Results from a Phase III international trial show that initial single-agent oral therapy with the targeted drug afatinib (BIBW 2992, Boehringer Ingelheim Pharmaceuticals), a selective, orally bioavailable, irreversible ErbB family blocker of epidermal growth factor receptor (EGFR or ErbB1), human epidermal receptor 2 (HER2 or ErbB2) and ErbB4, prolongs progression-free survival (PFS) in patients with advanced lung adenocarcinomas that harbor EGFR or ErbB1 mutations, compared with standard chemotherapy.
Researchers found that afatinib was particularly beneficial ? leading to a doubling of PFS ? in the majority of patients who had one of two common types of EGFR mutations, deletion 19 or L858R. These two mutations together account for approximately 90% of all EGFR mutations.
This is the first time findings from this trial ?LUX-lung 3 ? have been presented, and they are of particular interest because researchers compared afatinib with a relatively new first-line regimen for advanced, previously untreated lung adenocarcinoma: combined pemetrexed (Alimta?, Eli Lilly and Company) andcisplatin(Platinol?, Platinol?-AQ) chemotherapy. This form of disease is a subtype of non-small cell lung cancer. EGFR mutated, or driven, lung adenocarcinoma is often clinically associated with patients who have never smoked and patients of Asian descent. In the United States, it is estimated that over 18,000 patients will be diagnosed with lung adenocarcinoma harboring EGFR activating mutations each year.
Cancer cell growth
The EGFR pathway facilitates cancer cell growth, survival and spread. Laboratory studies have shown that afatinib chemically blocks this pathway more thoroughly and permanently than current EGFR-targeted treatments, such as gefitinib (Iressa?, AstraZeneca) and erlotinib (Tarceva?, Genentech). Additionally, afatinib blocks the broader ErbB family of receptors that are associated with the EGFR pathway, including HER2 (ErbB2) and HER4 (ErbB4), and can inactivate further cancer cell pathways.
?By more broadly and effectively blocking the molecular pathways that facilitate the growth of these cancers, afatinib appears to be more potent than other therapies,? said James Chih-Hsin Yang, MD, PhD, a Professor at the National Taiwan University and the principle investigator of this multi-national study. ?This new treatment could not only help patients live a longer period of time without further cancer progression, but because it?s given orally, it may also require fewer visits to the doctors? office than standard chemotherapy ? another important quality of life advantage.?
Trial design
In this study, researchers randomized 345 patients to afatinib or standard combination chemotherapy treatment, given intravenously. All participants had EGFR mutations that were identified through central testing, and the imaging scans were independently reviewed to evaluate treatment outcomes. After a median follow-up of 8 months, they found that afatinib delayed disease progression by more than 4 months over standard therapy (PFS: 11.1 vs. 6.9 months). Among the 308 patients with either deletion 19 or L858R, PFS was prolonged even further (13.6 vs. 6.9 months). Researchers noted that patients treated with afatinib were also slower to experience worsening of common lung cancer-related symptoms, including cough and dyspnea (shortness of breath) and showed a better quality of life when compared with patients receiving chemotherapy.
Side effects with afatinib were comparable to those of other EGFR-targeting therapies. Overall survival data are expected in about two years, according to Yang.
Presentation: Monday, June 4 Time: 3:00 PM-3:15 PM CDT
Abstract: #LBA7500
Title: 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.
Authors: Yang JC, Schuler MH, Yamamoto N, O’Byrne KJ, Hirsh V, Mok T, Background: Afatinib (A) is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4.
Clinical trials:
- NCT00656136 – LUX-Lung 1, a Phase IIb/III trial investigating afatinib plus best supportive care (BSC) versus placebo plus BSC in NSCLC patients who were previously treated with first-line chemotherapy and the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib.
- NCT00525148 – LUX-Lung 2, a Phase II trial evaluating afatinib in NSCLC patients with EGFR mutations, either treatment-na?ve or after one line of treatment with chemotherapy.
- NCT00949650 – LUX-Lung 3, a Phase III trial investigating afatinib as a first-line treatment in patients with advanced NSCLC with EGFR mutations.
- NCT00711594 – LUX-Lung 4, a Phase I/II trial investigating afatinib in NSCLC patients who have progressed after conventional EGFR-TKI treatment.
- NCT01085136 – LUX-Lung 5, a Phase III trial investigating afatinib in patients with advanced or metastatic NSCLC previously treated with erlotinib or gefitinib.
- NCT01121393 – LUX-Lung 6, a Phase III trial investigating the efficacy and safety of afatinib compared to standard chemotherapy for first-line treatment of NSCLC patients with EGFR mutations.
- NCT01466660 –LUX-Lung 7, a Phase IIb trial evaluating afatinib head-to-head versus gefitinib as a first-line treatment in patients with advanced NSCLC with EGFR mutations.
- NCT01523587 – LUX-Lung 8, a Phase III trial evaluating afatinib head-to-head versus erlotinib in second-line treatment of squamous cell carcinoma of the lung.
For more information:
- Afatinib Expanded Access Program
- Alimta– Highlights of Prescribing Information
