Afatinib Prolongs PFS in Lung Cancer Trial

James Chih-Hsin Yang, MD, PhD

Afatinib, a next-generation oral therapy, markedly prolonged progression-free survival (PFS) compared with standard chemotherapy in patients with advanced lung adenocarcinomas that tested positive for epidermal growth factor receptor (EGFR) mutations, particularly for participants with one of two common mutation types, according to clinical trial results released Sunday.

LUX-Lung 3 results, presented at the American Society of Clinical Oncology (ASCO) annual meeting, indicated a 4.2-month PFS advantage for afatinib over combined pemetrexed (Alimta) and cisplatin chemotherapy (11.1 months vs 6.9 months, respectively). The hazard ratio was a statistically significant 0.58.

For patients whose tumors had deletion 19 or L858R mutations, afatinib nearly doubled PFS compared with chemotherapy (13.6 months vs 6.9 months, respectively). Approximately 90% of the patients in the trial had one of these mutations.

The international study represents “the largest and most robust phase III trial in EGFR mutation-positive lung cancer patients,” lead investigator James Chih-Hsin Yang, MD, PhD, a professor and director of Cancer Research at the National Taiwan University in Taipei, said at a press briefing.

EGFR, also known as ErbB1 and HER1, is a member of the ErbB family of receptors that includes HER2, HER3, and HER4. The pathway can facilitate the growth and survival of cancer cells.

Afatinib is a tyrosine kinase inhibitor that has proved more potent in laboratory studies than current EGFR-targeted therapies such as gefitinib (Iressa) and erlotinib (Tarceva), said Yang. He said afatinib differs from those drugs in three ways: it is irreversible; it is a pan-HER inhibitor that blocks HER2, HER3, and HER4 dimerization; and it has shown in vitro activity against EGFR-resistant mutations.

In the LUX-Lung 3 study, Yang said 1269 patients were screened for EGFR mutations but only the 345 patients who tested positive for the mutations were enrolled. Participants had stage IIIB/IV lung adenocarcinoma, a subtype of non-small cell lung cancer (NSCLC) often associated with never-smokers and patients of Asian descent. They had no prior chemotherapy treatment.

Patients were randomized 2:1 to receive afatinib (230 patients) versus pemetrexed/cisplatin (115 patients). The primary endpoint was PFS.

In addition to a PFS advantage, the objective response rate was significantly higher with afatinib compared with pemetrexed/cisplatin (56% vs 23%; P <.0001), said Yang. The disease control rate, which includes complete and partial responses and stable disease, was 90% in the afatinib group versus 81% with pemetrexed/cisplatin.

Overall survival data are expected in approximately two years.

Yang said afatinib was well tolerated, with a lower discontinuation rate (7.9%) than pemetrexed/cisplatin (11.7%) due to treatment-related adverse events (AEs). He said AEs were consistent with those seen in other EGFR inhibitors, with diarrhea, skin rash, and stomatitis/mucositis as the most frequently reported events, all higher than with pemetrexed/cisplatin but manageable. The most common AE with the chemotherapy regimen was nausea.

Sylvia Adams, MD, an assistant professor of medicine at the New York University School of Medicine in New York City who moderated the briefing, said the study “shows that in this setting there is a clear clinical benefit for patients” with afatinib.

The LUX-Lung 3 study is among eight lung cancer trials involving afatinib that Boehringer Ingelheim Pharmaceuticals, Inc is conducting.

Yang JC-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. J Clin Oncol. 2012;30(suppl; abstr LBA7500).

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