9132 POSTER Efficacy Outcomes in First-line Treatment of Advanced NSCLC With Gefitinib (G) vs Carboplatin/paclitaxel (C/P) by Epidermal Growth Factor Receptor (EGFR) Gene-copy Number Score and by Most Common EGFR Mutation Subtypes – Exploratory Data From IPASS

Yang, Jae-Beom; Wu, Yi Long; Saijo, N.; Thongprasert, Sumitra; Chu, Da Tong; Chen, Y.M.; Duffield, Emma; Rukazenkov, Yuri; Mok, Tony; Fukuoka, M.

doi:10.1016/s0959-8049(11)72444-3

Cited by 9 publications

(5 citation statements)

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“…Previous studies have not suggested substantial differences in efficacy with chemotherapy between mutation types (median PFS ranged from 4.3–5.6 months with chemotherapy in Del19 patients and 5.8–6.8 months in those with L858R mutations) . While comparison of the median values suggests that patients with Del19 mutations in our study had a poorer response to chemotherapy than those with L858R mutations, this may be partly due to the nature of a subgroup analysis.…”

Section: Discussioncontrasting

confidence: 69%

“…The frequency of EGFR mutations in NSCLC is higher in Asian populations (up to 50–60%) than in Caucasian patients (approximately 10%) . Treatment with the first‐generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib demonstrated longer progression‐free survival (PFS), versus platinum‐based chemotherapy for first‐line treatment of EGFR mutation‐positive NSCLC in several randomized trials; however, an overall survival (OS) benefit was not observed …”

mentioning

confidence: 99%

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Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

et al. 2015

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In LUX-Lung 3, afatinib significantly improved progression-free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation-positive lung adenocarcinoma patients and overall survival (OS) in Del19 patients. Preplanned analyses in Japanese patients from LUX-Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut-off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut-off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment-related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation-positive lung adenocarcinoma patients and OS in Del19 but not L858R patients (www.clinicaltrials.gov; NCT00949650).

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Section: Discussioncontrasting

confidence: 69%

mentioning

confidence: 99%

Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

et al. 2015

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“…Our results indicate that neither patients with Del19 nor L858R have significant overall survival benefits from first-line, first generation EGFR-TKIs compared to chemotherapy. Our results agreed with the primary results from the individual firstline, first generation RCT analyses, such as EURTAC ( 10 ) and IPASS ( 16 ). Based on this analysis, we anticipate that patients with common EGFR mutations (Del19/L858R) share the same OS benefit when receiving first-line, first generation EGFRTKIs.…”

Section: Discussionsupporting

confidence: 88%

“…An analysis of a single study, such as IPASS ( 16 ) or NEJ002 ( 11 , 17 ) has demonstrated that patients with either Del19 or L858R treated with gefitinib had no survival advantage compared with first-line chemotherapy. However, several small studies have previously demonstrated that patients with Del19 have superior OS compared to patients with L858R ( 18 - 23 ).…”

Section: Introductionmentioning

confidence: 99%

Comparing overall survival between first generation EGFR-TKIs and chemotherapy in lung cancer patients with Del19/L858R

Deng¹,

Lei²,

Liu³

et al. 2016

Chinese Journal of Cancer Research

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ObjectiveCombined overall survival (OS) analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor (EGFR) exon 19 deletions (Del19) would benefit from first-line second generation EGFR tyrosine kinase inhibitors (TKIs) afatinib but not for those with L858R. This study was to investigate the survival difference between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups.MethodsEligibles were all prospective and retrospective studies comparing EGFR-TKIs with conventional chemotherapy or receiving single agent EGFR-TKIs and demonstrating survival analysis based on mutation types. The primary outcome was OS measured as pooled hazard ratios (HRs). All measures were pooled using randomeffects models and 95% confidential interval (95% CI) was calculated.ResultsA total of 14 studies incorporating 1,706 patients with either Del19 or L858R were included. Enrolling patients with Del19 or L858R in randomized controlled trials (RCTs), first-line first generation EGFR-TKIs were associated with no OS benefit, compared with chemotherapy (pooled HRTKI/Chemo for Del19: 0.82, 95% CI: 0.64-1.06, P = 0.14; pooled HRTKI/Chemo for L858R: 1.15, 95% CI: 0.85-1.56, P = 0.38). Direct comparison of Del19 with L858R receiving with first-line first generation EGFR-TKIs demonstrated no significant survival difference (pooled HR19/21: 0.88, 95% CI: 0.67-1.16, P = 0.37).ConclusionsAmong patients with advanced non-small cell lung cancer (NSCLC) harboring Del19 and L858R, first-line first generation EGFR-TKIs demonstrated no survival benefit comparing with chemotherapy. Direct comparison between Del19 and L858R revealed no significant survival difference after first-line first generation EGFR-TKIs.

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“…In contrast to afatinib, neither erlotinib nor gefitinib demonstrated an OS benefit versus chemotherapy in patients harboring Del19 or, indeed, L858R mutation-positive disease [ 21 , 26 , 28 ]. The lack of OS benefit with gefitinib or erlotinib versus chemotherapy, either in total datasets or in patients with the EGFR Del19 mutation (Table 1 ) [ 17 , 25 – 30 ], has been attributed, at least partially, to post-progression therapy with EGFR-TKIs in patients initially randomized to chemotherapy [ 17 , 25 – 27 , 29 , 30 ].…”

Section: Clinical Trials Of First-line Afatinib In Patients With Nsclmentioning

confidence: 99%

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

Hirsh

2015

BioDrugs

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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.

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9132 POSTER Efficacy Outcomes in First-line Treatment of Advanced NSCLC With Gefitinib (G) vs Carboplatin/paclitaxel (C/P) by Epidermal Growth Factor Receptor (EGFR) Gene-copy Number Score and by Most Common EGFR Mutation Subtypes – Exploratory Data From IPASS

Cited by 9 publications

References 0 publications

Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

Comparing overall survival between first generation EGFR-TKIs and chemotherapy in lung cancer patients with Del19/L858R

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

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