Gefitinib Improves Survival in Lung Cancer Patients with EGFR Mutations

Roxanne Nelson

December 23, 2009

December 23, 2009 — Another clinical trial has shown that Asian patients with lung cancer and epidermal growth-factor receptor (EGFR) mutations respond well to initial treatment with gefitinib (Iressa; AstraZeneca). In the latest study, gefitinib conferred superior progression-free survival time vs standard treatment with platinum-based combination chemotherapy.

The results, from a study in 177 patients, are reported by Tetsuya Mitsudomi, MD, from Aichi Cancer Center Hospital, Nagoya, Japan, in the December 21 online issue of Lancet Oncology.

Patients who received gefitinib had a median progression-free survival time of 9.2 months (95% confidence interval [CI], 8.0 - 13.9 months) vs 6.3 months (95% CI, 5.8 - 7.8 months; hazard ratio [HR], 0.489; 95% CI, 0.336 - 0.710; P < . 0001) for those treated with platinum doublet chemotherapy.

"It is not yet known whether the prolonged progression-free survival conferred by gefitinib will translate into prolonged overall survival," the study authors write, adding that they will continue to carefully monitor these patients to determine the long-term effects.

Two previous trials have already reported a similar finding of gefitinib efficacy in patients with lung cancer and EGRF mutations, both conducted in Asian populations, as previously reported by Medscape Oncology. A similar finding has also been reported for erlotinib from a Spanish study. This has led to suggestions that patients with lung cancer should be screened for EGRF mutations and that patients with these mutations should be treated with targeted agents first instead of chemotherapy.

Gefitinib Improves Progression-Free Survival Time

In this latest study, Dr. Mitsudomi and colleagues sought to determine if gefitinib offered a survival advantage vs platinum doublet chemotherapy, when used as a first-line treatment in patients with lung cancer selected by EGFR mutation.

The open label, phase 3 study enrolled 177 patients between March 31, 2006, and June 22, 2009, from 36 centers in Japan. All participants were chemotherapy naive, 75 years or younger, and had been diagnosed with stage IIIB/IV non–small-cell lung cancer or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R point mutation).

The patients were randomly assigned to receive either gefitinib (250 mg/day orally; n = 88) or cisplatin (80 mg/m² intravenously) plus docetaxel (60 mg/m² intravenously; n = 89), administered every 21 days for 3 to 6 cycles. The primary endpoint of the trial was progression-free survival time, and survival analysis was conducted with the modified intent-to-treat population.

The majority of patients had adenocarcinoma, 71 patients (41.3%) had postoperative recurrent disease, and 54 (31.4%) of the patients had a history of smoking. The median follow-up period was 81 days (range, 74 - 1253 days).

Overall, patients treated with gefitinib had significantly longer progression-free survival duration vs cisplatin plus docetaxel (HR, 0.489; 95% CI, 0.336 - 0.710; P < .0001). In both subgroups, progression-free survival time in the gefitinib group was longer vs the cisplatin-plus-docetaxel group, although it was not significant for patients with postoperative recurrence.

The objective response rate in patients with measurable disease was significantly higher among patients receiving gefitinib (62.1%) vs patients receiving cisplatin plus docetaxel (32.2%). The disease control rate was also higher in the gefitinib group (93.1%) vs the chemotherapy group (78%), with an overall difference of 15.5% (95% CI, 2.7 - 27.6; P = .020).

Both groups experienced adverse events, with myelosuppression, alopecia, with fatigue reported more frequently in the chemotherapy group, whereas skin toxicity, liver dysfunction, and diarrhea were more frequently reported in the gefitinib group. Overall, grade 3 or higher toxicities were infrequent except for liver dysfunction.

Thus far, there have been 17 events (deaths) in the gefitinib group vs 10 events in the chemotherapy group — with an HR for gefitinib of 1.638 (95% CI, 0.75 - 3.58), the study authors note. The data for overall survival duration are still immature, and follow-up is ongoing.

"Our study indicates that EGFR genetic testing is feasible and should be done when possible," write the study authors. "These results strongly suggest that the presence of EGFR mutations, and not the clinical background of patients, determines clinical efficacy, and this knowledge should lead to molecularly based, personalized treatment of lung cancer."

Novel EGFR Inhibitor

A novel structural class of EGFR kinase inhibitors has been identified by researchers from Harvard University and the Dana-Farber Cancer Institute in Boston, Massachusetts, and they are hopeful that it may prove to be more clinically effective and better tolerated than the agents currently available.

The clinical efficacy of gefitinib or erlotinib is limited by the development of acquired drug resistance, such as by mutation of the gatekeeper T790 residue (T790M), as noted in an article that appears in the December 24/31 issue of Nature. The T790M has been identified in half of all clinically resistant patients.

In an experimental study, Pasi A. Jänne, MD, PhD, an associate professor of medicine at Harvard University Medical School, and colleagues, identified covalent pyrimidine EGFR inhibitors by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These products were found to be 30- to 100-fold more potent against EGFR T790M than currently available agents, as well as 100-fold less potent against wild-type EGFR, when tested in vitro.

One of the substances, WZ4002, was tested in mouse models of lung cancer, and a 2-week efficacy study showed significant tumor regressions. Further histologic evaluation of the lungs after treatment confirmed a significant resolution of the tumor nodules, according to the authors.

"These findings suggest that WZ4002 could also be used as initial therapy for patients with EGFR-mutant NSCLC [non–small-cell lung cancer] and may ultimately lead to a longer time to disease progression than currently achieved with gefitinib," they write.

The Lancet Oncology study was supported by the West Japan Oncology Group. Several of the study authors have received lecture fees and/or honoraria from AstraZeneca, Chugai, Sanofi-Aventis, and/or Boehringer-Ingelheim.

The Nature study is supported by grants from the National Institutes of Health, National Cancer Institute Lung, the Cecily and Robert Harris Foundation, Uniting Against Lung Cancer, the Flight Attendant Medical Research Institute, the Hazel and Samuel Bellin Research Fund, and the Damon Runyon Foundation Cancer Innovation Award. The study authors have disclosed no relevant financial relationships.

Lancet Oncology. Published online December 21, 2009. Abstract

Nature. 2009;462:1070-1074.

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