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

Cappuzzo and colleagues have reviewed the present options of salvage therapy for advanced non-small-cell lung cancer (NSCLC). This issue is highly relevant nowadays, as many patients who fail palliative chemotherapy are still in sufficiently good condition to receive additional therapy. It is rather instructive to note that 10 years ago the use of systemic chemotherapy for advanced NSCLC was advocated but still not standard, and today we have several options for treating patients in the second- and even third-line setting. Among these options are agents that specifically target molecular features of lung cancer, such as the epidermal growth factor receptor (EGFR). Chemotherapy
Cappuzzo et al extensively review the studies that brought two chemotherapeutic drugs to approval: docetaxel (Taxotere) and pemetrexed (Alimta). Two randomized studies were performed with docetaxel, one comparing it to best supportive care and the other comparing it to two inactive control drugs, vinorelbine and ifosfamide. Both studies demonstrated a significant increase in survival when docetaxel was given at 75 mg/m²; however, the higher dose of docetaxel (100 mg/m²) was clearly more toxic and led to an unacceptable level of febrile neutropenia. This is different from breast cancer, for which the accepted dose is 100 mg/m², indicating that NSCLC patients are indeed more frail than breast cancer patients. Interestingly, although the response rate of docetaxel was below 10%, apparently the proportion of patients with stable disease was sufficient to shift the survival curves to the right. Also remarkable was the treatmentrelated improvement in symptoms, despite the toxicity. Nevertheless, the issue of toxicity is very important in patients relapsing after a first round of chemotherapy. Due to toxicity considerations, second-line therapy is mainly based on one drug, but one could envisage treatments that are less toxic and therefore easily combined. There is sufficient evidence in firstline chemotherapy studies to show that two drugs are better than one, and this may also also be the case in secondline treatment.[1] In terms of efficacy, pemetrexed has been shown to be equivalent to docetaxel, with a similar low response rate and similar survival, although with less hematologic toxicity. This is the first time that an agent has been approved on the basis of a noninferiority design, as Cappuzzo et al report in their review. This is certainly a new option for treatment and may be preferred to docetaxel in view of the more benign toxicity profile. However, cost-effectiveness comparisons will be required, as all novel agents appear to have a rather disproportionate cost compared to their benefits. Other cytotoxic agents, such as gemcitabine and paclitaxel, have been reviewed by Cappuzzo et al, and in view of their very low level of activity in second-line therapy, they are not recommended in this setting. Targeted Therapy
The most interesting developments in the past few years have occurred with the development of EGFR tyrosine kinase inhibitors. There are two molecules known to inhibit autophosphorylation by competing with ATP at the tyrosine kinase domain-gefitinib (Iressa) and erlotinib (Tarceva).[2] Both have recently been approved in the United States and several other countries. The approval of gefitinib was based on activity demonstrated in phase II studies in second- and thirdline treatment, whereas erlotinib demonstrated improvement in survival compared to best supportive care in these settings. The response rate of both agents is lower than 10% in third-line treatment, but apparently the number of stable disease patients was sufficient to shift the curves to the right in the BR.21 study with erlotinib. Interestingly, a much larger study of gefitinib vs best supportive care- the Iressa Survival Evaluation in Lung Cancer (ISEL)-failed to improve survival.[3] The reasons for this failure are still rather speculative although possibly a result of the relatively low dose of gefitinib selected. It is now known that EGFR mutations are present in a great number of patients who respond to EGFR tyrosine kinase inhibitors and that wild type EGFR is more sensitive to higher doses of these drugs. Real differences of efficacy between the two agents are nonetheless possible. Although not extensively discussed in the review by Cappuzzo et al, no patient selection was performed in the studies of these agents, based on the knowledge that EGFR expression is probably not a reliable marker with which to help select patients. The lack of enrichment may have played a major role in the failure of four large randomized studies that investigated gefitinib and erlotinib in combination with chemotherapy. The use of fluorescence in situ hybridization (FISH) and immunohistochemistry may be complementary to mutation analysis in the attempt to select patients for EGFR tyrosine kinase inhibitors.[ 4] Studies employing anti-EGFR monoclonal antibodies, however, may not require the same selection criteria, as EGFR mutations do not appear to predict response to cetuximab (Erbitux). A major breakthrough in targeted therapy was recently presented at the American Society of Clinical Oncology annual meeting, with the results of the Eastern Cooperative Oncology Group (ECOG) 4599 trial. This was a randomized study of carboplatin/paclitaxel with or without bevacizumab (Avastin) in patients with nonsquamous histology and without brain metastases. Bevacizumab is a monoclonal antibody that targets the vascular endothelial growth factor (VEGF). For the first time in years, a significant advantage in survival was demonstrated with the addition of a biologic agent to chemotherapy.[5] As salvage therapy, bevacizumab has been associated with erlotinib in a phase I/II trial in 40 patients with recurrent NSCLC, which showed promising results regarding response rate and median survival (12.6 months).[6] Combinations of targeted agents and many other antiangiogenic agents are currently under development in lung cancer and other malignancies. Other Agents
Among other molecules that were not discussed by Cappuzzo et al, bortezomib (Velcade), a proteosome inhibitor approved for the treatment of patients with multiple myeloma, shows promise in the treatment of advanced NSCLC. In a randomized phase II study of this agent as salvage therapy for NSCLC patients, bortezomib alone (n = 30) or combined with docetaxel (n = 32) produced response rates of 8% and 9%, median survivals of 7.4 and 7.8 months, and 1-year survival rates of 38.7% and 33.1%, respectively.[7] As Cappuzzo et al correctly conclude, patient selection and the study of the biology of NSCLC will help in devising better drugs for the right patients. These strategies will facilitate the appropriate use of drugs with activity in first-line treatment of advanced disease as well as in earlier stages of the disease.

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. Lilenbaum RC, Herndon JE 2nd, List MA, et al: Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 23:190-196, 2005.
2. Giaccone G: Epidermal growth factor receptor inhibitors in the treatment of non-smallcell lung cancer. J Clin Oncol 23:3235-3242, 2005.
3. Thatcher N, Chang A, Parikh P, et al: Results of a phase III placebo-controlled study (ISEL) of gefitinib (Iressa) plus best supportive care (BSC) in patients with advanced non-small cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens (abstract LB- 6). Proceedings of the 96th Annual Meeting of the American Association for Cancer Research, Anaheim, Calif, April 16-20, 2005.
4. Tsao MS, Sakurada A, Lorimer I, et al: Molecular analysis of the epidermal growth factor receptor (EGFR) gene and protein expression in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial BR.21 (abstract 7007). J Clin Oncol 23(16S):622s, 2005.
5. Sandler A, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial-E4599 (late-breaking abstract 4). J Clin Oncol 23(16S):2s, 2005.
6. Herbst RS, Johnson DH, Mininberg E, et al: Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/ epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent nonsmall- cell lung cancer. J Clin Oncol 23:2544- 2555, 2005.
7. Fanucchi M, Fossella F, Fidias P, et al: Bortezomib ± docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): A phase 2 study (abstract 7034). J Clin Oncol 23(16S):629s, 2005.