Commentary (Brandes/Brahmer): Perspectives on Salvage Therapy for Non–Small-Cell Lung Cancer

About 172,570 new cases of non-small-cell lung cancer (NSCLC) are expected to be diagnosed in 2005 in the United States, and almost as many will die of the disease. Patients with effusions or metastatic disease are candidates for combination chemotherapy. The regimens of choice are platinum-based combination chemotherapy schedules. Given that most patients will experience disease progression despite their initial treatment, they may be eligible for second- line chemotherapy, provided they have an acceptable performance status. Cappuzzo et al provide a comprehensive review of the currently accepted chemotherapeutic options for second-line chemotherapy in NSCLC. They point out the disappointing response rates of less than 10% associated with these approaches. Three drugs have been shown to have activity as second-line treatment: docetaxel (Taxotere), pemetrexed (Alimta), and erlotinib (Tarceva). Docetaxel
In the setting of NSCLC, docetaxel was accepted as a standard of care for salvage chemotherapy based on two trials. The study by Fosella et al[1] randomized patients to receive therapy with docetaxel every 3 weeks or schedules with ifosfamide or vinorelbine. Patient characteristics were very well matched in this study. Two separate analyses on the data set were performed. First, all patients with follow- up data were analyzed. Second, patients were censored if they received additional chemotherapy. The most important result of this study was an improvement in 1-year survival between the group receiving docetaxel at 75 mg/m² and the ifosfamide/ vinorelbine groups. It is important to point out that the interpretation of this observation by Cappuzzo et al is somewhat misleading. The statistical significance was strengthened by the censored analysis (32% vs 10%, P < .01), but the correlation is also present in the analysis of the noncensored data (32% vs 19%, P = .025) and not artificially induced as suggested. Response rates in the docetaxel arm are disappointing: 7% vs 1% in the vinorelbine and ifosfamide arms. However, this trial clearly shows the superiority of docetaxel at the 75 mg/m² dose over ifosfamide and vinorelbine. Part of this difference might be explained by a negative effect of vinorelbine and ifosfamide on overall survival. Both agents produced minimal response rates and significant toxicities including two treatment-related deaths. The trial by Shepherd et al[2] is the only randomized phase III trial that compares docetaxel chemotherapy with best supportive care. After a high number of treatment-related deaths, the dose was reduced from 100 mg/m² to 75 mg/m². The results in the 75 mg/m² group were very similar to the findings of the Fosella trial.[ 1] The 1 year survival rate in the docetaxel 75 mg/m² group vs the best supportive care group was 37% vs 11% (P = .003), and the median survival was 7.5 vs 4.6 months (P = .01). It is important to point out, however, that the patient populations were not equally randomized in this trial- 27.3% of patients in the docetaxel low-dose arm vs 19% of patients in the best supportive care arm had stage IIIA/B disease, not metastatic disease. While this probably does not explain the whole magnitude of the observed difference, it is an important confounder. Since 1-year survival is an important clinical parameter, we do not share Cappuzzo and colleagues' assessment that weekly docetaxel at a dose of 40 mg/m² is an appropriate regimen for patients in whom neutropenia is a particular concern. The study by Gervais et al[3] is well randomized. The median survival is 5.5.months in both arms, which is similar to the median response rates in the Fosella and Shepherd trials. However, the 1-year survival rate is 19% in the docetaxel every-3-week arm vs only 6% in the weekly docetaxel arm. Pemetrexed therefore seems to be the better alternative in patients for whom the development of neutropenia is of particular concern. Pemetrexed
We agree with Cappuzzo and coauthors' interpretation of the study by Hanna et al,[4] which showed that pemetrexed, 500 mg/m², is equally active compared to docetaxel, 75 mg/m2 every 3 weeks. Moreover, pemetrexed produces significantly less grade III/IV hematologic toxicity. Erlotinib
The authors nicely summarize the trials of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The study by Shepherd presented at the 2004 American Society of Clinical Oncology meeting is the only randomized trial that showed a survival benefit for an EGFR TKI.[5] It is also the only positive study that allowed participation of patients with an Eastern Cooperative Oncology Group performance status of 3. Patients with locally advanced or metastatic disease, refractory to at least one prior chemotherapy regimen, were eligible. Erlotinib improved median survival (6.7 vs 4.7 months) and the 1-year survival rate (31% vs 21%). Cappuzzo et al rightly point out that without information about the clinical and biologic predictors of response, it is impossible to compare this trial to the negative Iressa Survival Evaluation in Lung Cancer (ISEL) trial, which has not yet been published. While it is certainly correct that targeted therapies do not benefit every patient, we disagree with the authors' conclusion that EGFR inhibitors should only be offered to patients with the characteristics outlined in their Table 2. Although activating mutations in the EGFR are strong predictors for a response to an EGFR TKI, the absence of these mutations does not rule out the possibility of a response. Moreover, EFGR amplification or HER2 overexpression have not been reliably linked to a response to EGFR TKI.[6] The presence of k-ras mutations is the only biomarker that has been linked to a virtual absence of response to EGFR TKI.[7] In our opinion, the documented presence of a kras mutation might, at the present time, be the only situation in which it might be justified to not consider an EGFR TKI as second-line therapy. Conclusions
Docetaxel has been the standard of care in second-line therapy for NSCLC based on two large randomized trials. Due to inhomogeneity between control and treatment populations, the overall benefit of this approach might be somewhat overestimated. Pemetrexed has a favorable toxicity profile and will likely replace docetaxel as second-line chemotherapy for NSCLC. We could use erlotinib as second-line therapy in the subset of patients with clinical or biologic factors potentially predicting a response to this drug. Patients without these factors should not be excluded from treatment with erlotinib until more data are available.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354- 2362, 2000.
2. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with nonsmall- cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000.
3. Gervais R, Ducolone A, Breton JL, et al: Phase II randomised trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol 16:90-96, 2005.
4. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004.
5. Shepherd FA, Pereira J, Ciuleanu TE, et al: A randomized placebo controlled trial of erlotinib in patients with advanced NSCLC following failure of 1st line or 2nd line chemotherapy. A National Cancer Center of Canada Trial Group (NCIC CTG) trial (abstract 7022). Proc Am Soc Clin Oncol 23(suppl 14S):12, 2004.
6. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.
7. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17, 2005.