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Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib.

Hirsh V - BioDrugs (2015)

Bottom Line: Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung.The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members.Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events.

View Article: PubMed Central - PubMed

Affiliation: McGill Department of Oncology, Royal Victoria Hospital, 687 Pine Avenue W., Montreal, QC, H3A 1A1, Canada, vera.hirsh@muhc.mcgill.ca.

ABSTRACT
First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents, primarily due to secondary EGFR mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of afatinib, an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the EGFR, human epidermal growth factor receptor (HER)-2, HER3, and HER4 receptors. In two phase III trials in patients with EGFR mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) and health-related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, afatinib significantly improved overall survival in patients harboring EGFR Del19 mutations. Afatinib has also demonstrated clinical activity in NSCLC patients who had progressed on erlotinib/gefitinib, particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with paclitaxel versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung. The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events.

No MeSH data available.


Related in: MedlinePlus

Overall survival in patients with exon 19 deletions in LUX-Lung 3 and LUX-Lung 6 [68]. Reprinted from The Lancet Oncology, Vol. 16, Yang JC et al, Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, pp. 141–51, 2015, with permission from Elsevier. CI confidence interval, Cis/Gem cisplatin/gemcitabine, Cis/Pem cisplatin/pemetrexed, OS overall survival
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Fig3: Overall survival in patients with exon 19 deletions in LUX-Lung 3 and LUX-Lung 6 [68]. Reprinted from The Lancet Oncology, Vol. 16, Yang JC et al, Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, pp. 141–51, 2015, with permission from Elsevier. CI confidence interval, Cis/Gem cisplatin/gemcitabine, Cis/Pem cisplatin/pemetrexed, OS overall survival

Mentions: Median follow-up for OS was 41 and 33 months in LL3 and LL6, respectively [68]. In the overall dataset (all EGFR mutations), no significant difference in median OS was observed between the afatinib and chemotherapy arms (LL3 28.2 vs. 28.2 months; HR 0.88 [95 % CI 0.66–1.17; p = 0.39]; LL6 23.1 vs. 23.5 months; HR 0.93 [95 % CI 0.72–1.22; p = 0.61]). Interestingly, in a prespecified analysis, median OS was significantly improved with afatinib compared with chemotherapy in patients harboring Del19 mutations in both LL3 (33.3 vs. 21.1 months; HR 0.54 [95 % CI 0.36–0.79; p = 0.0015]) and LL6 (31.4 vs. 18.4 months; HR 0.64 [95 % CI 0.44–0.94; p = 0.0229]; Table 1; Fig. 3a/b); no OS difference was observed in the L858R mutation-positive subgroup. However, in a prespecified analysis of median OS in patients with common mutations (Del19/L858R), a trend towards OS benefit was observed (LL3 31.6 vs. 28.2 months; HR 0.78 [95 % CI 0.58–1.06; p = 0.11]; LL6 23.6 vs. 23.5 months; HR 0.83 [95 % CI 0.62–1.09; p = 0.18]; Table 1). Afatinib is the first agent to demonstrate improved OS versus standard-of-care platinum-doublet chemotherapy in a molecularly-defined population of patients with NSCLC. No head-to-head studies are currently available to allow direct comparison of OS achieved with afatinib versus first-generation EGFR-TKIs. However, a phase IIb trial comparing first-line afatinib versus gefitinib with EGFR mutation-positive lung adenocarcinoma is ongoing (NCT01466660).Fig. 3


Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib.

Hirsh V - BioDrugs (2015)

Overall survival in patients with exon 19 deletions in LUX-Lung 3 and LUX-Lung 6 [68]. Reprinted from The Lancet Oncology, Vol. 16, Yang JC et al, Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, pp. 141–51, 2015, with permission from Elsevier. CI confidence interval, Cis/Gem cisplatin/gemcitabine, Cis/Pem cisplatin/pemetrexed, OS overall survival
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4488453&req=5

Fig3: Overall survival in patients with exon 19 deletions in LUX-Lung 3 and LUX-Lung 6 [68]. Reprinted from The Lancet Oncology, Vol. 16, Yang JC et al, Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, pp. 141–51, 2015, with permission from Elsevier. CI confidence interval, Cis/Gem cisplatin/gemcitabine, Cis/Pem cisplatin/pemetrexed, OS overall survival
Mentions: Median follow-up for OS was 41 and 33 months in LL3 and LL6, respectively [68]. In the overall dataset (all EGFR mutations), no significant difference in median OS was observed between the afatinib and chemotherapy arms (LL3 28.2 vs. 28.2 months; HR 0.88 [95 % CI 0.66–1.17; p = 0.39]; LL6 23.1 vs. 23.5 months; HR 0.93 [95 % CI 0.72–1.22; p = 0.61]). Interestingly, in a prespecified analysis, median OS was significantly improved with afatinib compared with chemotherapy in patients harboring Del19 mutations in both LL3 (33.3 vs. 21.1 months; HR 0.54 [95 % CI 0.36–0.79; p = 0.0015]) and LL6 (31.4 vs. 18.4 months; HR 0.64 [95 % CI 0.44–0.94; p = 0.0229]; Table 1; Fig. 3a/b); no OS difference was observed in the L858R mutation-positive subgroup. However, in a prespecified analysis of median OS in patients with common mutations (Del19/L858R), a trend towards OS benefit was observed (LL3 31.6 vs. 28.2 months; HR 0.78 [95 % CI 0.58–1.06; p = 0.11]; LL6 23.6 vs. 23.5 months; HR 0.83 [95 % CI 0.62–1.09; p = 0.18]; Table 1). Afatinib is the first agent to demonstrate improved OS versus standard-of-care platinum-doublet chemotherapy in a molecularly-defined population of patients with NSCLC. No head-to-head studies are currently available to allow direct comparison of OS achieved with afatinib versus first-generation EGFR-TKIs. However, a phase IIb trial comparing first-line afatinib versus gefitinib with EGFR mutation-positive lung adenocarcinoma is ongoing (NCT01466660).Fig. 3

Bottom Line: Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung.The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members.Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events.

View Article: PubMed Central - PubMed

Affiliation: McGill Department of Oncology, Royal Victoria Hospital, 687 Pine Avenue W., Montreal, QC, H3A 1A1, Canada, vera.hirsh@muhc.mcgill.ca.

ABSTRACT
First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents, primarily due to secondary EGFR mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of afatinib, an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the EGFR, human epidermal growth factor receptor (HER)-2, HER3, and HER4 receptors. In two phase III trials in patients with EGFR mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) and health-related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, afatinib significantly improved overall survival in patients harboring EGFR Del19 mutations. Afatinib has also demonstrated clinical activity in NSCLC patients who had progressed on erlotinib/gefitinib, particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with paclitaxel versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung. The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events.

No MeSH data available.


Related in: MedlinePlus