Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

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Section: Second-line With Third-generation Egfr-tkismentioning

confidence: 90%

“…EGFR-TKI Combined with Targeted Therapy Double inhibition of EGFR using EGFR TKI plus EGFR monoclonal antibody (cetuximab) did not show any improvement in terms of PFS for afatinib + cetuximab versus afatinib alone [48].…”

Section: Egfr-tki Treatments Combinationsmentioning

confidence: 93%

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Reita

Pabst

Pencreach

et al. 2021

Cancers

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“…However, this also clearly shows that adding an anti‐EGFR mAb to afatinib enhances on‐target side effects associated with the inhibition of EGFR. Previous studies with TKI–antibody combinations already showed an increase in TRAEs, which resulted in more than 50% grade ≥3 toxicity 18,29 …”

Section: Discussionmentioning

confidence: 99%

“…Previous studies with TKI-antibody combinations already showed an increase in TRAEs, which resulted in more than 50% grade ≥3 toxicity. 18,29 In addition, other TKIs such as poziotinib and mobocertinib, specifically designed to target EGFR ex20ins mutations, could not preserve selectivity against wild-type EGFR. During poziotinib treatment, 28% and 26% of patients had grade ≥3 rash and diarrhea TRAEs, respectively.…”

mentioning

confidence: 99%

A phase 2 trial combining afatinib with cetuximab in patients with EGFR exon 20 insertion–positive non–small cell lung cancer

van Veggel,

van der Wekken,

Paats

et al. 2023

Cancer

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BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non–small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab.MethodsIn this single‐arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment.ResultsThirty‐seven patients started treatment, with a median age of 65 years (range, 40–80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression‐free survival was 5.5 months (95% CI, 3.7–8.3 months) and median overall survival was 16.8 months (95% CI, 10.7–25.8 months). The most common treatment‐related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients.ConclusionsCombination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction.

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“…Increased incidence of severe adverse events has been a signi cant concern, and for many of these combination therapies, a clear extension in overall patient survival has not yet been demonstrated. [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] In parallel, the emergence of third-generation EGFR-TKIs, particularly those developed in Asia, has been a focal point of recent research. These novel agents are garnering attention for their potential as rst-line treatments for EGFR-mutated NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of first-line treatments for patients with advanced epidermal growth factor receptor mutated non-small cell lung cancer: a network meta- analysis

Liu,

Wang,

Zhuang

et al. 2024

Preprint

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IMPORTANCE: Lung cancer, specifically non-small-cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality globally. The discovery of epidermal growth factor receptor (EGFR) mutations and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have significantly transformed the therapeutic landscape. However, identifying the most effective and safe first-line treatment for patients with advanced EGFR-mutated NSCLC remains challenging. OBJECTIVE: To assess and compare the effectiveness and safety of various first-line treatments for patients with advanced NSCLC harboring EGFR mutations, with a focus on overall outcomes and subgroup analyses based on specific EGFR mutations and clinicopathological characteristics. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from major oncology conferences (ASCO, ESMO, WCLC) were searched from inception to Dec 2023. STUDY SELECTION: Phase II/III randomized controlled trials assessing first-line treatments in patients with advanced EGFR-mutated NSCLC were included. Trials reporting on progression-free survival, overall survival, objective response rate, or toxicity were selected. DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by two authors and included study details, patient characteristics, treatments, and outcomes. Hazard ratios were used for survival outcomes, and risk ratios for binary outcomes, each with 95% credible intervals. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival. Secondary outcomes included overall survival, objective response rate, and incidence of severe adverse events (grade ≥ 3). RESULTS: The analysis encompassed 41 studies involving 11,302 patients across 26 treatment groups, osimertinib combined with pemetrexed plus platinum emerged as the most effective treatment, significantly extending progression-free survival (HR, 0.62; 95% CI, 0.41–0.94) in comparison to osimertinib alone. Lazertinib plus amivantamab also showed enhanced efficacy, marginally improving progression-free survival (HR, 0.70; 95% CI, 0.48–1.02) relative to osimertinib monotherapy. New Asian third-generation EGFR-TKIs demonstrated comparable efficacy to Osimertinib. Subgroup analyses, factoring in EGFR mutation types and clinicopathological features, consistently identified osimertinib combined with pemetrexed plus platinum, as well as lazertinib plus amivantamab, as among the most efficacious treatments for the majority of subgroups. Notably, furmonertinib was distinguished for its superior safety profile, whereas combination treatments generally exhibited a higher occurrence of grade 3 or more severe adverse events. CONCLUSIONS AND RELEVANCE: The combination of osimertinib and pemetrexed plus platinum, along with lazertinib combined with amivantamab, emerged as superior first-line treatment options for patients with advanced EGFR-mutated NSCLC, demonstrating efficacy across diverse mutation types and clinicopathological characteristics. However, promising combination treatments were associated with higher incidences of adverse events, emphasizing the need for cautious application and vigilant monitoring in clinical practice.

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First-Line Afatinib plus Cetuximab for EGFR-Mutant Non–Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study

Cited by 12 publications

References 39 publications

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

A phase 2 trial combining afatinib with cetuximab in patients with EGFR exon 20 insertion–positive non–small cell lung cancer

Efficacy and safety of first-line treatments for patients with advanced epidermal growth factor receptor mutated non-small cell lung cancer: a network meta- analysis

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