First-line Afatinib Superior to Standard Chemotherapy in Advanced EGFR-mutated Non–Small Cell Lung Cancer


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First-line therapy with the investigational oral agent afatinib improved progression-free survival compared with standard chemotherapy (pemetrexed (Alimta)/cisplatin) in patients with advanced non–small cell lung cancer (NSCLC) harboring an EGFR mutation. Afatinib improved progression-free survival by about 4 months in this advanced disease population, and progression-free survival benefits were almost doubled in favor of afatinib in patients with the most common EGFR mutations: deletion 19 or L858R. These results from the pivotal phase III international LUX-Lung 3 trial were presented at the 2012 ASCO Annual Meeting.1

Afatinib is an irreversible pan-HER (human epidermal growth factor receptor) blocker under development for NSCLC with EGFR mutations. Patients with EGFR-mutated NSCLC are commonly treated with the EGFR inhibitors erlotinib (Tarceva) and gefitinib. Neither of these drugs is FDA-approved as first-line treatment. In fact, no therapy is approved specifically for EGFR mutation–positive lung cancer. Afatinib not only blocks EGFR, but also blocks the ErbB family of receptors associated with the EGFR pathway, including HER2 and HER4.

“The study, met its primary endpoint of improving progression-free survival over chemotherapy,” said principal investigator James Chih-Hsin Yang, MD, PhD, National Taiwan University, Taipei, Taiwan.

More Potent Therapy

“Afatinib appears to be more potent than other EGFR-directed therapies because it blocks the molecular pathways that facilitate growth of these cancers more broadly and effectively. This new oral therapy may help patients live longer with no disease progression and requires fewer office visits than standard chemotherapy,” Dr. Yang continued.

This global registration study included 345 patients with NSCLC with a variety of EGFR mutations. Patients were randomized 2:1 to afatinib or standard chemotherapy with pemetrexed/cisplatin. Overall, 65% were female, 72% were East Asian, and 68% had never smoked.

Median progression-free survival in the afatinib arm was 11.1 months vs 6.9 months for standard chemotherapy, representing a 42% reduced risk of progression for those treated with afatinib (P = .0004). About 90% of patients enrolled in the trial had cancers that harbored the most common EGFR mutations, deletion 19 and L858R. In the subset of patients with these two common mutations, median progression-free survival was 13.6 months on the afatinib arm vs 6.9 months on the standard chemotherapy arm, representing a 53% reduced risk of progression with afatininb (P < .0001). Overall survival results are not yet mature and will be reported sometime in the next 2 years.

The most common drug-related adverse events associated with afatinib included diarrhea (95%), rash (62%), and paronychia (57%). In the chemotherapy arm, nausea (66%), decreased appetite (53%), and vomiting (32%) were the most common drug-related adverse events. Rates of discontinuation due to drug-related adverse events were 7.9% in the afatinib arm and 11.7% in the chemotherapy arm.

The randomized, open-label, phase III LUX-Lung 3 trial was conducted at 133 sites in 25 countries, and it is the largest phase III trial in the first-line setting for EGFR mutation–positive, advanced, metastatic NSCLC. LUX-Lung 3 was also the first trial to use pemetrexed/cisplatin as the comparator arm.

At an ASCO press conference, Dr. Yang told the audience that patients in the afatinib arm had improved quality of life, with fewer lung cancer–related symptoms and a longer time to worsening of cough and shortness of breath than patients assigned to standard chemotherapy. ■

Disclosure: Dr. Yang has served as consultant or advisor for and has received honoraria from Boehringer Ingelheim and Eli Lilly. He has not received honorarium from Boehringer Ingelheim since the LUX-Lung 3 study started to enroll patients.

Reference

1. Yang J C-H, Schuler MH, Yamamoto N, et al: LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. 2012 ASCO Annual Meeting. Abstract LBA7500. Presented June 4, 2012.


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Expert Point of View: Benjamin J. Solomon, MBBS, PhD

“The LUX-Lung 3 study has been much awaited. It is the first study to use cisplatin/pemetrexed [Alimta], which we now recognize as the best comparator arm. The study was positive for afatinib. While the use of maintenance pemetrexed may have dented the hazard ratio, I doubt this would have impacted ...


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