Roxanne Nelson

June 04, 2012

June 4, 2012 — The investigational drug afatinib (Boehringer Ingelheim) appears to prolong progression-free survival in patients with advanced lung adenocarcinomas that harbor epidermal growth-factor receptor (EGFR) mutations.

Compared with a standard treatment regimen of pemetrexed plus cisplatin, afatinib doubled progression-free survival in most patients who harbored 1 of 2 common EGFR mutations — the exon 19 deletion or the exon 21 L858R mutation. These 2 mutations account for about 90% of all EGFR mutations.

The results of the international LUX-Lung 3 study of afatinib were presented here at the 2012 Annual Meeting of the American Society of Clinical Oncology.

At a median follow-up of 8 months, the researchers found that afatinib delayed disease progression by more than 4 months, compared with standard therapy (median, 11.1 vs. 6.9 months; hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.43 to 0.78; P = .0004). In the 308 participants with the exon 19 deletion or the exon 21 L858R mutation, progression-free survival was even more pronounced with afatinib (13.6 vs 6.9 months; HR, 0.47; 95% CI, 0.34 to 0.65; P < .0001).

"LUX-Lung 3 is the most robust phase 3 trial in EGFR-mutation-positive lung cancer patients," said lead author James Chih-Hsin Yang, MD, PhD, from the National Taiwan University in Tainan.

The primary end point of progression-free survival was met, he explained during a press briefing held in advance of the presentation. "We not only measured progression time, we also measured tumor shrinkage," said Dr. Yang. "Symptoms such as cough and shortness of breath had a longer time to worsening with afatinib."

Afatinib is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. Reversible tyrosine kinase inhibitors have significantly improved outcomes for patients with EGFR-mutation-positive nonsmall-cell lung cancer, he said. "Afatinib is different because, unlike reversible EGFR tyrosine kinase inhibitors, it irreversibly blocks the entire ErbB family of receptors."

LUX-Lung 3 is the largest prospective trial of EGFR-mutation-positive lung cancer, and is the first study to compare the efficacy and safety of afatinib with pemetrexed plus cisplatin.

Results from the LUX-Lung 1 phase 2b/3 trial were presented at the 2010 annual meeting of the European Society for Medical Oncology.

In that study, progression-free survival was also longer with afatinib than with placebo (3.3 vs 1.1 months). In addition, at 8 weeks, tumor shrinkage was significantly higher in patients treated with afatinib than in those treated with placebo (disease control rate, 58% vs 19%; P < .0001).

Study Details of LUX-Lung 3

After central testing for EGFR mutations, Dr. Yang and colleagues randomized 345 chemotherapy-naïve patients with stage IIIB/IV PS 0 to 1 lung cancer to 1 of 2 study groups; 230 patients received afatinib 40 mg daily, and 115 received intravenous pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days for up to 6 cycles.

The baseline characteristics in the 2 study groups were similar. Median age in the cohort was 61 years; 65% of the cohort was female, 72% was Asian, 68% had never smoked, 49% had the exon 19 deletion, 40% had the exon 21 L858R mutation, and 11% had other mutations.

The objective response rate was also significantly higher with afatinib than with standard treatment (56% vs 23%; P < .0001). There was a significant delay in the time to deterioration of cancer-related symptoms of cough (HR, 0.60; P = .0072) and dyspnea (HR, 0.68; P = .0145).

Adverse events were as expected on the basis of previous anti-EGFR experience, Dr. Yang noted. "They were manageable and predictable."

The most common drug-related adverse events with afatinib were diarrhea (95%), rash (62%), and paronychia (57%); with standard therapy, the most common adverse events were nausea (66%), decreased appetite (53%), and vomiting (42%).

Overall survival data are expected in about 2 years, Dr. Yang noted.

"This study is important because it shows that in this setting, there is a clear benefit in progression-free survival and quality of life, compared with first-line chemotherapy," said news briefing moderator Sylvia Adams, MD, assistant professor in the Department of Medicine at Langone Medical Center, New York University, in New York City. "The other exciting part about this study is that this represents a new generation of tyrosine kinase inhibitors."

Several studies of afatinib, which is being investigated in other cancers, will be presented at the ASCO meeting. These include phase 3 trials of head and neck squamous cell carcinoma (abstract TPS5598), HER2-overexpressing metastatic breast cancer (abstract TPS649), and lung cancer (abstracts 7557 and 7558).

Dr. Yang reports serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim. Several of the coauthors report financial relationships with industry, as noted in the abstract

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract LBA7500. Presented June 4, 2012.

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