MILAN (EGMN) – The investigational oral agent afatinib tripled median progression-free survival, but failed to extend overall survival in the third- and fourth-line setting of non–small cell lung cancer in the LUX-Lung 1 trial.

The primary outcome of median overall survival was 10.78 months for afatinib plus best supportive care and 11.96 months for best supportive care plus placebo (hazard ratio, 1.07; log-rank P = .74), Dr. Vincent Miller reported from a late-breaking abstract during the presidential symposium at the annual congress of the European Society for Medical Oncology.

Median progression-free survival by independent review increased from 1.1 months in the placebo arm to 3.3 months in the afatinib arm (HR, 0.38; log rank P less than .0001). A robust and consistent benefit was seen across all subgroups, he said. The disease control rate also tripled with afatinib.

LUX-Lung 1 compared afatinib 50 mg once daily plus best supportive care vs. best supportive care plus placebo in 585 patients with stage IIIB/IV adenocarcinoma of the lung. All had progressed after one or two lines of chemotherapy, including one platinum-based regimen, and at least 12 weeks of treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib.

Afatinib, also known as BIBW 2992, is an irreversible TKI that is highly specific for EGFR and HER2, and has shown preclinical activity against EGFR-mutant tumors that also possess the T790M mutation.

Although the presence of EGFR-activating mutation in non–small cell lung cancer (NSCLC) confers sensitivity to EGFR TKIs, patients who are sensitive to gefitinib or erlotinib eventually progress, Dr. Miller explained. The T790NM mutation is the most common cause of resistance, detected in about half of such patients.

Despite the lack of overall survival benefit, he remained optimistic about the potential value of afatinib, noting that it induced objective regressions in a population with no or limited treatment options.

After at least 8 weeks of therapy, the disease control rate by independent review was significantly higher at 58% in the afatinib arm vs. 19% in the placebo arm (P less than .0001), said Dr. Miller of Memorial Sloan-Kettering Cancer Center in New York City.

Just 0.5% of controls had an unconfirmed or confirmed partial response, compared with 13% and 7%, respectively, of afatinib patients (P less than .01 for both). Dr. Miller reported stable disease after at least 8 weeks of therapy in 51% of patients on afatinib vs. 18% on placebo. The median duration of confirmed response was 24 weeks.

“These results, I believe, are both clinically and statistically significant,” he said.

Patients receiving afatinib also reported significant improvements in prespecified lung cancer–related symptoms including cough, dyspnea, and pain.

The safety profile of afatinib was as expected, with diarrhea (17% with grade 3) and rash (14% with grade 3) predominating, Dr. Miller said. In all, 8% of patients discontinued afatinib because of a treatment-related adverse event, compared with 1% on placebo.

Serious treatment-related adverse events were reported in 10% of afatinib patients and 1% of placebo patients. Two deaths were considered attributable to afatinib: one cardiac syndrome with heart failure and one hepatic and renal failure, he said.

The median survival of nearly 1 year was unexpected and could be explained in part by subsequent therapy that was received by patients, as well as by inherently favorable biology in patients who have EGFR mutations, Dr. Miller said. In all, 68% of afatinib and 79% of placebo patients did so, with pemetrexed chemotherapy being the treatment of choice at 36% and 47%, respectively.

Dr. Miller said that the results of EGFR mutation profiling, including the presence or absence of T790M mutation, were not complete and would be reported at a later date.

Even without the EGFR data, invited discussant Dr. Jean-Charles Soria said the unprecedented survival time in both arms was probably related to the trial population’s being highly selected. Most notably, 100% had adenocarcinoma, 60% were East Asian (an ethnicity known to have higher EGFR mutation rates), 60% were never- or light smokers, and 25% had a performance status of 0, even in the third- and fourth-line setting.

“That’s not what we have in our clinical daily practice in Western cultures,” he said. “This is a population that was very sensitive to previous EGFR mutation.”

Overall survival also may have been confounded by the heavy use of subsequent treatments. “At the end of the day, they are comparing afatinib vs. further chemotherapy with pemetrexed,” said Dr. Soria, a professor of medicine and medical oncology at the Institut de Cancérologie Gustave Roussy in Villejuif, France.

Dr. Miller has received honoraria for consulting and other support from Boehringer-Ingelheim, the study sponsor, as well as from Genentech, Pfizer, and Roche. Several coinvestigators have financial relationships including employment with Boehringer-Ingelheim. Prof. Soria receives consultancy fees from several companies including Boehringer-Ingelheim.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

米兰(EGMN)——纽约Sloan-Kettering纪念癌症中心的Vincent Miller博士在欧洲肿瘤内科学会年会上报告，LUX-Lung 1研究发现，试验性口服药物afatinib可将Ⅲ期和Ⅳ期非小细胞肺癌(NSCLC)患者的中位无进展生存期延长2倍，但未能延长总体生存期。

 

Afatinib又名BIBW2992，是一种EGFR和HER2特异性的不可逆TKI，已知其具有可抑制同时有T790M变异和EGFR变异的肿瘤的临床前活性。

 

LUX-Lung 1研究比较afatinib每日50 mg和安慰剂分别联合最佳支持治疗对于585例ⅢB期和Ⅳ期肺腺癌患者的疗效。所有患者经一种或两种方案的化疗后疾病均仍有进展，包括一种含铂的化疗方案和至少12周的表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)厄洛替尼或吉非替尼治疗。

 

LUX-Lung 1研究近期发布的初步结果显示，afatinib联合最佳支持治疗组中位总体生存时间为10.78个月，而最佳支持治疗联合安慰剂组的中位总体生存时间为11.96个月(危险比HR为1.07；log-rank检验P=0.74)。据独立评估显示，安慰剂组中位无进展生存时间为1.1个月，而afatinib组为3.3个月(HR为0.38；log-rank检验P<0.0001)。这种益处在所有亚组均表现非常稳定和一致。Afatinib组的疾病控制率亦是安慰剂组的3倍。

 

在治疗至少8周后，经独立评价发现，afatinib治疗组疾病控制率显著高于安慰剂组(分别为58%和19%，P<0.0001)。安慰剂组未确认或确认的部分缓解率为0.5%，而afatinib组分别为13%和7%(P均<0.01)。在治疗8周后afatinib组有51%的患者疾病稳定，而安慰剂组仅有18%。中位确认缓解持续时间为24周。虽然afatinib未带来总体生存益处，但这些结果无论在临床上还是在统计学上都有显著意义，为那些无治疗选择或治疗选择极少的患者带来了希望。

 

接受afatinib治疗的患者还报告其肺癌相关的症状有显著改善，包括咳嗽、呼吸困难和疼痛。其不良反应以腹泻(3级者17%)和皮疹(3级者14%)为主。总体上，8%的患者因治疗相关不良反应停用了afatinib，而安慰剂组停药率仅为1%。Afatinib组治疗相关严重不良反应发生率为10%，安慰剂组为1%。2例被认为死于afatinib：1例心脏综合征并心力衰竭，1例肝肾功能衰竭。

 

勃林格-殷格翰公司资助了LUX-Lung 1临床研究，研究者声明接受多家医药公司经济资助。

 

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