As reported in Journal of Clinical Oncology by Glenwood D. Goss, MD, of the Ottawa Hospital Cancer Center, and colleagues, the prematurely closed NCIC CTG BR19 study showed no apparent survival benefit of adjuvant gefitinib (Iressa, withdrawn from U.S. market) vs placebo in patients with completely resected non–small cell lung cancer (NSCLC).1
In this phase III trial, activated in 2002, patients with completely resected stage IB, II, or IIIA NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned to receive gefitinib at 250 mg/d or placebo for 2 years. The target population was 1,242 patients and study endpoints were overall survival, disease-free survival, and toxicity.
In December 2004, a phase III study in advanced NSCLC (ISEL study) showed no survival benefit of gefitinib vs placebo.2 An unplanned interim analysis of another trial (SWOG S0023 study) showed that maintenance gefitinib after chemoradiation in patients with stage III NSCLC did not improve overall survival and was potentially detrimental.3 In April 2005, based on these results, the BR19 Data and Safety Monitoring Committee recommended closure of the study and discontinuation of study medication. The trial committee elected to conduct a final analysis once all patients were followed for at least 4 years.
Due to early closure, only 503 of the planned patients were randomly assigned to gefitinib (n = 251) or placebo (n = 252). Patients in the gefitinib group and placebo group had median ages of 66 and 67 years, and 54% of both groups were male. The groups were well balanced for race, histology, smoking history, stage, Eastern Cooperative Oncology Group performance status, type of surgery, prior adjuvant chemotherapy, and prior radiotherapy.
Overall, only 17% of patients had received adjuvant chemotherapy and 5% had received adjuvant radiotherapy. Approximately 52%, 35%, and 13% of patients had stage IB, II, and IIIA disease, respectively, and 60% and 28% had adenocarcinoma and squamous cell carcinoma, respectively.
After a median follow-up of 4.7 years, median disease-free survival was 4.2 years in the gefitinib group and not reached in the placebo group (hazard ratio [HR] = 1.22, P = .15). Multivariate analysis showed that only tumor size ≥ 4 cm was significantly associated with poorer disease-free survival, with gefitinib treatment remaining nonsignificant and potentially harmful (HR = 1.27, P = .096).
Median overall survival was 5.1 years in the gefitinib group and had not been reached in the placebo group (HR = 1.24, P = .14). Multivariate analysis showed that age ≥ 65 years and tumor size ≥ 4 cm were significantly associated with poorer overall survival, with gefitinib treatment remaining nonsignificant and potentially harmful (HR = 1.27, P = .097).
Exploratory analyses showed no disease-free survival (HR = 1.28, P = .14) or overall survival benefit (HR = 1.24, P = .18) from gefitinib among 344 patients with EGFR wild-type tumors, and no disease-free survival (HR = 1.84, P = .40) or overall survival benefit (HR = 3.16, P = .15) from gefitinib among 15 patients with EGFR mutant tumors. No benefit of gefitinib was seen according to presence or absence of KRAS mutations. The study results did not appear to be related to nonprotocol treatment received after disease progression, which was balanced between treatment groups.
Safety and Tolerability
Median durations of treatment were 4.8 months in the gefitinib group and 8.9 months in the placebo group. Dose adjustment occurred in 39% of gefitinib patients and 20% of placebo patients, drug was held temporarily for 23% and 11%, and treatment was discontinued due to toxicity in 15% and 3%. The patient refusal or withdrawal rate after beginning therapy was 24% in the gefitinib group and 7% in the placebo group.
Gefitinib recipients had a higher incidence of any-grade rash, dry skin, diarrhea, anorexia, and nausea but less chest pain, muscle pain, and dyspnea. Grade 3 to 4 diarrhea, skin effects, and chest pain were reported in 5% to 8% of both groups. The most common serious adverse event in both cohorts was dyspnea, occurring in 13% and 7% of patients on gefitinib and placebo, respectively. One patient in each group had fatal pneumonitis. Five gefitinib and four placebo patients died from an adverse event; three of the five deaths in the gefitinib patients were considered drug-related.
The investigators concluded, “Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.” Based on a full intent-to-treat analysis, the conditional power observing a beneficial effect of gefitinib, had the study reached its target accrual, was only 17.5% supporting their conclusions. They noted that potential contributions to the findings include the underpowering of the study overall and with regard to EGFR mutation-positive patients, short duration of treatment, and the possibility that the EGFR pathway plays a less important role in early disease.
In addition, the authors stated, “BR19 has left us with unanswered questions, and we look forward to the results of the erlotinib [Tarceva] adjuvant trial RADIANT (NCT 00373425) and two adjuvant studies in EGFR mutation-positive patients, the Chinese study (NCT01405079) and the ongoing Japanese study of adjuvant gefitinib versus chemotherapy.” ■
Disclosure: The study was supported by the Canadian Cancer Society Research Institute, the U.S. National Cancer Institute, Ontario Cancer Research Network, and AstraZeneca. For full disclosures of the study authors, visit jco.ascopubs.org.
2. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005.
3. Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450-2456, 2008.