Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations
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Lecia V Sequist1, James Chih-Hsin Yang1, Nobuyuki Yamamoto1
1Lecia V. Sequist, Massachusetts General Hospital and Harvard Medical School, Boston, MA; James Chih-Hsin Yang, National Taiwan University Hospital; Chun-Ming Tsai, Taipei Veterans General Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Nobuyuki Yamamoto, Shizuoka Cancer Center, Shizuoka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; Kenneth O'Byrne, St James' Hospital, Dublin, Ireland; Vera Hirsh, McGill University, Montreal, Quebec, Canada; Tony Mok, Prince of Wales Hospital, Hong Kong, China; Sarayut Lucien Geater, Songklanagarind Hospital, Songkla, Thailand; Sergey Orlov, Pavlov State Medical University, St Petersburg; Vera Gorbunova, GU Russian Oncological Research Centre, Moscow, Russia; Michael Boyer, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Jaafar Bennouna, Institut de Cancérologie de l'Ouest-site René Gauducheau, Nantes, France; Ki Hyeong Lee, Chungbuk National University Hospital, Cheongju, South Korea; Riyaz Shah, Maidstone and Tunbridge Wells National Health Service Trust, Maidstone Hospital, Maidstone; Dan Massey, Victoria Zazulina, and Mehdi Shahidi, Boehringer Ingelheim, Bracknell, United Kingdom; and Martin Schuler, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
Purpose:
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).
Patients And Methods:
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).
Results:
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.
Conclusion:
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Insights
Afatinib significantly improved progression-free survival (PFS) in patients with advanced lung adenocarcinoma and EGFR mutations compared to chemotherapy. This targeted therapy offers better symptom control and prolonged PFS for eligible lung cancer patients.
Area of Science:
- Oncology
- Pharmacology
Background:
- Lung adenocarcinoma is a significant cause of cancer mortality.
- Epidermal Growth Factor Receptor (EGFR) mutations are key drivers in a subset of lung adenocarcinomas.
- Afatinib is a targeted therapy designed to inhibit the EGFR family of receptors.
Purpose of the Study:
- To compare the efficacy of afatinib versus standard chemotherapy in patients with advanced EGFR mutation-positive lung adenocarcinoma.
- To evaluate progression-free survival (PFS) as the primary endpoint.
Main Methods:
- A Phase III randomized controlled trial (LUX-Lung 3) involving 345 patients with stage IIIB/IV lung adenocarcinoma and EGFR mutations.
- Patients were randomized to receive either afatinib or cisplatin plus pemetrexed chemotherapy.
- Primary endpoint was PFS assessed by independent review.
Main Results:
- Afatinib demonstrated a median PFS of 11.1 months compared to 6.9 months for chemotherapy (HR 0.58, P = .001).
- In patients with common EGFR mutations (exon 19 deletions and L858R), median PFS was 13.6 months with afatinib versus 6.9 months with chemotherapy (HR 0.47, P = .001).
- Patient-reported outcomes favored afatinib, with improved control of cough, dyspnea, and pain.
Conclusions:
- Afatinib significantly prolongs PFS in patients with advanced lung adenocarcinoma harboring EGFR mutations.
- Afatinib represents an effective treatment option compared to standard chemotherapy for this patient population.
- Afatinib also improves patient-reported outcomes, enhancing quality of life.
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