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Glioblastoma is an aggressive form of central nervous system tumor. Recurrence rates following primary therapy are high, and few second-line treatment options provide durable clinical benefit. Aberrations of the epidermal growth factor receptor (EGFR) gene are observed in up to 57% of glioblastoma cases and EGFR overexpression has been identified in approximately 60% of primary glioblastomas. In preclinical studies, afatinib, a second-generation ErbB blocker, inhibited cell proliferation in cells harboring mutations commonly found in glioblastoma. In two previous Phase I/II studies of afatinib plus temozolomide in patients with glioblastoma, limited efficacy was observed; however, there was notable benefit in patients with the EGFR variant III (EGFRvIII) mutation, EGFR amplification, and those with loss of phosphatase and tensin homolog (PTEN). This case series report details treatment histories of three long-term responders from these trials. Next-generation sequencing of tumor samples identified alterations in a number of cancer-related genes, including mutations in, and amplification of, EGFR. Tumor samples from all three patients shared favorable prognostic factors, eg O6-methylguanine-DNA methyl-transferase (MGMT) gene promoter methylation; however, negative prognostic factors were also observed, suggesting that these shared genetic features did not completely account for the favorable responses. The genetic profile of the tumor from Patient 1 showed clear differences from the other two tumors: lack of involvement of EGFR aberrations but with a mutation occurring in PTPN11. Preclinical studies showed that single-agent afatinib and temozolomide both separately inhibit the growth of tumors with a C-terminal EGFR truncation, thus providing further rationale for combining these two agents in the treatment of glioblastomas harboring EGFR aberrations. These findings suggest that afatinib may provide treatment benefit in patients with glioblastomas that harbor ErbB family aberrations and, potentially, other genetic aberrations. Further studies are needed to establish which patients with newly diagnosed/recurrent glioblastomas may potentially benefit from treatment with afatinib.
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Aim: To explore the relationship between mutations in cfDNA and response to afatinib. Patients & methods: In total, 64 patients from one Chinese site with locally advanced/metastatic EGFRm+ non-small-cell lung cancer, who received afatinib 40 mg once daily, were included. Results: Overall, 33 (82.5%) patients became EGFRm- by visit 3; median progression-free survival was longer in these patients vs those who did not (11.0 vs 5.5 months). Progression-free survival was shorter in 42 (45.2%) patients with non-EGFR co-mutations at baseline vs those without (8.1 vs 12.5 months). Neither difference was significant. Conclusion: Afatinib provided clinical benefit for patients with EGFRm+ non-small-cell lung cancer across all subgroups. EGFRm status assessment in plasma cfDNA is a useful method of monitoring treatment.
We conducted a study in 64 Chinese patients with non-small-cell lung cancer to investigate the relationship between cancer mutations detected in the blood and the response to treatment with afatinib, which is known to be effective against EGFR mutations. Technology is now available to detect these mutations in the blood, as an alternative to obtaining and testing lung tissue samples. All 64 patients had EGFR mutations (and some patients had additional types of mutations) when afatinib was started (visit 1 in the study). By visit 3, most patients (82.5%) no longer had EGFR mutations detected in their blood, and these patients responded better to afatinib than those who still had EGFR mutations in their blood. Patients with additional types of mutations generally did not respond as well as those who had only EGFR mutations. Although results showed clinical benefit with afatinib using assessment of mutation status in the blood, statistical significance could not be shown due to the small size of the study. Clinical Trial Registration: NCT01953913 (ClinicalTrials.gov).
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Afatinib/uso terapêutico , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in real-world clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies. OBJECTIVE: To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC. PATIENTS AND METHODS: NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS). RESULTS: 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9-15.9), and median PFS was 12.1 months (95% CI 11.0-13.6). Median TTSP (13.8 months, 95% CI 12.7-16.1) and PFS (11.4 months, 95% CI 10.9-13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075). CONCLUSIONS: Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT01953913 (1 October 2013).
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Afatinib/farmacologia , Afatinib/uso terapêutico , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patologia , Mutação , Estudos Prospectivos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).
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Afatinib/uso terapêutico , Neoplasias Encefálicas , Glioblastoma , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Temozolomida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: LUX-Lung 8 was a randomised, controlled, phase 3 study comparing afatinib and erlotinib as second-line treatment of patients with advanced squamous cell carcinoma (SCC) of the lung. We report the final overall survival (OS) and safety analyses of LUX-Lung 8 and investigate the characteristics of patients who achieved long-term benefit (≥12 months' treatment). METHODS: LUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 in 183 cancer centres located in 23 countries worldwide and this final analysis had a data cut-off of March 2018. Eligible patients had stage IIIB or IV lung SCC and had progressed after at least four cycles of platinum-based chemotherapy. Patients were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. Endpoints included OS and safety; a post-hoc analysis of patients with long-term benefit (≥12 months on treatment) was also conducted. FINDINGS: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). OS was significantly prolonged with afatinib compared with erlotinib (median 7·8 months vs 6·8 months; hazard ratio 0·84; 95% CI 0·73-0·97; p = 0·0193). These findings were consistent with those of the primary analysis and were consistent across subgroups. Adverse events (AEs) were manageable with dose interruption and reduction, with similar AEs being experienced between both groups. Twenty-one (5·3%) patients receiving afatinib and 13 (3·3%) patients receiving erlotinib achieved long-term benefit; median OS was 34·6 months and 20·1 months, respectively. Amongst 132 afatinib-treated patients who underwent tumour genetic analysis, ERBB family mutations were more common in patients with long-term benefit than in the overall population (50% vs 21%). INTERPRETATION: Afatinib is a treatment option for patients with SCC of the lung progressing on chemotherapy who are ineligible for immunotherapy, particularly those with ERBB family genetic aberrations. Afatinib has a predictable and manageable tolerability profile, and long-term treatment may be well tolerated.
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BACKGROUND: Afatinib is approved for first-line treatment of patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC). Here, we report findings from a combined analysis of three phase IIIb studies of afatinib in EGFR tyrosine kinase inhibitor (TKI)-naïve patients. METHODS: EGFR-TKI-naïve patients with EGFRm+ NSCLC received afatinib 40 mg/day. Dose reductions were permitted for adverse events (AEs). Efficacy endpoints included progression-free survival (PFS), time to symptomatic progression (TTSP), and tumor response. Subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), presence of brain metastasis, age and common/uncommon EGFR mutations (plus other factors). RESULTS: 1108 patients were treated. Median age was 61 years (range, 25-89); 19.2% had baseline brain metastases, 4.4% had ECOG PS ≥2, and 17.9% had tumors harboring uncommon mutations. Treatment-related AEs (TRAEs) were reported in 97.2%, most commonly diarrhea and rash. 41.6% had AEs leading to dose reduction. Median PFS was 13.0 months [95% confidence interval (CI): 12.0-13.8]; median TTSP was 14.8 months (95% CI: 13.9-16.1). Objective response rate (ORR) was 55.0%. Age, presence of baseline brain metastases, major (G719X, L861Q, S768I) or compound uncommon mutations had little/no effect on PFS, TTSP, or ORR, while outcomes were poorer in patients with ECOG PS 2 or exon 20 insertion/T790M mutations. CONCLUSIONS: Afatinib was tolerable with no new safety signals. Afatinib demonstrated encouraging efficacy in a broad patient population, including those with brain metastases or uncommon EGFR mutations.
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BACKGROUND: This study evaluated outcomes among patients with advanced/metastatic non-small-cell lung cancer (NSCLC) treated at Asian centers participating in the global named-patient-use (NPU) program for afatinib. METHODS: Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day. Dose modifications were allowed, and afatinib was continued as long as deemed beneficial. Response and survival information was provided voluntarily. Safety reporting was mandatory. RESULTS: 2242 patients (26% aged ≥ 70 years, 96% with adenocarcinoma) received afatinib at centers in 10 Asian countries. Most were heavily pre-treated, including prior treatment with erlotinib or gefitinib. Of 1281 patients tested, 1240 had EGFR mutations (common: 1034/1101; uncommon: 117/1101). There were no new safety signals, the most common adverse events being rash and diarrhea. Objective response rate (ORR) was 24% overall (n = 431 with data available), 27% for patients with common EGFR mutations (n = 230) and 28% for those with uncommon mutations (n = 32); median time to treatment failure (TTF) in these groups was 7.6 months (n = 1550), 6.4 months (n = 692) and 8.4 months (n = 83), respectively. In patients with EGFR exon 20 insertions (n = 23) and HER2 mutations (n = 12), median TTF exceeded 12 months. CONCLUSIONS: Patient outcomes in this study were similar to those reported in the analysis of the global NPU. Afatinib achieved clinical benefits in patients with refractory NSCLC. ORR and TTF were similar between patients with tumors harboring uncommon and common EGFR mutations.
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BACKGROUND: The ErbB family blocker, afatinib, is approved for patients with squamous cell carcinoma (SqCC) of the lung following platinum-doublet chemotherapy but has not been explored following immunochemotherapy. Here, we assessed the characteristics and outcomes of patients with SqCC of the lung who received second-line afatinib or chemotherapy after first-line pembrolizumab plus chemotherapy in a "real-world" setting. METHODS: In this retrospective, multisite cohort study, community oncologists identified eligible patients and extracted data from electronic health records. Primary outcome measures were patient demographics and clinical characteristics, time on treatment, and incidence of severe immune-related adverse events (irAEs). RESULTS: Two hundred patients were included: 99 received second-line afatinib and 101 received second-line chemotherapy. Median age was 68 and 66 years, respectively; 35% and 3% of patients had mixed histology tumors, and 39% and 5% of tumors were epidermal growth factor receptor (EGFR) mutation-positive (EGFRm+). Median time on treatment was 7.3 months with afatinib (mixed histology/SqCC tumors: 8.1/5.8 months; EGFRm+/EGFRm- tumors: 7.4/5.9 months) and 4.2 months with chemotherapy. Grade 3/4 irAEs were observed in 6 patients in the afatinib cohort (all had a prior grade 3/4 irAE during first-line therapy) and no patients in the chemotherapy cohort. The most common adverse drug reactions with afatinib were diarrhea (26%), rash (6%), stomatitis, fatigue, and nausea (5% each). CONCLUSION: Encouraging time on treatment, and absence of newly diagnosed irAEs, indicate that afatinib is a treatment option following immunochemotherapy in patients with SqCC of the lung, and is currently the only approved oral agent in this setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Afatinib/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estudos RetrospectivosRESUMO
OBJECTIVES: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting. MATERIALS AND METHODS: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety. RESULTS: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions. CONCLUSIONS: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Afatinib/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Afatinib/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Neuregulina-1/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas QuinasesRESUMO
Unlike most other primary epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all EGFR mutations, are generally considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However, EGFR exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of EGFR mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon EGFR mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare EGFR exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare EGFR mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain EGFR exon 20 insertions, these findings warrant further investigation.
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AIM: The current study evaluated the efficacy and tolerability of second-line afatinib in patients with EGFR mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) following chemotherapy. PATIENTS & METHODS: In this open-label, single-arm Phase IV study, patients with EGFRm+ (Del19/L858R) NSCLC who had progressed following platinum-based chemotherapy received afatinib (starting dose 40 mg/day). The primary end point was confirmed objective response. RESULTS: 60 patients received afatinib for a median duration of 11.5 months. 50% of patients had a confirmed objective response, of median duration 13.8 months. Median progression-free survival was 10.9 months. The most common treatment-related adverse events were diarrhea (72%), rash (28%) and paronychia (23%). CONCLUSION: Our data support the use of afatinib (40 mg/day) as an effective and well-tolerated second-line treatment in EGFRm+ NSCLC.
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BACKGROUND: Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce. OBJECTIVE: To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib. PATIENTS AND METHODS: In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib. RESULTS: Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number. CONCLUSION: EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.
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Acrilamidas/uso terapêutico , Afatinib/farmacologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Biópsia Líquida/métodos , Mutação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: The global Phase III LUX-Lung 8 trial (ClinicalTrials.gov: NCT01523587) identified significant improvements in progression-free survival (PFS), overall survival (OS), and patient-reported outcomes (PROs) with second-line afatinib vs erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung. MATERIALS AND METHODS: We conducted a post hoc analysis of data for patients in LUX-Lung 8 from mainland China (n=67). Compared with erlotinib, afatinib reduced the risk of disease progression or death (PFS) in the Chinese subgroup by 30% (HR=0.70; 95% CI: 0.38-1.27). RESULTS: The risk of death was reduced by 31% (HR=0.69; 95% CI: 0.39-1.21). The proportion of Chinese patients with improvements in PROs also favored afatinib vs erlotinib (global health status/quality of life [QoL], 52.8% vs 29.6%, P=0.072; dyspnea, 47% vs 26%, P=0.091; "dyspnea walked", 44% vs 15%, P=0.017; QoL rate, 53% vs 26%, P=0.037). DISCUSSION: While this analysis was not powered to demonstrate differences compared to the overall trial population (OTP), and there were some differences in baseline characteristics (eg, the proportion of patients aged ≥65 years old), the benefits of afatinib treatment in Chinese patients with SCC of the lung appeared to be at least comparable to that observed in LUX-Lung 8. As with the OTP, the most common adverse events (AEs) with afatinib in the Chinese subgroup were diarrhea and rash/acne, and the incidence and type of the most frequently occurring AEs were similar. CONCLUSION: The results suggest that afatinib represents a feasible treatment option for Chinese patients with advanced SCC of the lung following progression on platinum-based chemotherapy.
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INTRODUCTION: Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup. METHODS: Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC. RESULTS: Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six). CONCLUSIONS: This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment.
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Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Receptor ErbB-2/genética , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Importance: Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers. Objective: To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens. Design, Setting, and Participants: Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017. Interventions: Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397). Main Outcomes and Measures: Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression. Results: Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome. Conclusions and Relevance: Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT01523587.
Assuntos
Afatinib/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Genes erbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
AIM: A global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010. MATERIALS & METHODS: Eligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials. RESULTS: Data, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents). Among 2595/3966 (65.4%) patients with tumor EGFR status, 2407 (92.8%) were EGFR mutation positive. Median time to treatment failure (2862/3966 [72.2%] patients with available data) was 4.4 months. Among 1141/2862 (39.9%) patients with response reported, objective response rate was 23.4% (267/1141). Safety findings were as expected. CONCLUSION: Time to treatment failure durations and objective response rates were encouraging.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Avaliação de Programas e Projetos de Saúde , Fatores de Tempo , Falha de TratamentoRESUMO
INTRODUCTION: Afatinib is an oral, irreversible ErbB family blocker approved for first-line treatment of metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The expanded access program (EAP) allowed early access to afatinib and provided additional data on its safety, tolerability, and efficacy. METHODS: The afatinib EAP was an open-label, multicenter, single-arm program in the United States that treated and followed patients with locally advanced or metastatic NSCLC harboring EGFR mutations. Afatinib 40 mg was administered orally once daily until discontinuation due to disease progression, adverse events (AEs), or transition to commercially available drug. RESULTS: Three hundred twenty-two patients received ≥1 dose of afatinib. Most patients had received prior therapies. Drug-related AEs occurred in 89.4% of patients, including 7.8% with serious AEs. The most common afatinib-related AEs (all grades) were diarrhea (77.0%) and rash (36.0%). Dose reductions occurred in 31.1% of patients. Discontinuation rates due to diarrhea (1.6%) or rash/acne (0.3%) were low. Efficacy data were collected and analyzed when available, with 17.1% and 69.9% of patients achieving objective response and disease control, respectively, in this highly pretreated population. CONCLUSIONS: No additional or unexpected safety concerns were revealed, and afatinib demonstrated antitumor activity in a heavily pretreated NSCLC patient population in a routine clinical setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01649284. FUNDING: Boehringer Ingelheim Pharmaceuticals, Inc.
RESUMO
There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical trial of afatinib (20-40 mg daily for 28 days) plus temozolomide (50 mg/m2 every 21/28 days). Next-generation sequencing analysis of the brain tumor specimen was performed. At the last assessment, 63 treatment cycles had been completed and the patient had survived for ~5 years since recurrence. Significant disease regression was observed after 5 cycles and was maintained during long-term follow-up. Adverse events were consistent with the known tolerability profile of afatinib and were managed by treatment interruption/dose reduction. The patient had several epidermal growth factor receptor (EGFR) aberrations, including gene amplification and EGFRvIII positivity. Three somatic mutations were identified, including an unprecedented extracellular-domain substitution (D247Y). The patient has survived ~6-fold longer than normally expected in patients with recurrent GBM. The complex EGFR genotype may underlie sustained response to afatinib plus temozolomide.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Proteínas Oncogênicas v-erbB/antagonistas & inibidores , Quinazolinas/uso terapêutico , Afatinib , Neoplasias Encefálicas/cirurgia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Dacarbazina/uso terapêutico , Receptores ErbB/genética , Feminino , Genótipo , Glioblastoma/cirurgia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgia , Proteínas Oncogênicas v-erbB/química , Radiossensibilizantes/uso terapêutico , Temozolomida , Resultado do TratamentoRESUMO
INTRODUCTION: Afatinib, an oral irreversible ErbB Family Blocker, has demonstrated efficacy and safety in epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. It is unknown whether such activity also occurs in patients with EGFR gene overexpression, regardless of mutation status. This phase II study investigated the activity and safety of afatinib in advanced non-small-cell lung cancer with increased EGFR gene copy number and/or gene amplification by fluorescence in situ hybridization (FISH), with or without EGFR mutation. METHODS: EGFR gene overexpression was assessed by FISH analysis; patients with high polysomy or gene amplification were considered FISH positive. Patients received daily afatinib less than or equal to 50 mg (monotherapy). Endpoints included objective response rate (ORR; primary), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 223 patients screened, 69 patients were FISH-positive and met eligibility criteria for treatment. The ORR was 13.0% overall (n =9 of 69). Higher ORRs were observed in patients with gene amplification (20.0%; n =5 of 25) and EGFR mutation-positive tumors (25.0%; n =3 of 12). The DCR was 50.7% overall (n = 35 of 69; median duration: 24.9 weeks) with higher DCRs observed in patients with gene amplification 64.0%; (n = 16 of 25), and in patients with EGFR mutation-positive tumors 66.7% (n = 8 of 12). In the overall population, median PFS was 8.4 weeks and median OS was 50.4 weeks. The most common afatinib-related adverse events were rash/acne (83%) and diarrhea (78%). CONCLUSIONS: First- or second-line afatinib demonstrated preliminary activity and manageable safety in EGFR FISH-positive patients with advanced non-small-cell lung cancer.