The experimental drug afatinib (BIBW 2992) improved progression-free survival rates in lung cancer patients whose cancer had progressed after treatment with the epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib, according to the results of a Phase IIb/III trial reported at the European Society for Medical Oncology Congress.
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“Our study showed that adding afatinib to best supportive care improved progression-free but not overall survival as compared to placebo and best supportive care in patients with advanced non-small cell lung cancer who previously received chemotherapy and either gefitinib or erlotinib,” said lead author Vincent A. Miller, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center.
Although the trial did not achieve its primary endpoint of improving overall survival rates, this does not diminish its potential value, he said, since currently, patients who have not responded to EGFR mutation tyrosine kinase inhibitors have no options: “The fact that afatinib induced objective regressions in a population with no or limited treatment options, delayed progression of cancer, and was associated with some improvement in cancer-related symptoms cannot be minimized.
Dr. Miller explained that patients sensitive to gefitinib or erlotinib eventually have disease progress. The cause is most commonly a second site mutation called T790M, which has been identified in two-thirds of patients.
Afatinib is an irreversible inhibitor of two cancer-associated cell surface molecules—EGFR and human epidermal growth factor receptor 2 (HER2)—that appears to work in patients with the T790M mutation.
In the study, 585 patients with Stage IIIB/IV adenocarcinoma of the lung were randomized to receive the experimental compound plus best supportive care or placebo plus best supportive care.
All the patients had non-small cell lung cancer with the EGFR and T790M mutations, although this was not confirmed by molecular profiling. They had disease progression after one or two lines of chemotherapy, including a platinum-based one, plus more than 12 weeks of gefitinib or erlotinib therapy.
Two-Month Improvement in PFS
The median overall survival time was 10.8 months for patients who received supportive care plus afatinib, compared with just under 12 months for those receiving supportive care plus placebo.
“The median overall survival for both arms was expected to be approximately five months,” Dr. Miller said. “The fact that it was nearly one year was unexpected.”
The median progression-free survival time was 3.3 months for patients given afatinib, compared with 1.1 months in the placebo group, which translates to a 62% improvement in progression-free survival in the afatinib arm,” Dr. Miller said.
The disease control rate after eight weeks of therapy was 58% in the afatinib arm, and 19% for the placebo arm. The overall response rate was 11% in afatinib patients, compared with 0.5% for those receiving placebo plus best supportive care.
Dr. Miller blamed the lack of overall survival benefit on crossover and the use of subsequent therapies. “If we had drugs truly reinventing the field, and one was used in one arm and not the other, this would overcome the effects of subsequent therapies the individuals might receive,” he said.
The most common adverse events were diarrhea and rash, which were controlled by drug interruption or reduction of dose.
Study discussant Jean-Charles Soria, MD, Professor of Medicine and Medical Oncology at Paris University XI, commented that the study “clearly establishes afatinib as an active agent in NSCLC.”
“The lack of overall survival benefit is most probably linked to the enrichment of the trial population in EGFR-mutated patients, who have an intrinsic good prognosis and therefore receive multiple lines of therapy,” he said.
ESMO press officer Fortunato Ciardiello, MD, PhD, Professor of Medical Oncology at the Second University of Naples, said further study is warranted, with the focus on defining subgroups of patients who would benefit most— “Theoretically an irreversible inhibitor of tyrosine kinase enzymes should be more active than reversible inhibitors such as erlotinib,” he said.
© 2010 Lippincott Williams & Wilkins, Inc.