Adjuvant Gefitinib in Patients With NSCLC: Bad Idea or Wrong Patient Selection?


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Daniel Morgensztern, MD

Roy S. Herbst, MD, PhD

Unlike the use of targeted therapy drugs in unselected patients, a better understanding of the tumor biology and the use of molecular predictors for response may provide the best treatment available for each patient, with an increased probability of survival improvement in resected NSCLC.

—Daniel Morgensztern, MD, and Roy S. Herbst, MD, PhD

Despite optimal surgical resection and adjuvant chemotherapy with cisplatin-based doublets, the 5-year overall survival for patients with early-stage non–small cell lung cancer (NSCLC) remains suboptimal. In the International Association for the Study of Lung Cancer (IASLC) staging project, the 5-year overall survival ranged from 36% to 73% in patients with pathologic stages IIB to IA, respectively.1 The Lung Adjuvant Cisplatin Evaluation (LACE) pooled analysis of five large trials involving 4,584 patients showed a 5-year overall survival benefit from chemotherapy of 5.4%.2 Furthermore, the updated analyses of two of the largest adjuvant trials showed less than a 50% 5-year overall survival.3,4 Therefore, novel therapies are still needed in this patient population in an attempt to improve survival.

BR.19 Study Findings

The National Cancer Institute of Canada (NCIC) BR.19 study—recently reported by Goss and colleagues in the Journal of Clinical Oncology and reviewed in the December 15 issue of The ASCO Post—planned to randomly assign 1,242 patients with completely resected NSCLC stages IB, II, or IIIA to gefitinib (Iressa) or placebo, with overall survival as the primary endpoint.5 The study, however, was closed early after the results of two randomized studies showed that gefitinib did not result in survival improvement in patients with advanced NSCLC6 and was potentially detrimental after chemoradiotherapy followed by docetaxel in patients with stage III disease.7

Among the 503 patients enrolled between 2002 and 2005, 251 were randomly assigned to gefitinib and 252 to placebo for 2 years. Only 87 patients received prior adjuvant chemotherapy since the study started before its establishment as a standard of care.

Adjuvant gefitinib was not associated with improved overall survival or disease-free survival either for the total population or for the 15 patients with activating epidermal growth factor receptor (EGFR) mutations, of whom 7 received gefitinib and 8 received placebo. Among the 96 patients with KRAS mutation, gefitinib was associated with a detrimental effect on disease-free survival.

Lessons From the BR.19 Trial

The BR.19 study was the third study showing a lack of benefit from gefitinib in patients with wild-type EGFR, with the spectrum now including all three clinical NSCLC settings: early-stage, locally advanced, and metastatic. This is in contrast to erlotinib (Tarceva), which was associated with improved overall survival in patients with metastatic disease.8

For the most part, the BR.19 trial predated the common use of adjuvant chemotherapy. Furthermore, in patients with advanced disease, chemotherapy has been shown to be clearly superior to gefitinib in patients with wild-type EGFR.9 Therefore, the role for adjuvant EGFR tyrosine kinase inhibitors is still not clarified.

Other Key Studies

While attempts to improve survival in patients with resected NSCLC are likely to involve targeted drugs, a significant benefit can only be achieved with the use of molecular predictors. In a study reported by Janjigian and colleagues,10 167 patients with resected NSCLC harboring activating EGFR mutations were evaluated, including 56 who received adjuvant gefitinib or erlotinib and 111 who did not receive adjuvant EGFR tyrosine kinase inhibitors. The 2-year disease-free survival was higher for the group receiving adjuvant EGFR tyrosine kinase inhibitors, although it did not reach statistical significance (89% vs 72%, hazard ratio = 0.53, P = .06), likely due to the small patient population.

The RADIANT trial, which randomly assigned patients with resected NSCLC and EGFR-positive tumors, defined by immunohistochemistry or fluorescence in situ hybridization, completed the accrual of 945 patients in 2010, with the results expected soon. However, neither immunohistochemistry nor fluorescence in situ hybridization is an established predictor for benefit from EGFR tyrosine kinase inhibitors.

Therefore, although the results of RADIANT and other adjuvant EGFR tyrosine kinase inhibitor studies are eagerly awaited, it is unclear how they will affect treatment decisions, particularly if the number of patients with EGFR mutations from these studies does not allow the detection of a statistically significant benefit. It may be interesting to evaluate whether some of the potential predictors of benefit from EGFR tyrosine kinase inhibitors in patients with wild-type EGFR metastatic disease, such as VeriStrat11 and the gene signature from the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial,12 can be used as predictors for efficacy in patients with earlier-stage disease. ■

Dr. Morgensztern is Associate Professor of Medical Oncology and Dr. Herbst is Chief of Medical Oncology at Yale Cancer Center, New Haven, Connecticut.

For more on the NCIC CTG BR.19 study, see The ASCO Post, December 15, 2013 article here.

Disclosure: Drs. Herbst and Morgensztern reported no potential conflicts of interest.

References

1. Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer Staging Project. J Thorac Oncol 2:706-714, 2007.

2. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation. J Clinical Oncol 6:3552-3559, 2008.

3. Butts CA, Ding K, Seymour L, et al: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer. J Clin Oncol 28:29-34, 2010.

4. Arriagada R, Dunant A, Pignon JP, et al: Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 28:35-42, 2010.

5. Goss GD, O’Callaghan C, Lorimer I, et al: Gefitinib versus placebo in completely resected non-small-cell lung cancer. J Clin Oncol 31:3320-3326, 2013.

6. 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. Lancet 366:1527-1537, 2005.

7. 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. J Clin Oncol 26:2450-2456, 2008.

8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer. Lancet Oncol 11:521-529, 2010.

9. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.

10. Janjigian YY, Park BJ, Zakowski MF, et al: Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol 6:569-575, 2011.

11. Lazzari C, Novello S, Barni S, et al: Randomized proteomic stratified phase III study of second-line erlotinib (E) versus chemotherapy (CT) in patients with inoperable non-small cell lung cancer (PROSE). J Clin Oncol 31:LBA8005, 2013.

12. Kim ES, Herbst RS, Wistuba II, et al: The BATTLE trial. Cancer Discov 1:44-53, 2011.


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