First-line gefitinib doubled PFS in NSCLC with mutated EGFR

Giving patients with non–small cell lung cancer and EGFR mutations front-line treatment with the EGFR tyrosine kinase inhibitor gefitinib resulted in a PFS twice as long as treatment with standard chemotherapy.

Results of a phase 3 randomized study conducted by the North-East Japan Study Group indicated that patients treated with gefitinib (Iressa, AstraZeneca) had a PFS of 10.8 months vs. 5.4 months with carboplatin/paclitaxel (HR=0.30; 95% CI, 0.22-0.41).

The results were published in The New England Journal of Medicine.

“We believe that the current study, in combination with our previous study of patients with mutated-EGFR NSCLC and poor performance status, establishes the clinical benefit of an EGFR tyrosine kinase inhibitor as first-line treatment in patients with NSCLC and sensitive EGFR mutations,” wrote the researchers, led by Makoto Maemondo, MD, PhD, of Miyagi Cancer Center.

The researchers said that unlike the IPASS study, in which the findings about gefitinib’s efficacy in patients with EGFR mutations was the result of a subgroup analysis, this study confirmed that EGFR status is the best criterion for the selection of patients who will benefit from treatment with the drug.

Improved PFS

This study included 230 patients with advanced NSCLC and EGFR mutations. Patients were aged 75 years or younger and had no previous treatment with chemotherapy. The patients were randomly assigned gefitinib or paclitaxel/carboplatin. The primary endpoint was PFS.

In May 2009, a preplanned interim analysis was conducted. At this time, a significant difference in PFS was identified between patients assigned gefitinib vs. those assigned chemotherapy. Patients on gefitinib had a median PFS of 10.4 months vs. 5.5 months for chemotherapy (P<.001).

When the final analysis was done in December, median PFS for patients assigned gefitinib had improved to 10.8 months.

In addition, gefitinib conferred a significantly improved objective response rate compared with chemotherapy (73.7% vs. 30.7%, P<.001).

No difference in OS was found between the groups.

Treatment with gefitinib resulted in rash (71.1%) and elevated aminotransferase levels (55.3%). Patients assigned chemotherapy most commonly reported neutropenia (77%), anemia (64.6%) appetite loss (56.6%) and sensory neuropathy (54.9%).

Timing of treatment

The researchers wrote that although the ideal timing of treatment with gefitinib is yet undetermined, data seem to indicate that first-line treatment may be most effective.

In this study, 95% of patients who failed on first-line treatment with chemotherapy were allowed to crossover to treatment with second-line gefitinib. OS was 7 months longer in the gefitinib group than in the chemotherapy group, which received second-line gefitinib, the researchers wrote.

In addition, overall response rate was worse in patients who received second-line gefitinib compared with those who received it in the first-line setting (58.5% vs. 73.7%).

“We believe that the prolonged PFS provided by the use of first-line gefitinib is valuable for patients with advanced non–small cell lung cancer, who have a poor prognosis” the researchers wrote. “If gefitinib is administered as second-line or third-line treatment, patients may miss the opportunity to receive treatment with gefitinib because of rapidly progressive disease during or after first-line treatment.”

Based on the growing body of evidence, first with INTEREST then IPASS and now North-East Japan Study Group, it is clear that we are able to replace cytotoxic chemotherapy with biologic therapy in second-line, as well as in selected first-line patients with NSCLC. This principle is an important establishment as we begin to treat patients with lung cancer more as a chronic disease, individualizing therapies. This study demonstrates prospective confirmation that when you treat patients that harbor EGFR mutations in their tumors, you really can choose a therapy that is beneficial for them. The advantages of giving an oral therapy tyrosine kinase inhibitor vs. a cytotoxic therapy are many fold. The first is reduced side effects, such as no hematologic side effects, no hair loss, no neuropathy, etc. The second is the convenience of being on a pill. When one observes other cancers, the direction we are trying to move is to replace older cytotoxic therapy with newer biologics. We are seeing it in breast cancer, in myeloma and now we are trying to incorporate it more into other solid tumors. Even when considering the treatments in a cost effectiveness standpoint, the associated costs of hospitalization and IV administration versus oral therapies may be better for everyone.

– Edward Kim, MD
Chief, Head and Neck Medical Oncology, Director, Clinical Research Operations, Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center

Maemondo M. N Engl J Med. 2010;362:2380-2388.